@Article{info:doi/10.2196/64902, author="Lester, Corey and Rowell, Brigid and Zheng, Yifan and Co, Zoe and Marshall, Vincent and Kim, Yong Jin and Chen, Qiyuan and Kontar, Raed and Yang, Jessie X.", title="Effect of Uncertainty-Aware AI Models on Pharmacists' Reaction Time and Decision-Making in a Web-Based Mock Medication Verification Task: Randomized Controlled Trial", journal="JMIR Med Inform", year="2025", month="Apr", day="18", volume="13", pages="e64902", keywords="artificial intelligence", keywords="AI", keywords="human-computer interaction", keywords="decision-making", keywords="human factors", keywords="randomized controlled trial", keywords="clinical decision support", keywords="prediction", keywords="pharmacist", keywords="verification", keywords="drug development", keywords="drug", keywords="diagnosis", keywords="clinical decision support systems", abstract="Background: Artificial intelligence (AI)--based clinical decision support systems are increasingly used in health care. Uncertainty-aware AI presents the model's confidence in its decision alongside its prediction, whereas black-box AI only provides a prediction. Little is known about how this type of AI affects health care providers' work performance and reaction time. Objective: This study aimed to determine the effects of black-box and uncertainty-aware AI advice on pharmacist decision-making and reaction time. Methods: Recruitment emails were sent to pharmacists through professional listservs describing a web-based, crossover, randomized controlled trial. Participants were randomized to the black-box AI or uncertainty-aware AI condition in a 1:1 manner. Participants completed 100 mock verification tasks with AI help and 100 without AI help. The order of no help and AI help was randomized. Participants were exposed to correct and incorrect prescription fills, where the correct decision was to ``accept'' or ``reject,'' respectively. AI help provided correct (79\%) or incorrect (21\%) advice. Reaction times, participant decisions, AI advice, and AI help type were recorded for each verification. Likelihood ratio tests compared means across the three categories of AI type for each level of AI correctness. Results: A total of 30 participants provided complete datasets. An equal number of participants were in each AI condition. Participants' decision-making performance and reaction times differed across the 3 conditions. Accurate AI recommendations resulted in the rejection of the incorrect drug 96.1\% and 91.8\% of the time for uncertainty-aware AI and black-box AI respectively, compared with 81.2\% without AI help. Correctly dispensed medications were accepted at rates of 99.2\% with black-box help, 94.1\% with uncertainty-aware AI help, and 94.6\% without AI help. Uncertainty-aware AI protected against bad AI advice to approve an incorrectly filled medication compared with black-box AI (83.3\% vs 76.7\%). When the AI recommended rejecting a correctly filled medication, pharmacists without AI help had a higher rate of correctly accepting the medication (94.6\%) compared with uncertainty-aware AI help (86.2\%) and black-box AI help (81.2\%). Uncertainty-aware AI resulted in shorter reaction times than black-box AI and no AI help except in the scenario where ``AI rejects the correct drug.'' Black-box AI did not lead to reduced reaction times compared with pharmacists acting alone. Conclusions: Pharmacists' performance and reaction times varied by AI type and AI accuracy. Overall, uncertainty-aware AI resulted in faster decision-making and acted as a safeguard against bad AI advice to approve a misfilled medication. Conversely, black-box AI had the longest reaction times, and user performance degraded in the presence of bad AI advice. However, uncertainty-aware AI could result in unnecessary double-checks, but it is preferred over false negative advice, where patients receive the wrong medication. These results highlight the importance of well-designed AI that addresses users' needs, enhances performance, and avoids overreliance on AI. Trial Registration: ClinicalTrials.gov NCT06795477; https://clinicaltrials.gov/study/NCT06795477 ", doi="10.2196/64902", url="https://medinform.jmir.org/2025/1/e64902" } @Article{info:doi/10.2196/67419, author="Jourdi, Georges and Selmi, Mayssa and Gaussem, Pascale and Truchot, Jennifer and Margaill, Isabelle and Siguret, Virginie", title="Evaluation of the Inverted Classroom Approach in a Case-Study Course on Antithrombotic Drug Use in a PharmD Curriculum: French Monocentric Randomized Study", journal="JMIR Med Educ", year="2025", month="Apr", day="10", volume="11", pages="e67419", keywords="antithrombotic drugs", keywords="case-study course", keywords="inverted classroom", keywords="pharmacy students", keywords="traditional educational approach", keywords="medical education", abstract="Background: Appropriate antithrombotic drug use is crucial knowledge for pharmacy students. Objective: We sought to compare the inverted classroom (IC) approach to a traditional question-and-answer educational approach with the aim of enhancing pharmacy students' engagement with a case-study course on antithrombotic drug use. Methods: Third-year PharmD (Doctor of Pharmacy) students from Paris Cit{\'e} University were randomly assigned to control (n=171) and IC (n=175) groups. The latter were instructed to read and prepare the preprovided course material 1 week before the in-class session to assume the instructor role on the target day, whereas students of the control group attended a traditional case-study course carried out by the same instructor. All students completed pre- and posttest multiple-choice questions surveys assessing their knowledge levels as well as stress, empathy, and satisfaction questionnaires. Results: A significantly higher participation rate was observed in the control group (93/171, 54\%) compared to the IC group (65/175, 37\%; P=.002). Women (110/213, 52\%) participated more than men (48/133, 36\%; P=.002) whatever the group was. Students' knowledge scores from both groups had similar results with no difference neither in the prescore (1.17, SD 0.66 and 1.24, SD 0.72 of 5, respectively) nor in the short-term knowledge retention (2.45, SD 0.61 and 2.35, SD 0.73, respectively). The IC approach did not increase student stress or enhance their empathy for the instructor. It increased the preclass workload (P=.02) and was not well received among students. Conclusions: This study showed that the traditional educational approach remains an efficient method for case-study courses in the early stages (ie, third-year) of the 6-year PharmD curriculum, yet dynamic methods improving the active role of students in the learning process are still needed. ", doi="10.2196/67419", url="https://mededu.jmir.org/2025/1/e67419" } @Article{info:doi/10.2196/62659, author="Schwitzguebel, Adrien and Ramirez Cadavid, Andres David and Da Silva, Tamara and Decavel, Pierre and Benaim, Charles", title="Effectiveness of Stromal Vascular Fraction (SVF) and Platelet-Rich Plasma (PRP) in Patients With Knee Osteoarthritis: Protocol for a Phase 3, Prospective, Randomized, Controlled, Multicenter Study (SPOST Study)", journal="JMIR Res Protoc", year="2025", month="Apr", day="8", volume="14", pages="e62659", keywords="stromal vascular fraction", keywords="platelet-rich plasma", keywords="osteoarthritis", keywords="adjuvant therapy", keywords="tissue regeneration", keywords="clinical efficacy", abstract="Background: Available evidence on the conservative treatment of knee osteoarthritis still leaves questions about the efficacy of platelet-rich plasma (PRP) and whether stromal vascular fraction (SVF) offers a superior therapeutic tool. Objective: This study aims to assess the clinical efficacy of SVF as adjuvant therapy to PRP on functionality and tissue regeneration for knee osteoarthritis. Methods: In a multicenter, randomized, triple-blind, controlled trial, 108 individuals with knee osteoarthritis will be block-randomized in a 1:1 ratio. Patients will receive an initial single PRP or PRP + SVF injection followed by PRP doses at 1 month and 2 months. The primary endpoint is functional improvement measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at the 6-month follow-up. Secondary endpoints, collected at the 1-month, 2-month, 3-month, 6-month, and 12-month follow-ups, will include the pain visual analogue scale during maximal physical activity, WOMAC score, length of time to return to work and sports in days, magnetic resonance imaging (MRI)--based Whole-Organ Magnetic Resonance Imaging Score (WORMS), Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score, MRI Area Measurement and Depth and Underlying Structures (AMADEUS) score at 6 months and at 12 months, adverse events, and serious adverse events. Results: Participant recruitment and data collection are expected to begin in July 2025 and finish in July 2027. Final end points will be gathered in August 2027, and the results are expected to be published in late 2027. Conclusions: The study results will provide insight into the clinical efficacy of SVF as adjuvant therapy to PRP on functionality and tissue regeneration in patients with knee osteoarthritis. Trial Registration: ClinicalTrials.gov (NCT05660824); https://clinicaltrials.gov/study/NCT05660824 International Registered Report Identifier (IRRID): PRR1-10.2196/62659 ", doi="10.2196/62659", url="https://www.researchprotocols.org/2025/1/e62659" } @Article{info:doi/10.2196/60801, author="Rajput, Shivshankar and Mata, Shweta and Saxena, Upma and Ota, Sarada and Gupta, Bharti", title="Ayurveda Management of Menorrhagia (Raktapradara): Protocol for a Randomized Controlled Trial", journal="JMIR Res Protoc", year="2025", month="Mar", day="31", volume="14", pages="e60801", keywords="Ashokarishta", keywords="Trinakantamani pishti", keywords="tranexamic acid", keywords="menorrhagia", keywords="Raktapradara", abstract="Background: In India, heavy menstrual bleeding or menorrhagia (Raktapradara) constitutes about 15\% to 20\% of all gynecological admissions in an institution. Of these, 43\% of patients are aged 20-40 years. This condition is worsening because of the high prevalence of anemia among Indian women. Menorrhagia can have a significant impact on women's lives. Medical treatment is usually the first choice in excessive bleeding, but it reduces menstrual blood loss by only 50\%, and up to 50\% of women undergo surgical treatment within 5 years. However, none of these treatments proved their definite efficacy in spite of the high price and side effects. This condition presents a major financial burden on health care services. In Ayurveda, encouraging work has been done on the compound drug Ashokarishta, and the drug Trinakantamani pishti is indicated in Ayurvedic classics and the Ayurvedic Formulary of India. Also, these medicines have been used in Ayurvedic practice for a long time. However, no clinical trial has been carried out on these formulations. Objective: The primary objective is to evaluate the efficacy of Ayurvedic intervention in the management of menorrhagia, and the secondary objective is to assess the efficacy of Ayurvedic intervention on the quality of life of the women with menorrhagia. Methods: This ongoing study is an open-label, interventional, randomized controlled trial, with a sample size of 140 in the treatment and control groups combined (including 20\% dropouts), and will be carried out within the duration of 36 months. Participants in the treatment group will receive Ayurvedic treatment, that is, 20 mL of Ashokarishta, 250 mg of Trinakantamani pishti, and 1 iron and folic acid tablet (100 mg of elemental iron and 1.5 mg of folic acid) twice a day orally for 3 months. Participants in the control group will receive a 500-mg tranexamic acid tablet thrice a day for 7 days from the first day of menses for 3 cycles and 1 iron and folic acid tablet twice a day orally for 3 months. The primary outcomes are changes in the amount of uterine bleeding evaluated by the Pictorial Blood Loss Assessment Chart, changes in the duration of bleeding, and attainment of a normal quantity of blood loss during the interval of cycles. The secondary outcome is changes in the Menorrhagia Impact Questionnaire. Results: As of December 2024, a total of 79 patients have been enrolled. Data analysis should be completed by February 2026. The study will be reported following standard guidelines for reporting randomized controlled trials. Clinical results will be disseminated through conferences and peer-reviewed publications in a relevant journal. Conclusions: The Ayurvedic approach may provide an evidence-based therapeutic tactic for the management of menorrhagia. Trial Registration: Clinical Trial Registry India CTRI/2023/05/052929; https://tinyurl.com/3cd6mxrn International Registered Report Identifier (IRRID): DERR1-10.2196/60801 ", doi="10.2196/60801", url="https://www.researchprotocols.org/2025/1/e60801" } @Article{info:doi/10.2196/66831, author="Garg, Shilpa and Kitchen, Robert and Gupta, Ramneek and Pearson, Ewan", title="Applications of AI in Predicting Drug Responses for Type 2 Diabetes", journal="JMIR Diabetes", year="2025", month="Mar", day="27", volume="10", pages="e66831", keywords="type 2 diabetes", keywords="artificial intelligence", keywords="machine learning", keywords="drug response", keywords="treatment response prediction", keywords="ML", keywords="AI", keywords="deep learning", doi="10.2196/66831", url="https://diabetes.jmir.org/2025/1/e66831" } @Article{info:doi/10.2196/65419, author="Ivanova, Julia and Cummins, R. Mollie and Soni, Hiral and Ong, Triton and Bunnell, E. Brian and L{\'o}pez, Esteban and Welch, M. Brandon", title="Mental Health Providers' Challenges and Solutions in Prescribing Over Telemedicine: Content Analysis of Semistructured Interviews", journal="JMIR Hum Factors", year="2025", month="Mar", day="20", volume="12", pages="e65419", keywords="telemedicine", keywords="telehealth", keywords="prescribe", keywords="prescription", keywords="drug", keywords="pharmacology", keywords="pharmacotherapy", keywords="pharmaceutical", keywords="medication", keywords="barrier", keywords="buprenorphine", keywords="mental health", keywords="digital health", keywords="informatics", keywords="qualitative analysis", keywords="content analysis", keywords="provider perspective", keywords="provider", keywords="experience", keywords="attitude", keywords="opinion", keywords="perception", keywords="perspective", abstract="Background: In response to the COVID-19 pandemic, the United States extended regulatory flexibilities to make telemedicine more accessible to providers and patients. Some of these flexibilities allowed providers to intake patients over telemedicine and prescribe certain scheduled medications without an in-person visit. Objective: We aim to understand providers' parameters for their comfort in prescribing over telemedicine and report on solutions providers have adopted in response to potential barriers and challenges in prescribing via telemedicine. Methods: As part of a larger mixed methods study between February and April 2024, we conducted 16 semistructured interviews with mental health providers who prescribe via telemedicine within the United States. We used the results of a web-based, cross-sectional survey to develop a codebook and support recruitment. We analyzed a subsection of the 16 interviews using content analysis to capture comfort, barriers, and workarounds in telemedicine prescribing. We reported codes by frequency and by provider. Results: Participants were typically male (11/16, 69\%), provided care mostly or completely over telemedicine (11/16, 69\%), and were psychiatrists (8/16, 50\%) or other physician (3/16, 19\%). Providers' primary states (10/16, 62\%) of practice included Oregon, Texas, New York, and California. The content analysis yielded a total of 234 codes, with three main codes---comfort (98/234, 41.9\%), barriers or challenges (85/234, 36.3\%), and workarounds or solutions (27/234, 11.5\%)---and two subcodes---uncomfortable prescribing (30/98, 31\%) and comfortable prescribing (68/98, 69\%) over telemedicine. Participants reported being comfortable prescribing over telemedicine as long as they could meet their main parameters of working within their expertise, having access to needed patient health information, and being compliant with rules and regulations. Participants reported frustrations with e-prescription workflows and miscommunications with pharmacies. Solutions to ease frustrations and alleviate discomforts in prescribing over telemedicine included developing workflows to help patients complete laboratory tests and physical examinations and directly communicating with pharmacies. Conclusions: By applying content analysis to the semistructured provider interviews, we found that physicians are comfortable prescribing via telemedicine when they feel they are practicing within their personal parameters for safety. While many providers experience frustrations such as miscommunication with pharmacies, these barriers appear to not prevent them from telemedicine prescribing. With expected changes in 2024 and 2025 to the US laws and regulations for telemedicine prescribing, we may see changes in provider comfort in prescribing. ", doi="10.2196/65419", url="https://humanfactors.jmir.org/2025/1/e65419" } @Article{info:doi/10.2196/60728, author="Porubcova, Slavka and Lajtmanova, Kristina and Szmicsekova, Kristina and Slezakova, Veronika and Tomka, Jan and Tesar, Tomas", title="Optimizing the Pharmacotherapy of Vascular Surgery Patients at Hospital Admission and Discharge (PHAROS): Protocol for a Quasi-Experimental Clinical Uncontrolled Trial", journal="JMIR Res Protoc", year="2025", month="Mar", day="19", volume="14", pages="e60728", keywords="pharmacotherapy", keywords="hospital pharmacy", keywords="vascular surgery", keywords="patient safety", keywords="risk reduction", keywords="pharmacist-proposed interventions", abstract="Background: Patient safety is essential in pharmacotherapy, especially in surgical contexts, due to the elevated risk of drug-related complications. Vascular surgery patients are particularly susceptible because of their complex medication needs and underlying health conditions. Improved safety monitoring and targeted pharmaceutical care in collaboration with physicians are crucial to minimize these risks and enhance patient outcomes. Objective: This protocol evaluates whether structured pharmaceutical care interventions---including medication reconciliation, medication review, and patient education---can reduce the prevalence of drug-related problems at hospital admission and discharge in vascular surgery patients. Methods: This prospective, uncontrolled study was conducted over 1 year in the Vascular Surgery Department at the National Institute of Cardiovascular Diseases in Bratislava, Slovakia. The study included adult patients with carotid artery disease or lower extremity artery disease who were on 3 or more medications, with an estimated sample size of approximately 100 patients. The primary intervention involved 3 key changes in practice: medication reconciliation at both admission and discharge, where hospital pharmacists review and verify medication lists; medication review to identify and address drug-related problems; and patient education at discharge. Pharmacist-proposed interventions were documented and communicated to the physician for treatment adjustments. The primary outcome is the change in drug-related problem prevalence from hospital admission to discharge. Secondary outcomes include the acceptance rate of pharmacist recommendations and patient understanding of pharmacotherapy. Data collection involved documenting the number, type, and frequency of drug-related problems; the anatomical therapeutic chemical classification of medications associated with drug-related problems; and patients' social, demographic, and clinical characteristics, with a focus on factors related to drug-related problems, comorbidities, and medication use. Data analysis will use the paired Wilcoxon signed-rank test to compare the prevalence of drug-related problems and medication counts between admission and discharge. Continuous variables will be presented as means (SDs), while categorical variables will be reported as counts and percentages. Patient understanding of pharmacotherapy will be evaluated using a 3-point scale, classifying understanding as good (2-3 points per medication), modest (1-2 points), or poor (0-1 point). Results: Recruitment began in September 2021 and concluded in August 2022. Data collection occurred continuously during hospital stays, capturing demographics, comorbidities, pharmacotherapy, and drug-related problems at admission and discharge. Important milestones included the initial data review, which began in August 2023 to assess recruitment and data quality, including an early evaluation of drug-related problems. The primary analysis was completed in January 2024, focusing on the reduction in drug-related problems, intervention acceptance, and patient understanding. The final report was to be prepared by June 2024, disseminating the findings on pharmacist-led intervention impacts. Conclusions: This study should demonstrate that pharmacist-led interventions in collaboration with physicians can reduce pharmacotherapy risks and optimize medicine management for patient safety. Trial Registration: ClinicalTrials.gov NCT04930302; https://clinicaltrials.gov/study/NCT04930302 International Registered Report Identifier (IRRID): RR1-10.2196/60728 ", doi="10.2196/60728", url="https://www.researchprotocols.org/2025/1/e60728" } @Article{info:doi/10.2196/55277, author="Lau, Jerry and Bisht, Shivani and Horton, Robert and Crisan, Annamaria and Jones, John and Gantotti, Sandeep and Hermes-DeSantis, Evelyn", title="Creation of Scientific Response Documents for Addressing Product Medical Information Inquiries: Mixed Method Approach Using Artificial Intelligence", journal="JMIR AI", year="2025", month="Mar", day="13", volume="4", pages="e55277", keywords="AI", keywords="LLM", keywords="GPT", keywords="biopharmaceutical", keywords="medical information", keywords="content generation", keywords="artificial intelligence", keywords="pharmaceutical", keywords="scientific response", keywords="documentation", keywords="information", keywords="clinical data", keywords="strategy", keywords="reference", keywords="feasibility", keywords="development", keywords="machine learning", keywords="large language model", keywords="accuracy", keywords="context", keywords="traceability", keywords="accountability", keywords="survey", keywords="scientific response documentation", keywords="SRD", keywords="benefit", keywords="content generator", keywords="content analysis", keywords="Generative Pre-trained Transformer", abstract="Background: Pharmaceutical manufacturers address health care professionals' information needs through scientific response documents (SRDs), offering evidence-based answers to medication and disease state questions. Medical information departments, staffed by medical experts, develop SRDs that provide concise summaries consisting of relevant background information, search strategies, clinical data, and balanced references. With an escalating demand for SRDs and the increasing complexity of therapies, medical information departments are exploring advanced technologies and artificial intelligence (AI) tools like large language models (LLMs) to streamline content development. While AI and LLMs show promise in generating draft responses, a synergistic approach combining an LLM with traditional machine learning classifiers in a series of human-supervised and -curated steps could help address limitations, including hallucinations. This will ensure accuracy, context, traceability, and accountability in the development of the concise clinical data summaries of an SRD. Objective: This study aims to quantify the challenges of SRD development and develop a framework exploring the feasibility and value addition of integrating AI capabilities in the process of creating concise summaries for an SRD. Methods: To measure the challenges in SRD development, a survey was conducted by phactMI, a nonprofit consortium of medical information leaders in the pharmaceutical industry, assessing aspects of SRD creation among its member companies. The survey collected data on the time and tediousness of various activities related to SRD development. Another working group, consisting of medical information professionals and data scientists, used AI to aid SRD authoring, focusing on data extraction and abstraction. They used logistic regression on semantic embedding features to train classification models and transformer-based summarization pipelines to generate concise summaries. Results: Of the 33 companies surveyed, 64\% (21/33) opened the survey, and 76\% (16/21) of those responded. On average, medical information departments generate 614 new documents and update 1352 documents each year. Respondents considered paraphrasing scientific articles to be the most tedious and time-intensive task. In the project's second phase, sentence classification models showed the ability to accurately distinguish target categories with receiver operating characteristic scores ranging from 0.67 to 0.85 (all P<.001), allowing for accurate data extraction. For data abstraction, the comparison of the bilingual evaluation understudy (BLEU) score and semantic similarity in the paraphrased texts yielded different results among reviewers, with each preferring different trade-offs between these metrics. Conclusions: This study establishes a framework for integrating LLM and machine learning into SRD development, supported by a pharmaceutical company survey emphasizing the challenges of paraphrasing content. While machine learning models show potential for section identification and content usability assessment in data extraction and abstraction, further optimization and research are essential before full-scale industry implementation. The working group's insights guide an AI-driven content analysis; address limitations; and advance efficient, precise, and responsive frameworks to assist with pharmaceutical SRD development. ", doi="10.2196/55277", url="https://ai.jmir.org/2025/1/e55277" } @Article{info:doi/10.2196/44027, author="Karamchand, Sumanth and Chipamaunga, Tsungai and Naidoo, Poobalan and Naidoo, Kiolan and Rambiritch, Virendra and Ho, Kevin and Chilton, Robert and McMahon, Kyle and Leisegang, Rory and Weich, Hellmuth and Hassan, Karim", title="Novel Versus Conventional Sequencing of $\beta$-Blockers, Sodium/Glucose Cotransportor 2 Inhibitors, Angiotensin Receptor-Neprilysin Inhibitors, and Mineralocorticoid Receptor Antagonists in Stable Patients With Heart Failure With Reduced Ejection Fraction (NovCon Sequencing Study): Protocol for a Randomized Controlled Trial", journal="JMIR Res Protoc", year="2025", month="Mar", day="10", volume="14", pages="e44027", keywords="heart failure", keywords="SGLT2i", keywords="sodium/glucose cotransporter 2 inhibitors", keywords="ARNi", keywords="angiotensin receptor-neprilysin inhibitors", keywords="HFrEF", keywords="heart failure with reduced ejection fraction", keywords="idiopathic dilated cardiomyopathy", keywords="heart", keywords="chronic heart failure", keywords="patient", keywords="control", keywords="clinical", keywords="adult", keywords="cardiomyopathy", keywords="therapy", abstract="Background: Chronic heart failure has high morbidity and mortality, with approximately half of the patients dying within 5 years of diagnosis. Recent additions to the armamentarium of anti--heart failure therapies include angiotensin receptor-neprilysin inhibitors (ARNIs) and sodium/glucose cotransporter 2 inhibitors (SGLT2is). Both classes have demonstrated mortality and morbidity benefits. Although these new therapies have morbidity and mortality benefits, it is not known whether rapid initiation is beneficial when compared with the conventional, slower-stepped approach. Many clinicians have been taught that starting with low-dose therapies and gradually increasing the dose is a safe way of intensifying treatment regimens. Pharmacologically, it is rational to use a combination of drugs that target multiple pathological mechanisms, as there is potential synergism and better therapeutic outcomes. Theoretically, the quicker the right combinations are used, the more likely the beneficial effects will be experienced. However, rapid up-titration must be balanced with patient safety and tolerability. Objective: This study aims to determine if early addition of ARNIs, SGLT2is, $\beta$-blockers, and mineralocorticoid receptor antagonists (within 4 weeks), when compared with the same therapies initiated slower (within 6 months), will reduce all-cause mortality and hospitalizations for heart failure in patients with stable heart failure with reduced ejection fraction. Methods: This is a single-center, randomized controlled, double-arm, assessor-blinded, active control, and pragmatic clinical trial. Adults with stable heart failure with reduced ejection fraction and idiopathic dilated cardiomyopathy will be randomized to conventional sequencing (the control arm; over 6 months) of anti--heart failure therapies, and a second arm will receive rapid sequencing (over 4 weeks). Study participants will be followed for 5 years to assess the safety, efficacy, and tolerability of the 2 types of sequencing. Posttrial access and care will be provided to all study participants throughout their lifespan. Results: We are currently in the process of obtaining ethical clearance and funding. Conclusions: We envisage that this study will help support evidence-based medicine and inform clinical practice guidelines on the optimal rate of sequencing of anti--heart failure therapies. A third placebo arm was considered, but costs would be too much and not providing study participants with therapies with known morbidity and mortality benefits may be unethical, in our opinion. Given the post--COVID-19 economic downturn and posttrial access to interventions, a major challenge will be acquiring funding for this study. International Registered Report Identifier (IRRID): PRR1-10.2196/44027 ", doi="10.2196/44027", url="https://www.researchprotocols.org/2025/1/e44027" } @Article{info:doi/10.2196/63987, author="Pironet, Antoine and Phillips, Alison L. and Vrijens, Bernard", title="Correlation Between Objective Habit Metrics and Objective Medication Adherence: Retrospective Study of 15,818 Participants From Clinical Studies", journal="Interact J Med Res", year="2025", month="Feb", day="6", volume="14", pages="e63987", keywords="medication adherence", keywords="compliance", keywords="habit", keywords="history", keywords="correlation", keywords="association", keywords="intake", keywords="electronic database", keywords="retrospective", keywords="medication", keywords="drug", keywords="adherence", abstract="Background: Medication adherence, or how patients take their medication as prescribed, is suboptimal worldwide. Improving medication-taking habit might be an effective way to improve medication adherence. However, habit is difficult to quantify, and conventional habit metrics are self-reported, with recognized limitations. Recently, several objective habit metrics have been proposed, based on objective medication-taking data. Objective: We aim to explore the correlation between objective habit metrics and objective medication adherence on a large dataset. Methods: The Medication Event Monitoring System Adherence Knowledge Center, a database of anonymized electronic medication intake data from ambulant participants enrolled in past clinical studies, was used as the data source. Electronic medication intake data from participants following a once-daily regimen and monitored for 14 days or more were used. Further, two objective habit metrics were computed from each participant's medication intake history: (1) SD of the hour of intake, representing daily variability in the timing of medication intakes, and (2) weekly cross-correlation, representing weekly consistency in the timing of medication intakes. The implementation component of medication adherence was quantified using (1) the proportion of doses taken and (2) the proportion of correct days. Results: A total of 15,818 participants met the criteria. These participants took part in 108 clinical studies mainly focused on treatments for hypertension (n=4737, 30\%) and osteoporosis (n=3353, 21\%). The SD of the hour of intake was significantly negatively correlated with the 2 objective adherence metrics: proportion of correct days (Spearman correlation coefficient, $\rho$S=--0.62, P<.001) and proportion of doses taken ($\rho$S=--0.09, P<.001). The weekly cross-correlation was significantly positively correlated with the 2 objective adherence metrics: proportion of correct days ($\rho$S=0.55, P<.001) and proportion of doses taken ($\rho$S=0.32, P<.001). A lower daily or weekly variability in the timing of medication intakes is thus associated with better medication adherence. However, no variability is not the norm, as only 3.6\% of participants have 95\% of their intakes in a 1-hour window. Among the numerous factors influencing medication adherence, habit strength is an important one as it explains over 30\% of the variance in medication adherence. Conclusions: Objective habit metrics are correlated to objective medication adherence. Such objective habit metrics can be used to monitor patients and identify those who may benefit from habit-building support. ", doi="10.2196/63987", url="https://www.i-jmr.org/2025/1/e63987" } @Article{info:doi/10.2196/59946, author="Tsai, Chuan-Ching and Kim, Yong Jin and Chen, Qiyuan and Rowell, Brigid and Yang, Jessie X. and Kontar, Raed and Whitaker, Megan and Lester, Corey", title="Effect of Artificial Intelligence Helpfulness and Uncertainty on Cognitive Interactions with Pharmacists: Randomized Controlled Trial", journal="J Med Internet Res", year="2025", month="Jan", day="31", volume="27", pages="e59946", keywords="CDSS", keywords="eye-tracking", keywords="medication verification", keywords="uncertainty visualization", keywords="AI helpfulness and accuracy", keywords="artificial intelligence", keywords="cognitive interactions", keywords="clinical decision support system", keywords="cognition", keywords="pharmacists", keywords="medication", keywords="interaction", keywords="decision-making", keywords="cognitive processing", abstract="Background: Clinical decision support systems leveraging artificial intelligence (AI) are increasingly integrated into health care practices, including pharmacy medication verification. Communicating uncertainty in an AI prediction is viewed as an important mechanism for boosting human collaboration and trust. Yet, little is known about the effects on human cognition as a result of interacting with such types of AI advice. Objective: This study aimed to evaluate the cognitive interaction patterns of pharmacists during medication product verification when using an AI prototype. Moreover, we examine the impact of AI's assistance, both helpful and unhelpful, and the communication of uncertainty of AI-generated results on pharmacists' cognitive interaction with the prototype. Methods: In a randomized controlled trial, 30 pharmacists from professional networks each performed 200 medication verification tasks while their eye movements were recorded using an online eye tracker. Participants completed 100 verifications without AI assistance and 100 with AI assistance (either with black box help without uncertainty information or uncertainty-aware help, which displays AI uncertainty). Fixation patterns (first and last areas fixated, number of fixations, fixation duration, and dwell times) were analyzed in relation to AI help type and helpfulness. Results: Pharmacists shifted 19\%-26\% of their total fixations to AI-generated regions when these were available, suggesting the integration of AI advice in decision-making. AI assistance did not reduce the number of fixations on fill images, which remained the primary focus area. Unhelpful AI advice led to longer dwell times on reference and fill images, indicating increased cognitive processing. Displaying AI uncertainty led to longer cognitive processing times as measured by dwell times in original images. Conclusions: Unhelpful AI increases cognitive processing time in the original images. Transparency in AI is needed in ``black box'' systems, but showing more information can add a cognitive burden. Therefore, the communication of uncertainty should be optimized and integrated into clinical workflows using user-centered design to avoid increasing cognitive load or impeding clinicians' original workflow. Trial Registration: ClinicalTrials.gov NCT06795477; https://clinicaltrials.gov/study/NCT06795477 ", doi="10.2196/59946", url="https://www.jmir.org/2025/1/e59946", url="http://www.ncbi.nlm.nih.gov/pubmed/39888668" } @Article{info:doi/10.2196/58031, author="da Rosa, Teixeira Andr{\'e} Luiz Schuh and da Costa, Barreto Marina Ribeiro and Sorato, Bezerra Gabriela and Manjabosco, Moura Felipe de and de Bem, Bonganhi {\'E}rica and Dellazari, Lucas and Falc{\~a}o, Bezerra Arthur and Cia, Oliveira Lucas de and Bezerra, Sorato Olivia and Borges, Boff Rog{\'e}rio and Rohde, Augusto Luis and Graeff-Martins, Soledade Ana", title="Clozapine for Treatment-Resistant Disruptive Behaviors in Youths With Autism Spectrum Disorder Aged 10-17 Years: Protocol for an Open-Label Trial", journal="JMIR Res Protoc", year="2025", month="Jan", day="30", volume="14", pages="e58031", keywords="neurodevelopmental disorders", keywords="clozapine", keywords="psychopharmacology", keywords="antipsychotic medication", keywords="autism spectrum disorder", keywords="youth", abstract="Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition emerging in early childhood, characterized by core features such as sociocommunicative deficits and repetitive, rigid behaviors, interests, and activities. In addition to these, disruptive behaviors (DB), including aggression, self-injury, and severe tantrums, are frequently observed in pediatric patients with ASD. The atypical antipsychotics risperidone and aripiprazole, currently the only Food and Drug Administration--approved treatments for severe DB in patients with ASD, often encounter therapeutic failure or intolerance. Given this, exploring pharmacological alternatives for more effective management of DB associated with ASD is essential. Clozapine, noted for its unique antiaggressive effects in schizophrenia and in various treatment-resistant neuropsychiatric disorders, independent from its antipsychotic efficacy, remains underexplored in youths with ASD facing severe and persistent DB. Objective: This study aimed to evaluate the efficacy, tolerability, and safety of clozapine for treatment-resistant DB in youths with ASD. Methods: This is a prospective, single-center, noncontrolled, open-label trial. After a cross-titration phase, 31 patients with ASD aged 10-17 years and with treatment-resistant DB received a flexible dosage regimen of clozapine (up to 600 mg/day) for 12 weeks. Standardized instruments were applied before, during, and after the treatment, and rigorous clinical monitoring was performed weekly. The primary outcome was assessed using the Irritability Subscale of the Aberrant Behavior Checklist. Other efficacy measures include the Clinical Global Impression Severity and Improvement, the Swanson, Nolan, and Pelham questionnaire-IV, the Childhood Autism Rating Scale, and the Vineland Adaptive Behavior Scale. Safety and tolerability measures comprised adverse events, vital signs, electrocardiography, laboratory tests, physical measurements, and extrapyramidal symptoms with the Simpsons-Angus Scale. Statistical analysis will include chi-square tests with Monte Carlo simulation for categorical variables, paired t tests or Wilcoxon tests for continuous variables, and multivariate linear mixed models to evaluate the primary outcome, adjusting for confounders. Results: Recruitment commenced in February 2023. Data collection was concluded by April 2024, with analysis ongoing. This article presents the protocol of the initially planned study to provide a detailed methodological description. The results of this trial will be published in a future paper. Conclusions: The urgent need for effective pharmacological therapies in mitigating treatment-resistant DB in pediatric patients with ASD underscores the importance of this research. Our study represents the first open-label trial to explore the anti-aggressive effects of clozapine in this specific demographic, marking a pioneering step in clinical investigation. Adopting a pragmatic approach, this trial protocol aims to mirror real-world clinical settings, thereby enhancing the applicability and relevance of our findings. The preliminary nature of future results from this research has the potential to pave the way for more robust studies and emphasize the need for continued innovation in ASD treatment. Trial Registration: Brazilian Clinical Trials Registry RBR-54j3726; https://ensaiosclinicos.gov.br/rg/RBR-54j3726 International Registered Report Identifier (IRRID): DERR1-10.2196/58031 ", doi="10.2196/58031", url="https://www.researchprotocols.org/2025/1/e58031" } @Article{info:doi/10.2196/56850, author="Wang, Ying-Mei and Shen, Hung-Wei and Chen, Tzeng-Ji and Chiang, Shu-Chiung and Lin, Ting-Guan", title="Performance of ChatGPT-3.5 and ChatGPT-4 in the Taiwan National Pharmacist Licensing Examination: Comparative Evaluation Study", journal="JMIR Med Educ", year="2025", month="Jan", day="17", volume="11", pages="e56850", keywords="artificial intelligence", keywords="ChatGPT", keywords="chat generative pre-trained transformer", keywords="GPT-4", keywords="medical education", keywords="educational measurement", keywords="pharmacy licensure", keywords="Taiwan", keywords="Taiwan national pharmacist licensing examination", keywords="learning model", keywords="AI", keywords="Chatbot", keywords="pharmacist", keywords="evaluation and comparison study", keywords="pharmacy", keywords="statistical analyses", keywords="medical databases", keywords="medical decision-making", keywords="generative AI", keywords="machine learning", abstract="Background: OpenAI released versions ChatGPT-3.5 and GPT-4 between 2022 and 2023. GPT-3.5 has demonstrated proficiency in various examinations, particularly the United States Medical Licensing Examination. However, GPT-4 has more advanced capabilities. Objective: This study aims to examine the efficacy of GPT-3.5 and GPT-4 within the Taiwan National Pharmacist Licensing Examination and to ascertain their utility and potential application in clinical pharmacy and education. Methods: The pharmacist examination in Taiwan consists of 2 stages: basic subjects and clinical subjects. In this study, exam questions were manually fed into the GPT-3.5 and GPT-4 models, and their responses were recorded; graphic-based questions were excluded. This study encompassed three steps: (1) determining the answering accuracy of GPT-3.5 and GPT-4, (2) categorizing question types and observing differences in model performance across these categories, and (3) comparing model performance on calculation and situational questions. Microsoft Excel and R software were used for statistical analyses. Results: GPT-4 achieved an accuracy rate of 72.9\%, overshadowing GPT-3.5, which achieved 59.1\% (P<.001). In the basic subjects category, GPT-4 significantly outperformed GPT-3.5 (73.4\% vs 53.2\%; P<.001). However, in clinical subjects, only minor differences in accuracy were observed. Specifically, GPT-4 outperformed GPT-3.5 in the calculation and situational questions. Conclusions: This study demonstrates that GPT-4 outperforms GPT-3.5 in the Taiwan National Pharmacist Licensing Examination, particularly in basic subjects. While GPT-4 shows potential for use in clinical practice and pharmacy education, its limitations warrant caution. Future research should focus on refining prompts, improving model stability, integrating medical databases, and designing questions that better assess student competence and minimize guessing. ", doi="10.2196/56850", url="https://mededu.jmir.org/2025/1/e56850" } @Article{info:doi/10.2196/53957, author="Scharf, Tamara and Huber, A. Carola and N{\"a}pflin, Markus and Zhang, Zhongxing and Khatami, Ramin", title="Trends in Prescription of Stimulants and Narcoleptic Drugs in Switzerland: Longitudinal Health Insurance Claims Analysis for the Years 2014-2021", journal="JMIR Public Health Surveill", year="2025", month="Jan", day="7", volume="11", pages="e53957", keywords="prescription trends", keywords="claims data", keywords="cross-sectional data", keywords="narcolepsy", keywords="prescribers", keywords="prescribing practices", keywords="medical care", keywords="stimulants", keywords="stimulant medication", abstract="Background: Stimulants are potent treatments for central hypersomnolence disorders or attention-deficit/hyperactivity disorders/attention deficit disorders but concerns have been raised about their potential negative consequences and their increasing prescription rates. Objective: We aimed to describe stimulant prescription trends in Switzerland from 2014 to 2021. Second, we aimed to analyze the characteristics of individuals who received stimulant prescriptions in 2021 and investigate the link between stimulant prescriptions and hospitalization rates in 2021, using hospitalization as a potential indicator of adverse health outcomes. Methods: Longitudinal and cross-sectional data from a large Swiss health care insurance were analyzed from all insureds older than 6 years. The results were extrapolated to the Swiss general population. We identified prescriptions for methylphenidate, lisdexamfetamine, modafinil, and sodium oxybate and calculated prevalences of each drug prescription over the period from 2014 to 2021. For 2021 we provide detailed information on the prescribers and evaluate the association of stimulant prescription and the number and duration of hospitalization using logistic regression models. Results: We observed increasing prescription rates of all stimulants in all age groups from 2014 to 2021 (0.55\% to 0.81\%, 43,848 to 66,113 insureds with a prescription). In 2021, 37.1\% (28,057 prescriptions) of the medications were prescribed by psychiatrists, followed by 36.1\% (n=27,323) prescribed by general practitioners and 1\% (n=748) by neurologists. Only sodium oxybate, which is highly specific for narcolepsy treatment, was most frequently prescribed by neurologists (27.8\%, 37 prescriptions). Comorbid psychiatric disorders were common in patients receiving stimulants. Patients hospitalized in a psychiatric institution were 5.3 times (odds ratio 5.3, 95\% CI 4.63?6.08, P<.001) more likely to have a stimulant prescription than those without hospitalization. There were no significant associations between stimulant prescription and the total length of inpatient stay (odds ratio 1, 95\% CI 1?1, P=.13). Conclusions: The prescription of stimulant medication in Switzerland increased slightly but continuously over years, but at lower rates compared to the estimated prevalence of central hypersomnolence disorders and attention-deficit/hyperactivity disorders/attention deficit disorders. Most stimulants are prescribed by psychiatrists, closely followed by general practitioners. The increased odds for hospitalization to psychiatric institutions for stimulant receivers reflects the severity of disease and the higher psychiatric comorbidities in these patients. ", doi="10.2196/53957", url="https://publichealth.jmir.org/2025/1/e53957" } @Article{info:doi/10.2196/65957, author="Beiler, Donielle and Chopra, Aanya and Gregor, M. Christina and Tusing, D. Lorraine and Pradhan, M. Apoorva and Romagnoli, M. Katrina and Kraus, K. Chadd and Piper, J. Brian and Wright, A. Eric and Troiani, Vanessa", title="Medical Marijuana Documentation Practices in Patient Electronic Health Records: Retrospective Observational Study Using Smart Data Elements and a Review of Medical Records", journal="JMIR Form Res", year="2024", month="Dec", day="23", volume="8", pages="e65957", keywords="cannabis", keywords="learning health system", keywords="Epic", keywords="prescription drug monitoring program", keywords="medical marijuana", keywords="electronic health records", keywords="physician", keywords="cannabis use", keywords="drug use", keywords="data sharing", keywords="patient care", keywords="legalization", keywords="dosage", keywords="chart review protocol", keywords="human data extraction", keywords="data collection", abstract="Background: Medical marijuana (MMJ) is available in Pennsylvania, and participation in the state-regulated program requires patient registration and receiving certification by an approved physician. Currently, no integration of MMJ certification data with health records exists in Pennsylvania that would allow clinicians to rapidly identify patients using MMJ, as exists with other scheduled drugs. This absence of a formal data sharing structure necessitates tools aiding in consistent documentation practices to enable comprehensive patient care. Customized smart data elements (SDEs) were made available to clinicians at an integrated health system, Geisinger, following MMJ legalization in Pennsylvania. Objective: The purpose of this project was to examine and contextualize the use of MMJ SDEs in the Geisinger population. We accomplished this goal by developing a systematic protocol for review of medical records and creating a tool that resulted in consistent human data extraction. Methods: We developed a protocol for reviewing medical records for extracting MMJ-related information. The protocol was developed between August and December of 2022 and focused on a patient group that received one of several MMJ SDEs between January 25, 2019, and May 26, 2022. Characteristics were first identified on a pilot sample (n=5), which were then iteratively reviewed to optimize for consistency. Following the pilot, 2 reviewers were assigned 200 randomly selected patients' medical records, with a third reviewer examining a subsample (n=30) to determine reliability. We then summarized the clinician- and patient-level features from 156 medical records with a table-format SDE that best captured MMJ information. Results: We found the review protocol for medical records was feasible for those with minimal medical background to complete, with high interrater reliability ($\kappa$=0.966; P<.001; odds ratio 0.97, 95\% CI 0.954-0.978). MMJ certification was largely documented by nurses and medical assistants (n=138, 88.5\%) and typically within primary care settings (n=107, 68.6\%). The SDE has 6 preset field prompts with heterogeneous documentation completion rates, including certifying conditions (n=146, 93.6\%), product (n=145, 92.9\%), authorized dispensary (n=137, 87.8\%), active ingredient (n=130, 83.3\%), certifying provider (n=96, 61.5\%), and dosage (n=48, 30.8\%). We found preset fields were overall well-recorded (mean 76.6\%, SD 23.7\% across all fields). Primary diagnostic codes recorded at documentation encounters varied, with the most frequent being routine examinations and testing (n=34, 21.8\%), musculoskeletal or nervous conditions, and signs and symptoms not classified elsewhere (n=21, 13.5\%). Conclusions: This method of reviewing medical records yields high-quality data extraction that can serve as a model for other health record inquiries. Our evaluation showed relatively high completeness of SDE fields, primarily by clinical staff responsible for rooming patients, with an overview of conditions under which MMJ is documented. Improving the adoption and fidelity of SDE data collection may present a valuable data source for future research on patient MMJ use, treatment efficacy, and outcomes. ", doi="10.2196/65957", url="https://formative.jmir.org/2024/1/e65957" } @Article{info:doi/10.2196/64300, author="Youn, G. Christopher and Kim, Yeon Joo and Yang, B. Vivian and Bae, H. Gordon", title="Improving Affordability in Dermatology: Cost Savings in Mark Cuban Cost Plus Drug Company Versus GoodRx", journal="JMIR Dermatol", year="2024", month="Dec", day="13", volume="7", pages="e64300", keywords="dermatology", keywords="cost", keywords="affordability", keywords="drug company", keywords="United States", keywords="US", keywords="financial burden", keywords="prescription", keywords="medication", keywords="pharmaceutical", keywords="dermatologic", keywords="burden", keywords="financial distress", keywords="health outcomes", keywords="pharmacist", keywords="pharmacy", keywords="convenience", doi="10.2196/64300", url="https://derma.jmir.org/2024/1/e64300" } @Article{info:doi/10.2196/59234, author="Takura, Tomoyuki and Yokoi, Hiroyoshi and Honda, Asao", title="Factors Influencing Drug Prescribing for Patients With Hospitalization History in Circulatory Disease--Patient Severity, Composite Adherence, and Physician-Patient Relationship: Retrospective Cohort Study", journal="JMIR Aging", year="2024", month="Dec", day="6", volume="7", pages="e59234", keywords="medication adherence", keywords="drug prescription switch", keywords="generic drug", keywords="logistic model", keywords="long-term longitudinal study", keywords="patient severity", keywords="systolic blood pressure", keywords="serum creatinine", keywords="aging", keywords="big data", abstract="Background: With countries promoting generic drug prescribing, their growth may plateau, warranting further investigation into the factors influencing this trend, including physician and patient perspectives. Additional strategies may be needed to maximize the switch to generic drugs while ensuring health care system sustainability, focusing on factors beyond mere low cost. Emphasizing affordability and clarifying other prescription considerations are essential. Objective: This study aimed to provide initial insights into how patient severity, composite adherence, and physician-patient relationships impact generic switching. Methods: This study used a long-term retrospective cohort design by analyzing data from a national health care database. The population included patients of all ages, primarily older adults, who required primary-to-tertiary preventive actions with a history of hospitalization for cardiovascular diseases (ICD-10 [International Statistical Classification of Diseases, Tenth Revision]) from April 2014 to March 2018 (4 years). We focused on switching to generic drugs, with temporal variations in clinical parameters as independent variables. Lifestyle factors (smoking and drinking) were also considered. Adherence was measured as a composite score comprising 11 elements. The physician-patient relationship was established based on the interval between physician change and prescription. Logistic regression analysis and propensity score matching were used, along with complementary analysis of physician-patient relationships, proportion of days covered, and adherence for a subset of the population. Results: The study included 48,456 patients with an average follow-up of 36.1 (SD 8.8) months. The mean age was 68.3\thinspace(SD 9.9)\thinspaceyears; BMI, 23.4\thinspace(SD\thinspace3.4)\thinspacekg/m2; systolic blood pressure, 131.2\thinspace(SD\thinspace15)\thinspacemm Hg; low-density lipoprotein cholesterol level, 116.6\thinspace(SD\thinspace29.3)\thinspacemg/dL; hemoglobin A1c (HbA1c), 5.9\%\thinspace(SD\thinspace0.8\%); and serum creatinine level, 0.9\thinspace(SD\thinspace0.8)\thinspacemg/dL. Logistic regression analysis revealed significant associations between generic switching and systolic blood pressure (odds ratio [OR] 0.996, 95\% CI 0.993-0.999), serum creatinine levels (OR 0.837, 95\% CI 0.729-0.962), glutamic oxaloacetic transaminase levels (OR 0.994, 95\% CI 0.990-0.997), proportion of days covered score (OR 0.959, 95\% CI 0.948-0.97), and adherence score (OR 0.910, 95\% CI 0.875-0.947). In addition, generic drug rates increased with improvements in the HbA1c level band and smoking level (P<.01 and P<.001). The group with a superior physician-patient relationship after propensity score matching had a significantly higher rate of generic drug prescribing (51.6\%, SD 15.2\%) than the inferior relationship group (47.7\%, SD17.7\%; P<.001). Conclusions: Although physicians' understanding influences the choice of generic drugs, patient condition (severity) and adherence also impact this decision. For example, improved creatinine levels are associated with generic drug choice, while stronger physician-patient relationships correlate with higher rates of generic drug use. These findings may contribute to the appropriate prescription of pharmaceuticals if the policy diffusion of generic drugs begins to slow down. Thus, preventing serious illness while building trust may result in clinical benefits and positive socioeconomic outcomes. ", doi="10.2196/59234", url="https://aging.jmir.org/2024/1/e59234" } @Article{info:doi/10.2196/57451, author="Jin, Kyung Hye and Kim, EunYoung", title="Performance of GPT-3.5 and GPT-4 on the Korean Pharmacist Licensing Examination: Comparison Study", journal="JMIR Med Educ", year="2024", month="Dec", day="4", volume="10", pages="e57451", keywords="GPT-3.5", keywords="GPT-4", keywords="Korean", keywords="Korean Pharmacist Licensing Examination", keywords="KPLE", abstract="Background: ChatGPT, a recently developed artificial intelligence chatbot and a notable large language model, has demonstrated improved performance on medical field examinations. However, there is currently little research on its efficacy in languages other than English or in pharmacy-related examinations. Objective: This study aimed to evaluate the performance of GPT models on the Korean Pharmacist Licensing Examination (KPLE). Methods: We evaluated the percentage of correct answers provided by 2 different versions of ChatGPT (GPT-3.5 and GPT-4) for all multiple-choice single-answer KPLE questions, excluding image-based questions. In total, 320, 317, and 323 questions from the 2021, 2022, and 2023 KPLEs, respectively, were included in the final analysis, which consisted of 4 units: Biopharmacy, Industrial Pharmacy, Clinical and Practical Pharmacy, and Medical Health Legislation. Results: The 3-year average percentage of correct answers was 86.5\% (830/960) for GPT-4 and 60.7\% (583/960) for GPT-3.5. GPT model accuracy was highest in Biopharmacy (GPT-3.5 77/96, 80.2\% in 2022; GPT-4 87/90, 96.7\% in 2021) and lowest in Medical Health Legislation (GPT-3.5 8/20, 40\% in 2022; GPT-4 12/20, 60\% in 2022). Additionally, when comparing the performance of artificial intelligence with that of human participants, pharmacy students outperformed GPT-3.5 but not GPT-4. Conclusions: In the last 3 years, GPT models have performed very close to or exceeded the passing threshold for the KPLE. This study demonstrates the potential of large language models in the pharmacy domain; however, extensive research is needed to evaluate their reliability and ensure their secure application in pharmacy contexts due to several inherent challenges. Addressing these limitations could make GPT models more effective auxiliary tools for pharmacy education. ", doi="10.2196/57451", url="https://mededu.jmir.org/2024/1/e57451" } @Article{info:doi/10.2196/55185, author="Van De Sijpe, Greet and Gijsen, Matthias and Van der Linden, Lorenz and Strouven, Stephanie and Simons, Eline and Martens, Emily and Persan, Nele and Grootaert, Veerle and Foulon, Veerle and Casteels, Minne and Verelst, Sandra and Vanbrabant, Peter and De Winter, Sabrina and Spriet, Isabel", title="A Prediction Model to Identify Clinically Relevant Medication Discrepancies at the Emergency Department (MED-REC Predictor): Development and Validation Study", journal="J Med Internet Res", year="2024", month="Nov", day="27", volume="26", pages="e55185", keywords="medication reconciliation", keywords="medication discrepancy", keywords="emergency department", keywords="prediction model", keywords="risk stratification", keywords="MED-REC predictor", keywords="MED-REC", keywords="predictor", keywords="patient", keywords="medication", keywords="hospital", keywords="software-implemented prediction model", keywords="software", keywords="geographic validation", keywords="geographic", abstract="Background: Many patients do not receive a comprehensive medication reconciliation, mostly owing to limited resources. We hence need an approach to identify those patients at the emergency department (ED) who are at increased risk for clinically relevant discrepancies. Objective: The aim of our study was to develop and externally validate a prediction model to identify patients at risk for at least 1 clinically relevant medication discrepancy upon ED presentation. Methods: A prospective, multicenter, observational study was conducted at the University Hospitals Leuven and General Hospital Sint-Jan Brugge-Oostende AV, Belgium. Medication histories were obtained from patients admitted to the ED between November 2017 and May 2022, and clinically relevant medication discrepancies were identified. Three distinct datasets were created for model development, temporal external validation, and geographic external validation. Multivariable logistic regression with backward stepwise selection was used to select the final model. The presence of at least 1 clinically relevant discrepancy was the dependent variable. The model was evaluated by measuring calibration, discrimination, classification, and net benefit. Results: We included 824, 350, and 119 patients in the development, temporal validation, and geographic validation dataset, respectively. The final model contained 8 predictors, for example, age, residence before admission, number of drugs, and number of drugs of certain drug classes based on Anatomical Therapeutic Chemical coding. Temporal validation showed excellent calibration with a slope of 1.09 and an intercept of 0.18. Discrimination was moderate with a c-index (concordance index) of 0.67 (95\% CI 0.61-0.73). In the geographic validation dataset, the calibration slope and intercept were 1.35 and 0.83, respectively, and the c-index was 0.68 (95\% CI 0.58-0.78). The model showed net benefit over a range of clinically reasonable threshold probabilities and outperformed other selection criteria. Conclusions: Our software-implemented prediction model shows moderate performance, outperforming random or typical selection criteria for medication reconciliation. Depending on available resources, the probability threshold can be customized to increase either the specificity or the sensitivity of the model. ", doi="10.2196/55185", url="https://www.jmir.org/2024/1/e55185" } @Article{info:doi/10.2196/59480, author="Gopukumar, Deepika and Menon, Nirup and Schoen, W. Martin", title="Medication Prescription Policy for US Veterans With Metastatic Castration-Resistant Prostate Cancer: Causal Machine Learning Approach", journal="JMIR Med Inform", year="2024", month="Nov", day="19", volume="12", pages="e59480", keywords="prostate cancer", keywords="metastatic castration resistant prostate cancer", keywords="causal survival forest", keywords="machine learning", keywords="heterogeneity", keywords="prescription policy tree", keywords="oncology", keywords="pharmacology", abstract="Background: Prostate cancer is the second leading cause of death among American men. If detected and treated at an early stage, prostate cancer is often curable. However, an advanced stage such as metastatic castration-resistant prostate cancer (mCRPC) has a high risk of mortality. Multiple treatment options exist, the most common included docetaxel, abiraterone, and enzalutamide. Docetaxel is a cytotoxic chemotherapy, whereas abiraterone and enzalutamide are androgen receptor pathway inhibitors (ARPI). ARPIs are preferred over docetaxel due to lower toxicity. No study has used machine learning with patients' demographics, test results, and comorbidities to identify heterogeneous treatment rules that might improve the survival duration of patients with mCRPC. Objective: This study aimed to measure patient-level heterogeneity in the association of medication prescribed with overall survival duration (in the form of follow-up days) and arrive at a set of medication prescription rules using patient demographics, test results, and comorbidities. Methods: We excluded patients with mCRPC who were on docetaxel, cabaxitaxel, mitoxantrone, and sipuleucel-T either before or after the prescription of an ARPI. We included only the African American and white populations. In total, 2886 identified veterans treated for mCRPC who were prescribed either abiraterone or enzalutamide as the first line of treatment from 2014 to 2017, with follow-up until 2020, were analyzed. We used causal survival forests for analysis. The unit level of analysis was the patient. The primary outcome of this study was follow-up days indicating survival duration while on the first-line medication. After estimating the treatment effect, a prescription policy tree was constructed. Results: For 2886 veterans, enzalutamide is associated with an average of 59.94 (95\% CI 35.60-84.28) more days of survival than abiraterone. The increase in overall survival duration for the 2 drugs varied across patient demographics, test results, and comorbidities. Two data-driven subgroups of patients were identified by ranking them on their augmented inverse-propensity weighted (AIPW) scores. The average AIPW scores for the 2 subgroups were 19.36 (95\% CI --16.93 to 55.65) and 100.68 (95\% CI 62.46-138.89). Based on visualization and t test, the AIPW score for low and high subgroups was significant (P=.003), thereby supporting heterogeneity. The analysis resulted in a set of prescription rules for the 2 ARPIs based on a few covariates available to the physicians at the time of prescription. Conclusions: This study of 2886 veterans showed evidence of heterogeneity and that survival days may be improved for certain patients with mCRPC based on the medication prescribed. Findings suggest that prescription rules based on the patient characteristics, laboratory test results, and comorbidities available to the physician at the time of prescription could improve survival by providing personalized treatment decisions. ", doi="10.2196/59480", url="https://medinform.jmir.org/2024/1/e59480" } @Article{info:doi/10.2196/51833, author="Yewale, Prasad and Rathi, Renu and Mate, Swapnali", title="Study to Evaluate the Comparative Efficacy of Medhya Rasayana (Pharmacological) Versus Nonpharmacological Interventions in Management of Gadget Addiction in Children: Protocol for Parallel, Triple-Arm, Randomized Clinical Trial", journal="JMIR Res Protoc", year="2024", month="Nov", day="11", volume="13", pages="e51833", keywords="addiction", keywords="Ayurveda", keywords="gadget addiction", keywords="children", keywords="Kaumarbhritya", keywords="Medhya Rasayana", keywords="yoga", keywords="complementary and alternative medicine", abstract="Background: Gadget addiction is a common behavioral problem among children. It is known to hamper social and academic life as well as adversely affect the lives of children. Ayurveda offers many therapeutic modalities and Ayurvedic medicines that can be used in the management of gadget addiction in children. The purpose of this study is to evaluate and compare the effectiveness of nonpharmacological therapies and the pharmaceutical intervention Medhya Rasayana in treating childhood gadget addiction. Objective: This study aims to provide a detailed description of the study methodology that will be used to compare the efficacy of nonpharmacological versus pharmaceutical interventions in the treatment of children's gadget addiction. Methods: A randomized, parallel, triple-arm interventional study will be conducted on diagnosed participants of gadget addiction with an age group of 6- to 16-year-old children, which will be selected and equally distributed in 2 groups. Group P will be given Medhya Rasayana (pharmacological intervention), group N will be nonpharmacological Ayurveda intervention, and group C (cognitive behavioral therapy) will be an external group. The Study duration is 180 days with assessment at baseline, midpoint, and endpoint Appropriate statistical techniques, such as ANOVA and regression analysis, will be used to examine the data and evaluate the efficacy of the 3 groups' interventions. We will perform subgroup analysis according to initial addiction severity, gender, and age. Primary outcome measures include a reduction in gadget addiction and changes in the psychosocial well-being of participants. Standardized questionnaires and instruments will be used to collect data. Results: In December 2023, the randomized controlled study got underway. Since participants may begin at any time, our goal is for everyone to be finished by December 2024. Conclusions: This research will provide crucial new information about the relative effectiveness of Ayurveda nonpharmacological therapies and Medhya Rasayana in treating children's gadget addiction. The results will guide evidence-based treatments aimed at reducing the negative impact of excessive gadget use on this susceptible population's psychosocial development. In the end, the findings are meant to help policy makers and medical professionals create sensible plans to deal with the rising issue of childhood gadget addiction. International Registered Report Identifier (IRRID): PRR1-10.2196/51833 ", doi="10.2196/51833", url="https://www.researchprotocols.org/2024/1/e51833" } @Article{info:doi/10.2196/65440, author="Ashraf, Reza Amir and Mackey, Ken Tim and Vida, Gy{\"o}rgy R{\'o}bert and Kulcs{\'a}r, Gy?z? and Schmidt, J{\'a}nos and Bal{\'a}zs, Orsolya and Domi{\'a}n, M{\'a}rk B{\'a}lint and Li, Jiawei and Cs{\'a}k{\'o}, Ibolya and Fittler, Andr{\'a}s", title="Multifactor Quality and Safety Analysis of Semaglutide Products Sold by Online Sellers Without a Prescription: Market Surveillance, Content Analysis, and Product Purchase Evaluation Study", journal="J Med Internet Res", year="2024", month="Nov", day="7", volume="26", pages="e65440", keywords="semaglutide", keywords="Ozempic", keywords="Wegovy", keywords="search engines", keywords="online pharmacies", keywords="patient safety", keywords="medication safety", keywords="nondelivery schemes", keywords="counterfeit", keywords="substandard and falsified medical products", abstract="Background: Over the past 4 decades, obesity has escalated into a global epidemic, with its worldwide prevalence nearly tripling. Pharmacological treatments have evolved with the recent development of glucagon-like peptide 1 agonists, such as semaglutide. However, off-label use of drugs such as Ozempic for cosmetic weight loss has surged in popularity, raising concerns about potential misuse and the emergence of substandard and falsified products in the unregulated supply chain. Objective: This study aims to conduct a multifactor investigation of product quality and patient safety risks associated with the unregulated online sale of semaglutide by examining product availability and vendor characteristics and assessing product quality through test purchases. Methods: We used a complex risk and quality assessment methodology combining online market surveillance, search engine results page analysis, website content assessment, domain traffic analytics, conducting targeted product test purchases, visual quality inspection of product packaging, microbiological sterility and endotoxin contamination evaluation, and quantitative sample analysis using liquid chromatography coupled with mass spectrometry. Results: We collected and evaluated 1080 links from search engine results pages and identified 317 (29.35\%) links belonging to online pharmacies, of which 183 (57.7\%) led to legal pharmacies and 134 (42.3\%) directed users to 59 unique illegal online pharmacy websites.?Web traffic data for the period between July and September 2023 revealed that the top 30 domains directly or indirectly affiliated with illegal online pharmacies accumulated over 4.7 million visits.?Test purchases were completed from?6 illegal online pharmacies with the highest number of links offering semaglutide products for sale without prescription at the lowest price range. Three injection vial purchases were delivered; none of the 3 Ozempic prefilled injection pens were received due to nondelivery e-commerce scams.?All purchased vials were considered probable substandard and falsified products, as visual inspection indicated noncompliance in more than half (59\%-63\%) of the evaluated criteria. The semaglutide content of samples substantially exceeded labeled amounts by 28.56\%-38.69\%, although no peptide-like impurities were identified. The lyophilized peptide samples were devoid of viable microorganisms at the time of testing; however, endotoxin was detected in all samples with levels ranging between 2.1645 EU/mg and 8.9511 EU/mg. Furthermore, the measured semaglutide purity was significantly low, ranging between 7.7\% and 14.37\% and deviating from the 99\% claimed on product labels by manufacturers. Conclusions: Glucagon-like peptide 1 agonist drugs promoted for weight loss, similar to erectile dysfunction medications more than 2 decades ago, are becoming the new blockbuster lifestyle medications for the illegal online pharmacy market. Protecting the pharmaceutical supply chain from substandard and falsified weight loss products and raising awareness regarding online medication safety must be a public health priority for regulators and technology platforms alike. ", doi="10.2196/65440", url="https://www.jmir.org/2024/1/e65440" } @Article{info:doi/10.2196/55614, author="Sullivan, Sean Patrick and Mera-Giler, M. Robertino and Bush, Staci and Shvachko, Valentina and Sarkodie, Eleanor and O'Farrell, Daniel and Dubose, Stephanie and Magnuson, David", title="Claims-Based Algorithm to Identify Pre-Exposure Prophylaxis Indications for Tenofovir Disoproxil Fumarate and Emtricitabine Prescriptions (2012-2014): Validation Study", journal="JMIR Form Res", year="2024", month="Nov", day="4", volume="8", pages="e55614", keywords="pre-exposure prophylaxis", keywords="PrEP", keywords="classification", keywords="electronic medical record", keywords="EMR", keywords="algorithm", keywords="electronic health record", keywords="EHR", keywords="drug", keywords="pharmacology", keywords="pharmacotherapy", keywords="pharmaceutical", keywords="medication", keywords="monotherapy", keywords="HIV", keywords="prevention", abstract="Background: To monitor the use of tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) and related medicines for pre-exposure prophylaxis (PrEP) as HIV prevention using commercial pharmacy data, it is necessary to determine whether TDF/FTC prescriptions are used for PrEP or for some other clinical indication. Objective: This study aimed to validate an algorithm to distinguish the use of TDF/FTC for HIV prevention or infectious disease treatment. Methods: An algorithm was developed to identify whether TDF/FTC prescriptions were for PrEP or for other indications from large-scale administrative databases. The algorithm identifies TDF/FTC prescriptions and then excludes patients with International Classification of Diseases (ICD)--9 diagnostic codes, medications, or procedures that suggest indications other than for PrEP (eg, documentation of HIV infection, chronic hepatitis B, or use of TDF/FTC for postexposure prophylaxis). For evaluation, we collected data by clinician assessment of medical records for patients with TDF/FTC prescriptions and compared the assessed indication identified by the clinician review with the assessed indication identified by the algorithm. The algorithm was then applied and evaluated in a large, urban, community-based sexual health clinic. Results: The PrEP algorithm demonstrated high sensitivity and moderate specificity (99.6\% and 49.6\%) in the electronic medical record database and high sensitivity and specificity (99\% and 87\%) in data from the urban community health clinic. Conclusions: The PrEP algorithm classified the indication for PrEP in most patients treated with TDF/FTC with sufficient accuracy to be useful for surveillance purposes. The methods described can serve as a basis for developing a robust and evolving case definition for antiretroviral prescriptions for HIV prevention purposes. ", doi="10.2196/55614", url="https://formative.jmir.org/2024/1/e55614", url="http://www.ncbi.nlm.nih.gov/pubmed/39141024" } @Article{info:doi/10.2196/60370, author="Hernandez, Christopher and Rowe, Christopher and Ikeda, Janet and Arenander, Justine and Santos, Glenn-Milo", title="Interest in the Use of Herbal Supplements to Close the Treatment Gap for Hazardous Alcohol Use Among Men Who Have Sex With Men: Secondary Analysis of a Cross-Sectional Study", journal="JMIR Form Res", year="2024", month="Oct", day="29", volume="8", pages="e60370", keywords="alcohol use disorder", keywords="herbal supplements", keywords="HIV", keywords="herbal", keywords="supplement", keywords="alcohol", keywords="alcoholic", keywords="alcohol use", keywords="alcohol consumption", keywords="cross-sectional study", keywords="California", keywords="USA: binge drinking", keywords="alcohol dependence", keywords="men", keywords="social", keywords="clinical", keywords="logistic regression", keywords="drinking", abstract="Background: Hazardous alcohol consumption is highly prevalent for men who have sex with men (MSM). The 4 treatments currently approved by the Food and Drug Administration for alcohol use are reaching an alarmingly low percentage of people who would benefit from a reduction in their alcohol use. There is increasing interest in alternative methods of treatment, such as herbal supplements, to address hazardous drinking. However, research on the acceptability of alternative pharmacotherapies among MSM remains limited. Objective: We examined the prevalence and correlates of expressing interest in using herbal supplements for alcohol treatment among MSM with hazardous alcohol consumption. Methods: We conducted a secondary data analysis from a cross-sectional study of MSM who use alcohol, conducted from March 2015 to July 2017 in San Francisco, California, to assess the overall prevalence of interest in using herbal supplements to help reduce alcohol consumption. Associations between expressing interest in herbal supplements and demographic, social, and clinical characteristics were examined using bivariate and multivariable logistic regression models. Results: One-third (66/200, 33\%) of the participants expressed interest in an herbal supplement for reducing alcohol consumption. In the multivariable analyses, weekly binge drinking (adjusted odds ratio [aOR] 2.85, 95\% CI 1.17-6.93), interest in abstaining from alcohol use (aOR 5.04, 95\% CI 1.46-17.40), higher severity of alcohol dependence score (aOR 1.22, 95\% CI 1.04-1.41), and interest in naltrexone (aOR 3.22, 95\% CI 2.12-4.91) were independently associated with higher odds of being interested in using an herbal supplement to reduce alcohol consumption, adjusting for age, race or ethnicity, and education. Conclusions: We found that MSM who have hazardous drinking habits, more severe alcohol dependence, and interest in pharmacotherapy were more likely to express interest in using an herbal supplement for reducing alcohol consumption. To our knowledge, this is the first study that has evaluated correlates of interest in herbal supplements for alcohol use among MSM. As researchers implement novel alcohol treatment studies, they should focus on recruitment efforts among MSM with a motivation to reduce their alcohol use patterns. ", doi="10.2196/60370", url="https://formative.jmir.org/2024/1/e60370" } @Article{info:doi/10.2196/57285, author="Abejew, Agalu Asrat and Wubetu, Yismaw Gizachew and Fenta, Gedif Teferi", title="Antibiotic Prescribing Behavior of Physicians in Outpatient Departments in Hospitals in Northwest Ethiopia: Structural Equation Modeling Approach", journal="Interact J Med Res", year="2024", month="Oct", day="23", volume="13", pages="e57285", keywords="antibiotic prescribing behavior", keywords="Ethiopia", keywords="outpatient departments", keywords="physicians", keywords="SEM", keywords="TPB", abstract="Background: Antibiotic resistance, fueled by irrational prescribing, is a global threat associated with health, social, and economic consequences. Understanding antibiotic prescribing behavior and associated factors is important to promote good prescribing practice. Objective: This study aimed to determine the factors affecting antibiotic prescribing behaviors of physicians based on the theory of planned behavior in hospitals in northwest Ethiopia in 2022. Methods: A cross-sectional study was conducted from September 2022 to October 2022. A total of 185 health professionals were included, and a self-administered questionnaire was used to collect data. A structural equation model based on the modified theory of planned behavior was used to determine factors affecting antibiotic prescribing behavior. The percentages of physicians' estimated prescriptions for patients with upper respiratory tract infections (URTIs) and during weekly outpatient visits were used to predict antibiotic prescribing behavior and finally linked with behavioral constructs. A P value <.05 was considered significant. Results: Physicians estimated that they prescribed antibiotics for 54.8\% (9896/18,049) of weekly outpatient encounters, and 178 (96.2\%) of the 185 physicians estimated they prescribed antibiotics for patients who presented with symptoms of a URTI. Physicians aged ?30 years were less likely to prescribe antibiotics (48/100, 48\%) for patients who presented with a URTI than physicians older than 30 years (51/100, 51\%; P=.004), and general practitioners were less likely to prescribe antibiotics (47/100, 47\%) for patients who presented with a URTI than residents (51/100, 51\%; P=.03). Similarly, during outpatient visits, physicians ?30 years old were less likely to prescribe antibiotics (54/100, 54\%) than physicians older than 30 years (57/100, 57\%; P<.001), male physicians were less likely to prescribe antibiotics (53/100, 53\%) than female physicians (64/100, 64\%; P=.03), and general practitioners were less likely to prescribe antibiotics (53/100, 53\%) than residents (57/100, 57\%; P=.02). Physicians with good knowledge were less affected by perceived social pressure (mean 4.4, SD 0.6) than those with poor knowledge (mean 4.0, SD 0.9; P<.001) and felt it was easy to make rational decisions (mean 4.1, SD 1.1) compared with those with poor knowledge (mean 3.8, SD 1; P<.001). However, intentions to reduce and prescribe antibiotics were not affected by attitudes, subjective norms, or perceived behavioral control, and perceived antibiotic prescribing behavior was not related to intentions to reduce or prescribe antibiotics. Conclusions: Antibiotic prescribing behavior was not under the volitional control of physicians. This calls for a systematic approach to change antibiotic prescribing practices in hospital. ", doi="10.2196/57285", url="https://www.i-jmr.org/2024/1/e57285", url="http://www.ncbi.nlm.nih.gov/pubmed/39441643" } @Article{info:doi/10.2196/51351, author="Mohamed, Abubaker and Ismail, Enas and Adam, Z. Razia", title="A Comparison of Conventional Root Canal Sealers With Ones That Use Green Synthesized Nanoparticles for Antimicrobial Activity: Protocol for a Systematic Review", journal="JMIR Res Protoc", year="2024", month="Oct", day="11", volume="13", pages="e51351", keywords="root-canal sealers", keywords="nanoparticles", keywords="antimicrobial activity", keywords="root canal", keywords="antimicrobial", keywords="dentistry", abstract="Background: Root canal failure and secondary endodontic infection are frequent clinical scenarios in dentistry. The main microorganisms implicated in root canal therapy failure are persistent Enterococcus faecalis, Candida albicans, and Staphylococcus aureus. To combat the impact of disease resistance, scientists are concentrating on alternative antimicrobial root canal sealers. Nanomaterials are a recent development in endodontic materials that exhibit great antimicrobial properties, making them an ideal material choice for root canal sealers. Objective: This systematic review aims to compare the antimicrobial properties of conventional root canal sealers to those incorporating green synthesized nanoparticles between 2010 and 2024. Methods: A well-constructed protocol was established and registered with PROSPERO (CRD42021286373). Ethics approval was obtained from the Biomedical Research and Ethics Committee from the University of the Western Cape (UWC; BM22/1/4). PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) reporting guidelines were followed. The included criteria demonstrate the green synthesized nanoparticles studies where the nanoparticles (NPs) are incorporated in root canal sealers. MeSH (Medical Subject Headings) terms were used for the search strategy of the systematic electronic databases for articles published in English between 2010 and 2024. The selected databases included Scopus, PubMed, Web of Science, Science Direct, EBSCOhost, SpringerLink, and Wiley Online. A quality assessment tool for laboratory studies will be used to critically appraise the included studies. If applicable, statistical measures (mean, SD, etc) will be used for data analysis and presentation of the results. Results: The protocol is registered with PROSPERO. A preliminary search was conducted using a determined search strategy across 8 electronic databases, and the review is now complete. Conclusions: It is anticipated that the results of this systematic review may reveal the increased interest and application for nanoparticle-enhanced root canal sealers. This will aid in the future development of root canal sealants and mitigate the risk of endodontic failure. Trial Registration: PROSPERO CRD42021286373; https://www.crd.york.ac.uk/prospero/display\_record.php?RecordID=286373 International Registered Report Identifier (IRRID): DERR1-10.2196/51351 ", doi="10.2196/51351", url="https://www.researchprotocols.org/2024/1/e51351" } @Article{info:doi/10.2196/58018, author="Ashoor, Dana and Marzouq, Maryam and Fathallah, M-Dahmani", title="Comparison of the Neutralization Power of Sotrovimab Against SARS-CoV-2 Variants: Development of a Rapid Computational Method", journal="JMIR Bioinform Biotech", year="2024", month="Oct", day="10", volume="5", pages="e58018", keywords="in silico", keywords="anti--SARS-CoV-2", keywords="neutralizing antibody", keywords="Sotrovimab", keywords="S309", keywords="variants", keywords="SARS-CoV-2", keywords="Omicron", keywords="subvariants", keywords="computational method", keywords="monoclonal", keywords="amino acid", keywords="protein", keywords="mutation", abstract="Background: The rapid evolution of SARS-CoV-2 imposed a huge challenge on disease control. Immune evasion caused by genetic variations of the SARS-CoV-2 spike protein's immunogenic epitopes affects the efficiency of monoclonal antibody--based therapy of COVID-19. Therefore, a rapid method is needed to evaluate the efficacy of the available monoclonal antibodies against the new emerging variants or potential novel variants. Objective: The aim of this study is to develop a rapid computational method to evaluate the neutralization power of anti--SARS-CoV-2 monoclonal antibodies against new SARS-CoV-2 variants and other potential new mutations. Methods: The amino acid sequence of the extracellular domain of the spike proteins of the severe acute respiratory syndrome coronavirus (GenBank accession number YP\_009825051.1) and SARS-CoV-2 (GenBank accession number YP\_009724390.1) were used to create computational 3D models for the native spike proteins. Specific mutations were introduced to the curated sequence to generate the different variant spike models. The neutralization potential of sotrovimab (S309) against these variants was evaluated based on its molecular interactions and Gibbs free energy in comparison to a reference model after molecular replacement of the reference receptor-binding domain with the variant's receptor-binding domain. Results: Our results show a loss in the binding affinity of the neutralizing antibody S309 with both SARS-CoV and SARS-CoV-2. The binding affinity of S309 was greater to the Alpha, Beta, Gamma, and Kappa variants than to the original Wuhan strain of SARS-CoV-2. However, S309 showed a substantially decreased binding affinity to the Delta and Omicron variants. Based on the mutational profile of Omicron subvariants, our data describe the effect of the G339H and G339D mutations and their role in escaping antibody neutralization, which is in line with published clinical reports. Conclusions: This method is rapid, applicable, and of interest to adapt the use of therapeutic antibodies to the treatment of emerging variants. It could be applied to antibody-based treatment of other viral infections. ", doi="10.2196/58018", url="https://bioinform.jmir.org/2024/1/e58018", url="http://www.ncbi.nlm.nih.gov/pubmed/39388246" } @Article{info:doi/10.2196/53828, author="Zhu, Jiayue Nina and Weldegiorgis, Misghina and Carter, Emma and Brown, Colin and Holmes, Alison and Aylin, Paul", title="Economic Burden of Community-Acquired Antibiotic-Resistant Urinary Tract Infections: Systematic Review and Meta-Analysis", journal="JMIR Public Health Surveill", year="2024", month="Oct", day="9", volume="10", pages="e53828", keywords="cost-effectiveness", keywords="urinary tract infection", keywords="antibiotic resistance", keywords="mortality", keywords="hospital length of stay", abstract="Background: Antibiotic resistance (ABR) poses a major burden to global health and economic systems. ABR in community-acquired urinary tract infections (CA-UTIs) has become increasingly prevalent. Accurate estimates of ABR's clinical and economic burden are needed to support medical resource prioritization and cost-effectiveness evaluations of urinary tract infection (UTI) interventions. Objective: This study aims to systematically synthesize the evidence on the economic costs associated with ABR in CA-UTIs, using published studies comparing the costs of antibiotic-susceptible and antibiotic-resistant cases. Methods: We searched the PubMed, Ovid MEDLINE and Embase, Cochrane Review Library, and Scopus databases. Studies published in English from January 1, 2008, to January 31, 2023, reporting the economic costs of ABR in CA-UTI of any microbe were included. Independent screening of titles/abstracts and full texts was performed based on prespecified criteria. A quality assessment was performed using the Integrated Quality Criteria for Review of Multiple Study Designs (ICROMS) tool. Data in UTI diagnosis criteria, patient characteristics, perspectives, resource costs, and patient and health economic outcomes, including mortality, hospital length of stay (LOS), and costs, were extracted and analyzed. Monetary costs were converted into 2023 US dollars. Results: This review included 15 studies with a total of 57,251 CA-UTI cases. All studies were from high- or upper-middle-income countries. A total of 14 (93\%) studies took a health system perspective, 13 (87\%) focused on hospitalized patients, and 14 (93\%) reported UTI pathogens. Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are the most prevalent organisms. A total of 12 (80\%) studies reported mortality, of which, 7 reported increased mortality in the ABR group. Random effects meta-analyses estimated an odds ratio of 1.50 (95\% CI 1.29-1.74) in the ABR CA-UTI cases. All 13 hospital-based studies reported LOS, of which, 11 reported significantly higher LOS in the ABR group. The meta-analysis of the reported median LOS estimated a pooled excess LOS ranging from 1.50 days (95\% CI 0.71-4.00) to 2.00 days (95\% CI 0.85-3.15). The meta-analysis of the reported mean LOS estimated a pooled excess LOS of 2.45 days (95\% CI 0.51?4.39). A total of 8 (53\%) studies reported costs in monetary terms---none discounted the costs. All 8 studies reported higher medical costs spent treating patients with ABR CA-UTI in hospitals. The highest excess cost was observed in UTIs caused by carbapenem-resistant Enterobacterales. No meta-analysis was performed for monetary costs due to heterogeneity. Conclusions: ABR was attributed to increased mortality, hospital LOS, and economic costs among patients with CA-UTI. The findings of this review highlighted the scarcity of research in this area, particularly in patient morbidity and chronic sequelae and costs incurred in community health care. Future research calls for a cost-of-illness analysis of infections, standardizing therapy-pathogen combination comparators, medical resources, productivity loss, intangible costs to be captured, and data from community sectors and low-resource settings and countries. ", doi="10.2196/53828", url="https://publichealth.jmir.org/2024/1/e53828" } @Article{info:doi/10.2196/51635, author="Li, Xingang and Guo, Heng and Li, Dandan and Zheng, Yingming", title="Engine of Innovation in Hospital Pharmacy: Applications and Reflections of ChatGPT", journal="J Med Internet Res", year="2024", month="Oct", day="4", volume="26", pages="e51635", keywords="ChatGPT", keywords="hospital pharmacy", keywords="natural language processing", keywords="drug information", keywords="drug therapy", keywords="drug interaction", keywords="scientific research", keywords="innovation", keywords="pharmacy", keywords="quality", keywords="safety", keywords="pharmaceutical care", keywords="tool", keywords="medical care quality", doi="10.2196/51635", url="https://www.jmir.org/2024/1/e51635", url="http://www.ncbi.nlm.nih.gov/pubmed/39365643" } @Article{info:doi/10.2196/55129, author="Thomas, Benjamin and Barclay, Greg and Lo, Angela Wing-Shan and Mullan, Judy and Mansfield, Kylie", title="Dexmedetomidine Versus Midazolam for End-of-Life Sedation and Agitation: Protocol for a Randomized Controlled Trial (The DREAMS Trial)", journal="JMIR Res Protoc", year="2024", month="Sep", day="4", volume="13", pages="e55129", keywords="palliative", keywords="sedation", keywords="delirium", keywords="dexmedetomidine", keywords="midazolam", keywords="antipsychotics", keywords="deep sedation", keywords="palliative care", keywords="sedative", keywords="adult", keywords="inpatient", keywords="Australia", keywords="quality of life", keywords="end of life", keywords="protocol", keywords="dexmedetomidine for the reduction of end-of-life agitation and for optiMised sedation", keywords="DREAMS trial", keywords="DREAMS", abstract="Background: Sedation at the end of life is used to relieve distressing symptoms including agitation and delirium. Standard care may include infused benzodiazepines or antipsychotics. These agents often result in deep sedation with loss of interaction with loved ones, which may be distressing. Objective: The DREAMS (Dexmedetomidine for the Reduction of End-of-life Agitation and for optiMised Sedation) trial aimed to compare the sedative and antidelirium effects of the alpha-2 agonist dexmedetomidine, a novel palliative care sedative, compared with midazolam, a benzodiazepine when administered by subcutaneous infusion at the end of life, with doses of both agents targeting lighter, or potentially interactive sedation. Methods: Participants were recruited from adult inpatients admitted for end-of-life care under a palliative care team in regional New South Wales, Australia. Inclusion criteria included patients older than 18 years, with a preference for lighter sedation at the end of life. Exclusion criteria included severe cardiac dysfunction (contraindication to dexmedetomidine). Participants consented and were placed on a treatment-pending list. Upon experiencing terminal deterioration, patients were randomized to either arm 1 (dexmedetomidine) or arm 2 (midazolam) as their treatment arm. These treatments were administered by continuous subcutaneous infusion. The level of consciousness and agitation of the patients were measured by the Richmond Agitation-Sedation Scale--Palliative version and the Memorial Delirium Assessment Score. Richmond Agitation-Sedation Scale--Palliative version assessments were performed by both nursing and medical staff, while Memorial Delirium Assessment Score assessments were carried out by medical staff only. Families and patients were asked to complete, as able, a patient comfort assessment form, to gauge perceptions of distress. Data were collected and matched with the breakthrough medication doses administered, along with qualitative comments in the medical record. In addition, the study tracked symptoms and patient functional status that were recorded as part of the Palliative Care Outcomes Collaborative, a national tracking project for monitoring symptom outcomes in palliative care. Results: The DREAMS trial was funded in May 2020, approved by the ethics committee in November 2020, and started recruiting participants in May 2021. Data collection commenced in May 2021 and is anticipated to continue until December 2024. Publication of results is anticipated from 2024 to 2026. Conclusions: The evidence base for sedative dosing in palliative care for distress and agitation is not robust, with standard care based primarily on clinical experience and not robust scientific evidence. This study is important because it will compare a standard and a novel sedative used in end-of-life treatment. By assessing the potential efficacy and benefits of both, it seeks to optimize the quality of dying by providing targeted sedation that can improve the communication between dying patients and their loved ones. Trial Registration: Australia New Zealand Clinical Trials Register ACTRN12621000052831; https://uat.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380889 International Registered Report Identifier (IRRID): DERR1-10.2196/55129 ", doi="10.2196/55129", url="https://www.researchprotocols.org/2024/1/e55129", url="http://www.ncbi.nlm.nih.gov/pubmed/39230940" } @Article{info:doi/10.2196/63808, author="Kongkaew, Chuenjid and Phan, Anh Dang Thuc and Janusorn, Prathan and Mongkhon, Pajaree", title="Estimating Adverse Events Associated With Herbal Medicines Using Pharmacovigilance Databases: Systematic Review and Meta-Analysis", journal="JMIR Public Health Surveill", year="2024", month="Aug", day="29", volume="10", pages="e63808", keywords="herbal medicine", keywords="pharmacovigilance", keywords="adverse event", keywords="spontaneous reporting system", keywords="meta-analysis", abstract="Background: Herbal medicines (HMs) are extensively used by consumers/patients worldwide. However, their safety profiles are often poorly reported and characterized. Previous studies have documented adverse events (AEs) associated with HMs, such as hepatotoxicity, renal failure, and allergic reactions. However, the prevalence rate of AEs related to HMs has been reported to be low. To date, no systematic review and meta-analysis has comprehensively analyzed the AEs of HMs using published data acquired from pharmacovigilance (PV) databases. Objective: This study aimed to (1) estimate the reporting rate of the AEs of HMs using PV databases and (2) assess the detailed data provided in AE reports. Methods: In this systematic review and meta-analysis, MEDLINE/PubMed, SCOPUS, EMBASE, and CINAHL were systematically searched for relevant studies (until December 2023). The DerSimonian-Laird random effects model was used for pooling the data, and subgroup analyses, the meta-regression model, and sensitivity analysis were used to explore the source of heterogeneity. Crombie's checklist was used to evaluate the risk of bias (ROB) of the included studies. Results: In total, 26 studies met the eligibility criteria. The reporting rate of the AEs of HMs ranged considerably, from 0.03\% to 29.84\%, with a median overall pooled estimate of 1.42\% (IQR 1.12\%-1.72\%). Subgroup analyses combined with the meta-regression model revealed that the reporting rate of the AEs of HMs was associated with the source of the reporter (P=.01). None of the included studies provided full details of suspected herbal products, only the main ingredients were disclosed, and other potentially harmful components were not listed. Conclusions: This systematic review and meta-analysis highlighted risks related to HMs, with a wide range of reporting rates, depending on the source of the reporter. Continuous efforts are necessary to standardize consumer reporting systems in terms of the reporting form, education, and follow-up strategy to improve data quality assurance, aiming to enhance the reliability and utility of PV data for monitoring the safety of HMs. Achieving effective monitoring and reporting of these AEs necessitates collaborative efforts from diverse stakeholders, including patients/consumers, manufacturers, physicians, complementary practitioners, sellers/distributors, and health authorities. Trial Registration: PROSPERO (Prospective International Register of Systematic Reviews) CRD42021276492 ", doi="10.2196/63808", url="https://publichealth.jmir.org/2024/1/e63808" } @Article{info:doi/10.2196/53513, author="Gualtieri, Lisa and Rigby, Mathilda and Wang, Deelia and Mann, Elaine", title="Medication Management Strategies to Support Medication Adherence: Interview Study With Older Adults", journal="Interact J Med Res", year="2024", month="Aug", day="13", volume="13", pages="e53513", keywords="home medication management", keywords="medication adherence", keywords="prescription drugs", keywords="adherence devices", keywords="adherence apps", keywords="pill cases", keywords="aging in place", keywords="independent living", keywords="aging", keywords="medication", keywords="older adults", keywords="prescription", keywords="interview", keywords="interview design", keywords="design", keywords="app", keywords="mobile phone", abstract="Background: Home medication management has been insufficiently studied, including the factors that impact the development and effectiveness of adherence strategies under both routine and anomalous circumstances. Older adults are a particularly important population to study due to the greater likelihood of taking medication in combination with the desire to ``age in place.'' Objective: This interview study aims to understand how older adults develop medication management strategies, identify when and why such strategies succeed or fail, learn more about how older adults think about their medication, and explore interventions that increase medication adherence. Methods: This study used a qualitative, semistructured interview design to elicit older adults' experiences with home medication management. Overall, 22 participants aged ?50 years taking 1 to 3 prescription medications were recruited and interviewed. Interview responses were recorded, and thematic, qualitative analysis was performed by reviewing recordings and identifying recurring patterns and themes. Responses were systematically coded, which not only facilitated the identification of these themes but also allowed us to quantify the prevalence of behaviors and perceptions, providing a robust understanding of medication management and medication adherence. Results: Participants reported developing home medication management strategies on their own, with none of the participants receiving guidance from health care providers and 59\% (13/22) of the participants using trial and error. The strategies developed by study participants were all unique and generally encompassed prescription medication and vitamins or supplements, with no demarcation between what was prescribed or recommended by a physician and what they selected independently. Participants thought about their medications by their chemical name (10/22, 45\%), by the appearance of the pill (8/22, 36\%), by the medication's purpose (2/22, 9\%), or by the medication's generic name (2/22, 9\%). Pill cases (17/22, 77\%) were more popular than prescription bottles (5/22, 23\%) for storage of daily medication. Most participants (19/22, 86\%) stored their pill cases or prescription bottles in visible locations in the home, and those using pill cases varied in their refill routines. Participants used ?2 routines or objects as triggers to take their medication. Nonadherence was associated with a disruption to their routine. Finally, only 14\% (3/22) of the participants used a time-based reminder or alarm, and none of the participants used a medication adherence device or app. Conclusions: Participants in our study varied considerably in their home medication management strategies and developed unique routines to remember to take their medication as well as to refill their pill cases. To reduce trial and error in establishing a strategy, there are opportunities for physicians and pharmacists to provide adherence guidance to older adults. To minimize the impact of disruptions on adherence, there are opportunities to develop more durable strategies and to design aids to medication adherence that leverage established daily routines. ", doi="10.2196/53513", url="https://www.i-jmr.org/2024/1/e53513", url="http://www.ncbi.nlm.nih.gov/pubmed/39137021" } @Article{info:doi/10.2196/58635, author="Lang, Yan and Chen, Kay-Yut and Zhou, Yuan and Kosmari, Ludmila and Daniel, Kathryn and Gurses, Ayse and Young, Richard and Arbaje, Alicia and Xiao, Yan", title="Perception of Medication Safety--Related Behaviors Among Different Age Groups: Web-Based Cross-Sectional Study", journal="Interact J Med Res", year="2024", month="Aug", day="12", volume="13", pages="e58635", keywords="medication safety", keywords="patient engagement", keywords="aged adults", keywords="survey", keywords="Amazon Mechanical Turk", keywords="medication", keywords="engagement", keywords="older adults", keywords="elderly", keywords="safety", keywords="United States", keywords="USA", keywords="crowdsourcing", keywords="community", keywords="patient portal", keywords="primary care", keywords="medications", keywords="safety behavior", keywords="younger adults", keywords="age", keywords="correlation", keywords="statistical test", abstract="Background: Previous research and safety advocacy groups have proposed various behaviors for older adults to actively engage in medication safety. However, little is known about how older adults perceive the importance and reasonableness of these behaviors in ambulatory settings. Objective: This study aimed to assess older adults' perceptions of the importance and reasonableness of 8 medication safety behaviors in ambulatory settings and compare their responses with those of younger adults. Methods: We conducted a survey of 1222 adults in the United States using crowdsourcing to evaluate patient behaviors that may enhance medication safety in community settings. A total of 8 safety behaviors were identified based on the literature, such as bringing medications to office visits, confirming medications at home, managing medication refills, using patient portals, organizing medications, checking medications, getting help, and knowing medications. Respondents were asked about their perception of the importance and reasonableness of these behaviors on a 5-point Likert rating scale in the context of collaboration with primary care providers. We assessed the relative ranking of behaviors in terms of importance and reasonableness and examined the association between these dimensions across age groups using statistical tests. Results: Of 1222 adult participants, 125 (10.2\%) were aged 65 years or older. Most participants were White, college-educated, and had chronic conditions. Older adults rated all 8 behaviors significantly higher in both importance and reasonableness than did younger adults (P<.001 for combined behaviors). Confirming medications ranked highest in importance (mean score=3.78) for both age groups while knowing medications ranked highest in reasonableness (mean score=3.68). Using patient portals was ranked lowest in importance (mean score=3.53) and reasonableness (mean score=3.49). There was a significant correlation between the perceived importance and reasonableness of the identified behaviors, with coefficients ranging from 0.436 to 0.543 (all P<.001). Conclusions: Older adults perceived the identified safety behaviors as more important and reasonable than younger adults. However, both age groups considered a behavior highly recommended by professionals as the least important and reasonable. Patient engagement strategies, common and specific to age groups, should be considered to improve medication safety in ambulatory settings. ", doi="10.2196/58635", url="https://www.i-jmr.org/2024/1/e58635" } @Article{info:doi/10.2196/54117, author="Leung, Lam Chung and Alacapa, Jason and Tasca, Gon{\c{c}}alves Bianca and Villanueva, Daniel Andre and Masulit, Saniata and Ignacio, Louie Marvin and Uy, Nicole Kathleen and Pell, Christopher and van Kalmthout, Kristian and Powers, Rachel and Fielding, Katherine and Jerene, Degu", title="Digital Adherence Technologies and Differentiated Care for Tuberculosis Treatment and Their Acceptability Among Persons With Tuberculosis, Health Care Workers, and Key Informants in the Philippines: Qualitative Interview Study", journal="JMIR Hum Factors", year="2024", month="Jul", day="23", volume="11", pages="e54117", keywords="tuberculosis", keywords="digital adherence technologies", keywords="implementation", keywords="acceptability", keywords="qualitative research", keywords="Philippines", keywords="digital health", keywords="tuberculosis treatment", keywords="support strategy", keywords="support", keywords="medication adherence", keywords="health care workers", keywords="interview", keywords="interviews", keywords="user", keywords="user privacy", keywords="privacy", keywords="digital adherence", abstract="Background: Digital adherence technologies (DATs) are being studied to determine their potential to support tuberculosis (TB) treatment and address the shortcomings of directly observed therapy. Previous research has shown inconclusive results on whether DATs can enhance medication adherence among persons with TB. Objective: This study aims to understand the acceptability of DATs, namely, medication labels and smart pillboxes, among persons with TB, health care workers (HCWs), and key informants (KIs) in the Philippines. The objective is to gain valuable insights that can inform the design and implementation of DATs in the Southeast Asian region, which meet the needs and preferences of end users. Methods: Persons with TB, HCWs, and KIs were recruited from intervention facilities to participate in in-depth interviews conducted between March 2022 and January 2023. These interviews were transcribed and translated into English. A thematic analysis was carried out using NVivo software (Lumivero) to identify and analyze themes. Themes were then structured within a modified social-ecological model. Results: A total of 25 persons with drug-sensitive TB and 20 HCWs or KIs were interviewed. Both groups emphasized that users' technology literacy level, financial conditions, and motivation to be cured determined how they interacted with the DAT. They also acknowledged that DATs helped foster their relationship with HCWs and enabled efficient treatment support. Concerning technology, persons with TB found DATs easy to use and able to reduce clinic visits. HCWs mentioned that DATs added to their workload but also allowed them to support users who missed doses. However, both groups experienced technical challenges with DATs. Regarding program implementation, users appreciated the clear explanations and demonstrations provided by HCWs. Yet, some users reported inconsistencies between DAT settings and the information provided. HCWs stressed the importance of comprehensive training and sufficient resources for effective program implementation in the future. At the community level, both groups noted that DATs and program design protected users' privacy and reduced the risk of stigma. Finally, users and HCWs shared various contextual factors that influenced their experience with DAT, including infrastructure challenges and the impact of the COVID-19 pandemic. Conclusions: In the Philippines, persons with TB and HCWs showed a high level of acceptance and satisfaction with the impact of DAT and program design. They expressed a desire for the continuation of DATs. The challenges encountered underscore the need for ongoing technological development to minimize malfunctions, enhance the capacity of health facilities, and improve infrastructure. DATs have demonstrated their ability to strengthen user-HCW relationships and protect users from stigmatization. Additional efforts are required to scale up the DAT program in the Philippines. ", doi="10.2196/54117", url="https://humanfactors.jmir.org/2024/1/e54117" } @Article{info:doi/10.2196/56277, author="Soerensen, Lykkegaard Ann and Haase Juhl, Marie and Krogh, Lunddal Marlene and Gr{\o}nkj{\ae}r, Mette and Kristensen, Kolding Jette and Olesen, Estrup Anne", title="Deprescribing as a Way to Reduce Inappropriate Use of Drugs for Overactive Bladder in Primary Care (DROP): Protocol for a Cluster Randomized Controlled Trial With an Embedded Explanatory Sequential Mixed Methods Study", journal="JMIR Res Protoc", year="2024", month="Jul", day="23", volume="13", pages="e56277", keywords="deprescribing", keywords="overactive bladder", keywords="general practice", keywords="patient safety", keywords="potentially inappropriate medication", keywords="geriatric", keywords="elderly", keywords="medication safety", keywords="geriatrics", keywords="anticholinergic drugs", keywords="safety", keywords="prescription", keywords="Denmark", keywords="general practitioner", keywords="evidence-based intervention", keywords="evidence-based", keywords="intervention", keywords="health care", keywords="medication", keywords="efficacy", keywords="DROP study", keywords="DROP", abstract="Background: Potentially inappropriate medication remains a significant concern in general practices, particularly in the context of overactive bladder (OAB) treatment for individuals aged 65 years and older. This study focuses on the exploration of alternative options for treating OAB and the deprescribing of anticholinergic drugs commonly used in OAB. The research aims to comprehensively evaluate the efficiency of deprescribing through a mixed methods approach, combining quantitative assessment and qualitative exploration of perceptions, experiences, and potential barriers among patients and health care personnel. Objective: This study aims to evaluate the efficiency and safety of the intervention in which health care staff in primary care encourage patients to participate in deprescribing their drugs for OAB. In addition, we aim to identify factors contributing to or obstructing the deprescribing process that will drive more informed decisions in the field of deprescribing and support effective and safe treatment of patients. Methods: The drugs for overactive bladder in primary care (DROP) study uses a rigorous research design, using a randomized controlled trial (RCT) with an embedded sequential explanatory mixed methods approach. All general practices within the North Denmark Region will be paired based on the number of general practitioners (GPs) and urban or rural locations. The matched pairs will be randomized into intervention and control groups. The intervention group will receive an algorithm designed to guide the deprescribing of drugs for OAB, promoting appropriate medication use. Quantitative data will be collected from the RCT including data from Danish registries for prescription analysis. Qualitative data will be obtained through interviews and focus groups with GPs, staff members, and patients. Finally, the quantitative and qualitative findings are merged to understand deprescribing for OAB comprehensively. This integrated approach enhances insights and supports future intervention improvement. Results: The DROP study is currently in progress, with randomization of general practices underway. While they have not been invited to participate yet, they will be. The inclusion of GP practices is scheduled from December 2023 to April 2024. The follow-up period for each patient is 6 months. Results will be analyzed through an intention-to-treat analysis for the RCT and a thematic analysis for the qualitative component. Quantitative outcomes will focus on changes in prescriptions and symptoms, while the qualitative analysis will explore experiences and perceptions. Conclusions: The DROP study aims to provide an evidence-based intervention in primary care that ensures the deprescription of drugs for OAB when there is an unfavorable risk-benefit profile. The DROP study's contribution lies in generating evidence for deprescribing practices and influencing best practices in health care. Trial Registration: ClinicalTrials.gov NCT06110975; https://clinicaltrials.gov/study/NCT06110975 International Registered Report Identifier (IRRID): DERR1-10.2196/56277 ", doi="10.2196/56277", url="https://www.researchprotocols.org/2024/1/e56277" } @Article{info:doi/10.2196/49230, author="Sharma, Videha and McDermott, John and Keen, Jessica and Foster, Simon and Whelan, Pauline and Newman, William", title="Pharmacogenetics Clinical Decision Support Systems for Primary Care in England: Co-Design Study", journal="J Med Internet Res", year="2024", month="Jul", day="23", volume="26", pages="e49230", keywords="personalized medicine", keywords="genomic medicine", keywords="pharmacogenetics", keywords="user-centred design", keywords="medical informatics", keywords="clinical decision support systems", keywords="side effect", keywords="information technology", keywords="data", keywords="primary care", keywords="health informatic", abstract="Background: Pharmacogenetics can impact patient care and outcomes through personalizing the selection of medicines, resulting in improved efficacy and a reduction in harmful side effects. Despite the existence of compelling clinical evidence and international guidelines highlighting the benefits of pharmacogenetics in clinical practice, implementation within the National Health Service in the United Kingdom is limited. An important barrier to overcome is the development of IT solutions that support the integration of pharmacogenetic data into health care systems. This necessitates a better understanding of the role of electronic health records (EHRs) and the design of clinical decision support systems that are acceptable to clinicians, particularly those in primary care. Objective: Explore the needs and requirements of a pharmacogenetic service from the perspective of primary care clinicians with a view to co-design a prototype solution. Methods: We used ethnographic and think-aloud observations, user research workshops, and prototyping. The participants for this study included general practitioners and pharmacists. In total, we undertook 5 sessions of ethnographic observation to understand current practices and workflows. This was followed by 3 user research workshops, each with its own topic guide starting with personas and early ideation, through to exploring the potential of clinical decision support systems and prototype design. We subsequently analyzed workshop data using affinity diagramming and refined the key requirements for the solution collaboratively as a multidisciplinary project team. Results: User research results identified that pharmacogenetic data must be incorporated within existing EHRs rather than through a stand-alone portal. The information presented through clinical decision support systems must be clear, accessible, and user-friendly as the service will be used by a range of end users. Critically, the information should be displayed within the prescribing workflow, rather than discrete results stored statically in the EHR. Finally, the prescribing recommendations should be authoritative to provide confidence in the validity of the results. Based on these findings we co-designed an interactive prototype, demonstrating pharmacogenetic clinical decision support integrated within the prescribing workflow of an EHR. Conclusions: This study marks a significant step forward in the design of systems that support pharmacogenetic-guided prescribing in primary care settings. Clinical decision support systems have the potential to enhance the personalization of medicines, provided they are effectively implemented within EHRs and present pharmacogenetic data in a user-friendly, actionable, and standardized format. Achieving this requires the development of a decoupled, standards-based architecture that allows for the separation of data from application, facilitating integration across various EHRs through the use of application programming interfaces (APIs). More globally, this study demonstrates the role of health informatics and user-centered design in realizing the potential of personalized medicine at scale and ensuring that the benefits of genomic innovation reach patients and populations effectively. ", doi="10.2196/49230", url="https://www.jmir.org/2024/1/e49230" } @Article{info:doi/10.2196/46137, author="van Wyk, S. Susanna and Nliwasa, Marriott and Lu, Fang-Wen and Lan, Chih-Chan and Seddon, A. James and Hoddinott, Graeme and Viljoen, Lario and G{\"u}nther, Gunar and Ruswa, Nunurai and Shah, Sarita N. and Claassens, Mareli", title="Drug-Resistant Tuberculosis Case-Finding Strategies: Scoping Review", journal="JMIR Public Health Surveill", year="2024", month="Jun", day="26", volume="10", pages="e46137", keywords="tuberculosis", keywords="drug-resistant tuberculosis", keywords="drug-resistant tuberculosis case finding", keywords="drug-resistant tuberculosis case detection", keywords="drug-resistant tuberculosis screening", keywords="drug-resistant tuberculosis contact investigation", keywords="scoping review", keywords="TB symptom", keywords="anti-tuberculosis drug", keywords="strategies", keywords="multidrug-resistant", keywords="systematic review", keywords="drug resistant", keywords="drug resistance", keywords="medication", keywords="diagnosis", keywords="screening", abstract="Background: Finding individuals with drug-resistant tuberculosis (DR-TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge, systematic reviews assessing the effectiveness, cost-effectiveness, acceptability, and feasibility of different DR-TB case-finding strategies to inform research, policy, and practice, have not been conducted and the scope of primary research is unknown. Objective: We therefore assessed the available literature on DR-TB case-finding strategies. Methods: We looked at systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that sought to improve DR-TB case detection specifically. We excluded studies that included patients seeking care for tuberculosis (TB) symptoms, patients already diagnosed with TB, or were laboratory-based. We searched the academic databases of MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL (Cumulated Index to Nursing and Allied Health Literature), Epistemonikos, and PROSPERO (The International Prospective Register of Systematic Reviews) using no language or date restrictions. We screened titles, abstracts, and full-text articles in duplicate. Data extraction and analyses were carried out in Excel (Microsoft Corp). Results: We screened 3646 titles and abstracts and 236 full-text articles. We identified 6 systematic reviews and 61 primary studies. Five reviews described the yield of contact investigation and focused on household contacts, airline contacts, comparison between drug-susceptible tuberculosis and DR-TB contacts, and concordance of DR-TB profiles between index cases and contacts. One review compared universal versus selective drug resistance testing. Primary studies described (1) 34 contact investigations, (2) 17 outbreak investigations, (3) 3 airline contact investigations, (4) 5 epidemiological analyses, (5) 1 public-private partnership program, and (6) an e-registry program. Primary studies were all descriptive and included cross-sectional and retrospective reviews of program data. No trials were identified. Data extraction from contact investigations was difficult due to incomplete reporting of relevant information. Conclusions: Existing descriptive reviews can be updated, but there is a dearth of knowledge on the effectiveness, cost-effectiveness, acceptability, and feasibility of DR-TB case-finding strategies to inform policy and practice. There is also a need for standardization of terminology, design, and reporting of DR-TB case-finding studies. ", doi="10.2196/46137", url="https://publichealth.jmir.org/2024/1/e46137" } @Article{info:doi/10.2196/55948, author="Zhao, Li and Guo, Yiping and Zhou, Xuelei and Mao, Wei and Chen, Linlin and Xie, Ying and Li, Linji", title="Efficacy and Safety of Remimazolam Versus Etomidate for Induction of General Anesthesia: Protocol for a Systematic Review and Meta-Analysis", journal="JMIR Res Protoc", year="2024", month="Jun", day="12", volume="13", pages="e55948", keywords="general anesthesia", keywords="anesthesia induction", keywords="postinduction hypotension", keywords="remimazolam", keywords="etomidate", keywords="meta-analysis", abstract="Background: Postinduction hypotension (PIHO) is a hemodynamic abnormality commonly observed during the induction of general anesthesia. Etomidate is considered a safer drug for the induction of anesthesia because it has only minor adverse effects on the cardiovascular and pulmonary systems. Recent evidence indicates that the novel benzodiazepine remimazolam has minimal inhibitory effects on the circulation and respiration. However, the efficacy and safety of remimazolam versus etomidate in the induction of anesthesia are unclear. Objective: To further understand the potential of remimazolam in anesthesia induction, it is necessary to design a meta-analysis to compare its effects versus the classic safe anesthetic etomidate. The aim of this study is to determine which drug has more stable hemodynamics and a lower incidence of PIHO. Our study will also yield data on sedation efficiency, time to loss of consciousness, time to awakening, incidence of injection pain, and postoperative nausea and vomiting with the two drugs. Methods: We plan to search the Web of Science, Cochrane Library, Embase, PubMed, China National Knowledge Infrastructure, and Wanfang databases from the date of their creation until March 31, 2025. The language is limited to English and Chinese. The search terms are ``randomized controlled trials,'' ``etomidate,'' and ``remimazolam.'' The incidence of PIHO is the primary outcome measure. Secondary outcomes include depth of anesthesia after induction, sedation success rate, time to loss of consciousness, hemodynamic profiles, recovery time, incidence of injection pain, and postoperative nausea and vomiting. Reviews, meta-analyses, case studies, abstracts from conferences, and commentaries will not be included. The heterogeneity of the results will be evaluated by sensitivity and subgroup analyses. RevMan software and Stata software will be used for data analysis. We will evaluate the quality of included studies using version 2 of the Cochrane risk-of-bias tool. The confidence of the evidence will be assessed through the Grading of Recommendations, Assessments, Developments, and Evaluations system. Results: The protocol was registered in the international PROSPERO (Prospective Register of Systematic Reviews) registry in November 2023. As of June 2024, we have performed a preliminary article search and retrieval for further review. The review and analyses are expected to be completed in March 2025. We expect to submit manuscripts for peer review by the end of June 2025. Conclusions: By synthesizing the available evidence and comparing remimazolam and etomidate, we hope to provide valuable insights into the selection of anesthesia-inducing drugs to reduce the incidence of PIHO and improve patient prognosis. Trial Registration: PROSPERO CRD42023463120; https://tinyurl.com/333jb8bm International Registered Report Identifier (IRRID): PRR1-10.2196/55948 ", doi="10.2196/55948", url="https://www.researchprotocols.org/2024/1/e55948", url="http://www.ncbi.nlm.nih.gov/pubmed/38865185" } @Article{info:doi/10.2196/56646, author="Chandhiruthil Sathyan, Anjana and Yadav, Pramod and Gupta, Prashant and Mahapathra, Kumar Arun and Galib, Ruknuddin", title="In Silico Approaches to Polyherbal Synergy: Protocol for a Scoping Review", journal="JMIR Res Protoc", year="2024", month="Jun", day="10", volume="13", pages="e56646", keywords="polyherbal formulation", keywords="Ayurveda system", keywords="Ayurveda", keywords="Ayurvedic medicine", keywords="Ayurvedic treatment", keywords="herbal", keywords="herbal drug", keywords="pharmacodynamic", keywords="pharmacology", keywords="computer-aided drug design", keywords="in silico methodology", keywords="scoping review", abstract="Background: According to the World Health Organization, more than 80\% of the world's population relies on traditional medicine. Traditional medicine is typically based on the use of single herbal drugs or polyherbal formulations (PHFs) to manage diseases. However, the probable mode of action of these formulations is not well studied or documented. Over the past few decades, computational methods have been used to study the molecular mechanism of phytochemicals in single herbal drugs. However, the in silico methods applied to study PHFs remain unclear. Objective: The aim of this protocol is to develop a search strategy for a scoping review to map the in silico approaches applied in understanding the activity of PHFs used as traditional medicines worldwide. Methods: The scoping review will be conducted based on the methodology developed by Arksey and O'Malley and the recommendations of the Joanna Briggs Institute (JBI). A set of predetermined keywords will be used to identify the relevant studies from five databases: PubMed, Embase, Science Direct, Web of Science, and Google Scholar. Two independent reviewers will conduct the search to yield a list of relevant studies based on the inclusion and exclusion criteria. Mendeley version 1.19.8 will be used to remove duplicate citations, and title and abstract screening will be performed with Rayyan software. The JBI System for the Unified Management, Assessment, and Review of Information tool will be used for data extraction. The scoping review will be reported based on the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. Results: Based on the core areas of the scoping review, a 3-step search strategy was developed. The initial search produced 3865 studies. After applying filters, 875 studies were short-listed for further review. Keywords were further refined to yield more relevant studies on the topic. Conclusions: The findings are expected to determine the extent of the knowledge gap in the applications of computational methods in PHFs for any traditional medicine across the world. The study can provide answers to open research questions related to the phytochemical identification of PHFs, criteria for target identification, strategies applied for in silico studies, software used, and challenges in adopting in silico methods for understanding the mechanisms of action of PHFs. This study can thus provide a better understanding of the application and types of in silico methods for investigating PHFs. International Registered Report Identifier (IRRID): PRR1-10.2196/56646 ", doi="10.2196/56646", url="https://www.researchprotocols.org/2024/1/e56646", url="http://www.ncbi.nlm.nih.gov/pubmed/38857494" } @Article{info:doi/10.2196/53784, author="Klein, R. Morgan and Darnall, D. Beth and You, S. Dokyoung", title="Feasibility of Web-Based Single-Session Empowered Relief in Patients With Chronic Pain Taking Methadone or Buprenorphine: Protocol for a Single-Arm Trial", journal="JMIR Res Protoc", year="2024", month="Jun", day="6", volume="13", pages="e53784", keywords="chronic pain", keywords="opioid use disorder", keywords="methadone", keywords="buprenorphine", keywords="behavioral medicine", keywords="telehealth", keywords="psychology", abstract="Background: Chronic pain affects tens of millions of US adults and continues to rise in prevalence. Nonpharmacologic behavioral pain treatments are greatly needed and yet are often inaccessible, particularly in settings where medication prescribing is prioritized. Objective: This study aims to test the feasibility of a live-instructor, web-based 1-session pain relief skills class in an underserved and potentially at-risk population: people with chronic pain prescribed methadone or buprenorphine either solely for pain or for comorbid opioid use disorder (OUD). Methods: This is a national, prospective, single-arm, uncontrolled feasibility trial. The trial is untethered from medical care; to enhance participants' willingness to join the study, no medical records or drug-monitoring records are accessed. At least 45 participants will be recruited from outpatient pain clinics and from an existing research database of individuals who have chronic pain and are taking methadone or buprenorphine. Patient-reported measures will be collected at 6 time points (baseline, immediately post treatment, 2 weeks, and months 1-3) via a web-based platform, paper, or phone formats to include individuals with limited internet or computer access and low literacy skills. At baseline, participants complete demographic questions and 13 study measures (Treatment Expectations, Body Pain Map, Medication Use, Pain Catastrophizing Scale [PCS], Patient-Reported Outcomes Measurement Information System [PROMIS] Measures, and Opioid Craving Scale). Immediately post treatment, a treatment satisfaction and acceptability measure is administered on a 0 (very dissatisfied) to 10 (completely satisfied) scale, with 3 of these items being the primary outcome (perceived usefulness, participant satisfaction, and likelihood of using the skills). At each remaining time point, the participants complete all study measures minus treatment expectations and satisfaction. Participants who do not have current OUD will be assessed for historical OUD, with presence of OUD (yes or no), and history of OUD (yes or no) reported separately. Feasibility threshold is set as an overall group treatment satisfaction rating of 8 of 10. In-depth qualitative interviews will be conducted with about 10 participants to obtain additional data on patient perceptions, satisfactions, needs, and wants. To assess preliminary efficacy, we will examine changes in pain catastrophizing, pain intensity, pain bothersomeness, sleep disturbance, pain interference, depression, anxiety, physical function, global impression of change, and opioid craving at 1 month post treatment. Results: This project opened to enrollment in September 2021 and completed the recruitment in October 2023. The data collection was completed in February 2024. Results are expected to be published in late 2024. Conclusions: Results from this trial will inform the feasibility and preliminary efficacy of Empowered Relief in this population and will inform the design of a future randomized controlled trial testing web-based Empowered Relief in chronic pain and comorbid OUD. Trial Registration: ClinicalTrials.gov NCT05057988; https://clinicaltrials.gov/study/NCT05057988 International Registered Report Identifier (IRRID): DERR1-10.2196/53784 ", doi="10.2196/53784", url="https://www.researchprotocols.org/2024/1/e53784", url="http://www.ncbi.nlm.nih.gov/pubmed/38843513" } @Article{info:doi/10.2196/56899, author="Nickel, Brooke and Heiss, Raffael and Shih, Patti and Gram, Grundtvig Emma and Copp, Tessa and Taba, Melody and Moynihan, Ray and Zadro, Joshua", title="Social Media Promotion of Health Tests With Potential for Overdiagnosis or Overuse: Protocol for a Content Analysis", journal="JMIR Res Protoc", year="2024", month="Jun", day="4", volume="13", pages="e56899", keywords="social media", keywords="influencers", keywords="tests", keywords="overdiagnosis", keywords="overuse", keywords="evidence-based medicine", keywords="promotion", abstract="Background: In recent years, social media have emerged as important spaces for commercial marketing of health tests, which can be used for the screening and diagnosis of otherwise generally healthy people. However, little is known about how health tests are promoted on social media, whether the information provided is accurate and balanced, and if there is transparency around conflicts of interest. Objective: This study aims to understand and quantify how social media is being used to discuss or promote health tests with the potential for overdiagnosis or overuse to generally healthy people. Methods: Content analysis of social media posts on the anti-Mullerian hormone test, whole-body magnetic resonance imaging scan, multicancer early detection, testosterone test, and gut microbe test from influential international social media accounts on Instagram and TikTok. The 5 tests have been identified as having the following criteria: (1) there are evidence-based concerns about overdiagnosis or overuse, (2) there is evidence or concerns that the results of tests do not lead to improved health outcomes for generally healthy people and may cause harm or waste, and (3) the tests are being promoted on social media to generally healthy people. English language text-only posts, images, infographics, articles, recorded videos including reels, and audio-only posts are included. Posts from accounts with <1000 followers as well as stories, live videos, and non-English posts are excluded. Using keywords related to the test, the top posts were searched and screened until there were 100 eligible posts from each platform for each test (total of 1000 posts). Data from the caption, video, and on-screen text are being summarized and extracted into a Microsoft Excel (Microsoft Corporation) spreadsheet and included in the analysis. The analysis will take a combined inductive approach when generating key themes and a deductive approach using a prespecified framework. Quantitative data will be analyzed in Stata SE (version 18.0; Stata Corp). Results: Data on Instagram and TikTok have been searched and screened. Analysis has now commenced. The findings will be disseminated via publications in peer-reviewed international medical journals and will also be presented at national and international conferences in late 2024 and 2025. Conclusions: This study will contribute to the limited evidence base on the nature of the relationship between social media and the problems of overdiagnosis and overuse of health care services. This understanding is essential to develop strategies to mitigate potential harm and plan solutions, with the aim of helping to protect members of the public from being marketed low-value tests, becoming patients unnecessarily, and taking resources away from genuine needs within the health system. International Registered Report Identifier (IRRID): DERR1-10.2196/56899 ", doi="10.2196/56899", url="https://www.researchprotocols.org/2024/1/e56899", url="http://www.ncbi.nlm.nih.gov/pubmed/38833693" } @Article{info:doi/10.2196/53703, author="Cardinale, Fabio and Barattini, Franco Dionisio and Sbrocca, Federica and Centi, Alessandro and Giuntini, Greta and Morariu Bordea, Maria and Herteg, Dorina and Rosu, Serban and Matei, Radu Cristian", title="The Effects of a Dietary Supplement (PediaFl{\`u}) Plus Standard of Care in Children With Acute Tonsillopharyngitis/Rhinopharyngitis: Protocol for a Randomized Controlled Trial", journal="JMIR Res Protoc", year="2024", month="May", day="31", volume="13", pages="e53703", keywords="dietary supplements", keywords="tonsillitis", keywords="pharyngitis", keywords="nasopharyngitis", keywords="Pelargonium", keywords="propolis", keywords="zinc", keywords="severity score", abstract="Background: A dietary supplement containing Pelargonium sidoides extract, propolis, zinc, and honey has been recently developed and proven to be an effective adjuvant in clinical practice for seasonal diseases and the treatment of respiratory tract disorders. Objective: This trial aims to verify the efficacy of the tested dietary supplement in a pediatric population with acute tonsillopharyngitis/rhinopharyngitis (ATR). Methods: The trial includes children aged between 3 and 10 years with ATR ?48 h, a negative rapid test for beta-hemolytic streptococcus or culture identification of nasal and/or pharyngeal exudates, and SARS-CoV-2 infection. The dietary supplement tested is an oral solution already on the market based on Pelagon P-70 (equivalent to Pelargonium sidoides d.e. 133.3 mg/100 ml), propolis, zinc, and honey. The product is administered at 5 ml 3 times a day for 6 days for children younger than 6 years and 10 ml 3 times a day for 6 days for children older than 6 years. The study design is open label, randomized, and controlled, with the tested dietary supplement plus standard of care (SoC) versus SoC alone. Patients are enrolled from 3 sites in Romania. The change in Tonsillitis Severity Score and number of treatment failures (using ibuprofen or high-dose paracetamol as rescue medication) are the primary end points. Based on the Tonsillitis Severity Score and the 2-sample comparison of the means formula with a 5\% significance level, 80\% power, and a minimally clinically important difference of 2 (SD 3.85) points, 120 patients are required. To account for potential screening failures and dropouts, we need to screen a population of approximately 150 children. Results: Patient enrollment began on June 3, 2021 (first patient's first visit), and ended on August 12, 2021 (last patient's last visit). The data collection period was from June 3, 2021, to September 16, 2021. The study was funded in February 2023. Data analysis is currently ongoing (April 2024). We expect the results to be published in a peer-reviewed clinical journal in the third quarter of 2024 and presented at scientific meetings in the last quarter of 2024. Conclusions: The data from this trial may help identify new adjuvant treatments for children with ATR when streptococcal infection is excluded by a negative rapid test, thereby avoiding unnecessary antibiotic administration. Trial Registration: ClinicalTrials.gov NCT04899401 https://clinicaltrials.gov/study/NCT04899401 International Registered Report Identifier (IRRID): DERR1-10.2196/53703 ", doi="10.2196/53703", url="https://www.researchprotocols.org/2024/1/e53703", url="http://www.ncbi.nlm.nih.gov/pubmed/38819917" } @Article{info:doi/10.2196/48572, author="Yue, Qi-Xuan and Ding, Ruo-Fan and Chen, Wei-Hao and Wu, Lv-Ying and Liu, Ke and Ji, Zhi-Liang", title="Mining Real-World Big Data to Characterize Adverse Drug Reaction Quantitatively: Mixed Methods Study", journal="J Med Internet Res", year="2024", month="May", day="3", volume="26", pages="e48572", keywords="clinical drug toxicity", keywords="adverse drug reaction", keywords="ADR severity", keywords="ADR frequency", keywords="mathematical model", abstract="Background: Adverse drug reactions (ADRs), which are the phenotypic manifestations of clinical drug toxicity in humans, are a major concern in precision clinical medicine. A comprehensive evaluation of ADRs is helpful for unbiased supervision of marketed drugs and for discovering new drugs with high success rates. Objective: In current practice, drug safety evaluation is often oversimplified to the occurrence or nonoccurrence of ADRs. Given the limitations of current qualitative methods, there is an urgent need for a quantitative evaluation model to improve pharmacovigilance and the accurate assessment of drug safety. Methods: In this study, we developed a mathematical model, namely the Adverse Drug Reaction Classification System (ADReCS) severity-grading model, for the quantitative characterization of ADR severity, a crucial feature for evaluating the impact of ADRs on human health. The model was constructed by mining millions of real-world historical adverse drug event reports. A new parameter called Severity\_score was introduced to measure the severity of ADRs, and upper and lower score boundaries were determined for 5 severity grades. Results: The ADReCS severity-grading model exhibited excellent consistency (99.22\%) with the expert-grading system, the Common Terminology Criteria for Adverse Events. Hence, we graded the severity of 6277 standard ADRs for 129,407 drug-ADR pairs. Moreover, we calculated the occurrence rates of 6272 distinct ADRs for 127,763 drug-ADR pairs in large patient populations by mining real-world medication prescriptions. With the quantitative features, we demonstrated example applications in systematically elucidating ADR mechanisms and thereby discovered a list of drugs with improper dosages. Conclusions: In summary, this study represents the first comprehensive determination of both ADR severity grades and ADR frequencies. This endeavor establishes a strong foundation for future artificial intelligence applications in discovering new drugs with high efficacy and low toxicity. It also heralds a paradigm shift in clinical toxicity research, moving from qualitative description to quantitative evaluation. ", doi="10.2196/48572", url="https://www.jmir.org/2024/1/e48572", url="http://www.ncbi.nlm.nih.gov/pubmed/38700923" } @Article{info:doi/10.2196/51587, author="Fink, Franziska and Kalter, Ivonne and Steindorff, Jenny-Victoria and Helmbold, Konrad Hans and Paulicke, Denny and Jahn, Patrick", title="Identifying Factors of User Acceptance of a Drone-Based Medication Delivery: User-Centered Design Approach", journal="JMIR Hum Factors", year="2024", month="Apr", day="30", volume="11", pages="e51587", keywords="human-drone interaction", keywords="medical supplies", keywords="participative research", keywords="user-centered design", keywords="technology acceptance", abstract="Background: The use of drones in the health care sector is increasingly being discussed against the background of the aging population and the growing shortage of skilled workers. In particular, the use of drones to provide medication in rural areas could bring advantages for the care of people with and without a need for care. However, there are hardly any data available that focus on the interaction between humans and drones. Objective: This study aims to disclose and analyze factors associated with user acceptance of drone-based medication delivery to derive practice-relevant guidance points for participatory technology development (for apps and drones). Methods: A controlled mixed methods study was conducted that supports the technical development process of an app design for drone-assisted drug delivery based on a participatory research design. For the quantitative analysis, established and standardized survey instruments to capture technology acceptance, such as the System Usability Scale; Technology Usage Inventory (TUI); and the Motivation, Engagement, and Thriving in User Experience model, were used. To avoid possible biasing effects from a continuous user development (eg, response shifts and learning effects), an ad hoc group was formed at each of the 3 iterative development steps and was subsequently compared with the consisting core group, which went through all 3 iterations. Results: The study found a positive correlation between the usability of a pharmacy drone app and participants' willingness to use it (r=0.833). Participants' perception of usefulness positively influenced their willingness to use the app (r=0.487; TUI). Skepticism had a negative impact on perceived usability and willingness to use it (r=?0.542; System Usability Scale and r=?0.446; TUI). The study found that usefulness, skepticism, and curiosity explained most of the intention to use the app (F3,17=21.12; P<.001; R2=0.788; adjusted R2=0.751). The core group showed higher ratings on the intention to use the pharmacy drone app than the ad hoc groups. Results of the 2-tailed t tests showed a higher rating on usability for the third iteration of the core group compared with the first iteration. Conclusions: With the help of the participatory design, important aspects of acceptance could be revealed by the people involved in relation to drone-assisted drug delivery. For example, the length of time spent using the technology is an important factor for the intention to use the app. Technology-specific factors such as user-friendliness or curiosity are directly related to the use acceptance of the drone app. Results of this study showed that the more participants perceived their own competence in handling the app, the more they were willing to use the technology and the more they rated the app as usable. ", doi="10.2196/51587", url="https://humanfactors.jmir.org/2024/1/e51587", url="http://www.ncbi.nlm.nih.gov/pubmed/38687589" } @Article{info:doi/10.2196/41557, author="Oyibo, Kiemute and Gonzalez, A. Paola and Ejaz, Sarah and Naheyan, Tasneem and Beaton, Carla and O'Donnell, Denis and Barker, R. James", title="Exploring the Use of Persuasive System Design Principles to Enhance Medication Incident Reporting and Learning Systems: Scoping Reviews and Persuasive Design Assessment", journal="JMIR Hum Factors", year="2024", month="Mar", day="21", volume="11", pages="e41557", keywords="medication incident", keywords="reporting system", keywords="persuasive technology", keywords="persuasive design", keywords="medication", keywords="persuasive system design", keywords="pharmacy", keywords="pharmaceutic", keywords="pharmacology", keywords="drug reporting", keywords="drug event", keywords="adverse event", keywords="incident management", abstract="Background: Medication incidents (MIs) causing harm to patients have far-reaching consequences for patients, pharmacists, public health, business practice, and governance policy. Medication Incident Reporting and Learning Systems (MIRLS) have been implemented to mitigate such incidents and promote continuous quality improvement in community pharmacies in Canada. They aim to collect and analyze MIs for the implementation of incident preventive strategies to increase safety in community pharmacy practice. However, this goal remains inhibited owing to the persistent barriers that pharmacies face when using these systems. Objective: This study aims to investigate the harms caused by medication incidents and technological barriers to reporting and identify opportunities to incorporate persuasive design strategies in MIRLS to motivate reporting. Methods: We conducted 2 scoping reviews to provide insights on the relationship between medication errors and patient harm and the information system--based barriers militating against reporting. Seven databases were searched in each scoping review, including PubMed, Public Health Database, ProQuest, Scopus, ACM Library, Global Health, and Google Scholar. Next, we analyzed one of the most widely used MIRLS in Canada using the Persuasive System Design (PSD) taxonomy---a framework for analyzing, designing, and evaluating persuasive systems. This framework applies behavioral theories from social psychology in the design of technology-based systems to motivate behavior change. Independent assessors familiar with MIRLS reported the degree of persuasion built into the system using the 4 categories of PSD strategies: primary task, dialogue, social, and credibility support. Results: Overall, 17 articles were included in the first scoping review, and 1 article was included in the second scoping review. In the first review, significant or serious harm was the most frequent harm (11/17, 65\%), followed by death or fatal harm (7/17, 41\%). In the second review, the authors found that iterative design could improve the usability of an MIRLS; however, data security and validation of reports remained an issue to be addressed. Regarding the MIRLS that we assessed, participants considered most of the primary task, dialogue, and credibility support strategies in the PSD taxonomy as important and useful; however, they were not comfortable with some of the social strategies such as cooperation. We found that the assessed system supported a number of persuasive strategies from the PSD taxonomy; however, we identified additional strategies such as tunneling, simulation, suggestion, praise, reward, reminder, authority, and verifiability that could further enhance the perceived persuasiveness and value of the system. Conclusions: MIRLS, equipped with persuasive features, can become powerful motivational tools to promote safer medication practices in community pharmacies. They have the potential to highlight the value of MI reporting and increase the readiness of pharmacists to report incidents. The proposed persuasive design guidelines can help system developers and community pharmacy managers realize more effective MIRLS. ", doi="10.2196/41557", url="https://humanfactors.jmir.org/2024/1/e41557", url="http://www.ncbi.nlm.nih.gov/pubmed/38512325" } @Article{info:doi/10.2196/55662, author="Wang, Kai-Hung and Shen, Hsuan-Shu and Chu, Sung-Chao and Wang, Tso-Fu and Lin, Ching-Wei and Huang, Wei-Han and Wu, Yi-Feng and Ho, Ching-Chun and Pang, Cheng-Yoong and Li, Chi-Cheng", title="Effectiveness of Chinese Herbal Medicine as a Complementary Treatment for Neutropenia Prevention and Immunity Modulation During Chemotherapy in Patients With Breast Cancer: Protocol for a Real-World Pragmatic Clinical Trial", journal="JMIR Res Protoc", year="2024", month="Mar", day="11", volume="13", pages="e55662", keywords="complementary treatment for cancer", keywords="neutropenia", keywords="real-world study", keywords="bedside to bench study", keywords="immune cell profile", keywords="programmed cell death protein 1", keywords="PD-1", keywords="breast cancer", keywords="breast", keywords="cancer", keywords="oncology", keywords="Chinese medicine", keywords="herb", keywords="herbs", keywords="herbal", keywords="complementary", keywords="immunity", keywords="immunology", keywords="immunomodulation", keywords="immunological", keywords="neutrophil", keywords="chemotherapy", keywords="blood cell", keywords="blood cells", abstract="Background: In recent years, advancements in cancer treatment have enabled cancer cell inhibition, leading to improved patient outcomes. However, the side effects of chemotherapy, especially leukopenia, impact patients' ability to tolerate their treatments and affect their quality of life. Traditional Chinese medicine is thought to provide complementary cancer treatment to improve the quality of life and prolong survival time among patients with cancer. Objective: This study aims to evaluate the effectiveness of Chinese herbal medicine (CHM) as a complementary treatment for neutropenia prevention and immunity modulation during chemotherapy in patients with breast cancer. Methods: We will conduct a real-world pragmatic clinical trial to evaluate the effectiveness of CHM as a supplementary therapy to prevent neutropenia in patients with breast cancer undergoing chemotherapy. Patients will be classified into CHM or non-CHM groups based on whether they received CHM during chemotherapy. Using generalized estimating equations or repeated measures ANOVA, we will assess differences in white blood cell counts, absolute neutrophil counts, immune cells, and programmed cell death protein 1 (PD-1) expression levels between the 2 groups. Results: This study was approved by the research ethics committee of Hualien Tzu Chi Hospital (IRB 110-168-A). The enrollment process began in September 2021 and will stop in December 2024. A total of 140 patients will be recruited. Data cleaning and analysis are expected to finish in the middle of 2025. Conclusions: Traditional Chinese medicine is the most commonly used complementary medicine, and it has been reported to significantly alleviate chemotherapy-related side effects. This study's findings may contribute to developing effective interventions targeting chemotherapy-related neutropenia among patients with breast cancer in clinical practice. Trial Registration: International Traditional Medicine Clinical Trial Registry ITMCTR2023000054; https://tinyurl.com/yc353hes International Registered Report Identifier (IRRID): DERR1-10.2196/55662 ", doi="10.2196/55662", url="https://www.researchprotocols.org/2024/1/e55662", url="http://www.ncbi.nlm.nih.gov/pubmed/38466979" } @Article{info:doi/10.2196/45202, author="Kim, Dohyun and Choi, Hyun-Soo and Lee, DongHoon and Kim, Minkyu and Kim, Yoon and Han, Seon-Sook and Heo, Yeonjeong and Park, Ju-Hee and Park, Jinkyeong", title="A Deep Learning--Based Approach for Prediction of Vancomycin Treatment Monitoring: Retrospective Study Among Patients With Critical Illness", journal="JMIR Form Res", year="2024", month="Mar", day="8", volume="8", pages="e45202", keywords="critically ill", keywords="deep learning", keywords="inflammation", keywords="machine learning", keywords="pharmacokinetic", keywords="therapeutic drug monitoring", keywords="vancomycin", abstract="Background: Vancomycin pharmacokinetics are highly variable in patients with critical illnesses, and clinicians commonly use population pharmacokinetic (PPK) models based on a Bayesian approach to dose. However, these models are population-dependent, may only sometimes meet the needs of individual patients, and are only used by experienced clinicians as a reference for making treatment decisions. To assist real-world clinicians, we developed a deep learning--based decision-making system that predicts vancomycin therapeutic drug monitoring (TDM) levels in patients in intensive care unit. Objective: This study aimed to establish joint multilayer perceptron (JointMLP), a new deep-learning model for predicting vancomycin TDM levels, and compare its performance with the PPK models, extreme gradient boosting (XGBoost), and TabNet. Methods: We used a 977-case data set split into training and testing groups in a 9:1 ratio. We performed external validation of the model using 1429 cases from Kangwon National University Hospital and 2394 cases from the Medical Information Mart for Intensive Care--IV (MIMIC-IV). In addition, we performed 10-fold cross-validation on the internal training data set and calculated the 95\% CIs using the metric. Finally, we evaluated the generalization ability of the JointMLP model using the MIMIC-IV data set. Results: Our JointMLP model outperformed other models in predicting vancomycin TDM levels in internal and external data sets. Compared to PPK, the JointMLP model improved predictive power by up to 31\% (mean absolute error [MAE] 6.68 vs 5.11) on the internal data set and 81\% (MAE 11.87 vs 6.56) on the external data set. In addition, the JointMLP model significantly outperforms XGBoost and TabNet, with a 13\% (MAE 5.75 vs 5.11) and 14\% (MAE 5.85 vs 5.11) improvement in predictive accuracy on the inner data set, respectively. On both the internal and external data sets, our JointMLP model performed well compared to XGBoost and TabNet, achieving prediction accuracy improvements of 34\% and 14\%, respectively. Additionally, our JointMLP model showed higher robustness to outlier data than the other models, as evidenced by its higher root mean squared error performance across all data sets. The mean errors and variances of the JointMLP model were close to zero and smaller than those of the PPK model in internal and external data sets. Conclusions: Our JointMLP approach can help optimize treatment outcomes in patients with critical illnesses in an intensive care unit setting, reducing side effects associated with suboptimal vancomycin administration. These include increased risk of bacterial resistance, extended hospital stays, and increased health care costs. In addition, the superior performance of our model compared to existing models highlights its potential to help real-world clinicians. ", doi="10.2196/45202", url="https://formative.jmir.org/2024/1/e45202", url="http://www.ncbi.nlm.nih.gov/pubmed/38152042" } @Article{info:doi/10.2196/50513, author="Fogel, L. Evan and Easler, J. Jeffrey and Yuan, Ying and Yadav, Dhiraj and Conwell, L. Darwin and Vege, Swaroop Santhi and Han, Y. Samuel and Park, Walter and Patrick, Vanessa and White, A. Fletcher", title="Safety, Tolerability, and Dose-Limiting Toxicity of Lacosamide in Patients With Painful Chronic Pancreatitis: Protocol for a Phase 1 Clinical Trial to Determine Safety and Identify Side Effects", journal="JMIR Res Protoc", year="2024", month="Mar", day="7", volume="13", pages="e50513", keywords="abdominal pain", keywords="opioid-induced hyperalgesia", keywords="pain", keywords="abdomen", keywords="protocol", keywords="toxicity", keywords="toxic", keywords="lacosamide", keywords="pancreas", keywords="pancreatitis", keywords="opioid", abstract="Background: Chronic abdominal pain is the hallmark symptom of chronic pancreatitis (CP), with 50\% to 80\% of patients seeking medical attention for pain control. Although several management options are available, outcomes are often disappointing, and opioids remain a mainstay of therapy. Opioid-induced hyperalgesia is a phenomenon resulting in dose escalation, which may occur partly because of the effects of opioids on voltage-gated sodium channels associated with pain. Preclinical observations demonstrate that the combination of an opioid and the antiseizure drug lacosamide diminishes opioid-induced hyperalgesia and improves pain control. Objective: In this phase 1 trial, we aim to determine the safety, tolerability, and dose-limiting toxicity of adding lacosamide to opioids for the treatment of painful CP and assess the feasibility of performance of a pilot study of adding lacosamide to opioid therapy in patients with CP. As an exploratory aim, we will assess the efficacy of adding lacosamide to opioid therapy in patients with painful CP. Methods: Using the Bayesian optimal interval design, we will conduct a dose-escalation trial of adding lacosamide to opioid therapy in patients with painful CP enrolled in cohorts of size 3. The initial dose will be 50 mg taken orally twice a day, followed by incremental increases to a maximum dose of 400 mg/day, with lacosamide administered for 7 days at each dose level. Adverse events will be documented according to Common Terminology Criteria for Adverse Events (version 5.0). Results: As of December 2023, we have currently enrolled 6 participants. The minimum number of participants to be enrolled is 12 with a maximum of 24. We expect to publish the results by March 2025. Conclusions: This trial will test the feasibility of the study design and provide reassurance regarding the tolerability and safety of opioids in treating painful CP. It is anticipated that lacosamide will prove to be safe and well tolerated, supporting a subsequent phase 2 trial assessing the efficacy of lacosamide+opioid therapy in patients with painful CP, and that lacosamide combined with opiates will lower the opioid dose necessary for pain relief and improve the safety profile of opioid use in treating painful CP. Trial Registration: Clinicaltrials.gov NCT05603702; https://clinicaltrials.gov/study/NCT05603702 International Registered Report Identifier (IRRID): PRR1-10.2196/50513 ", doi="10.2196/50513", url="https://www.researchprotocols.org/2024/1/e50513", url="http://www.ncbi.nlm.nih.gov/pubmed/38451604" } @Article{info:doi/10.2196/54882, author="Kitahiro, Yumi and Yamamoto, Kazuhiro and Yakushijin, Kimikazu and Ioroi, Takeshi and Tanda, Masaaki and Itohara, Kotaro and Omura, Tomohiro and Minami, Hironobu and Yano, Ikuko", title="The Efficacy of Bepotastine Besilate Compared With Hydroxyzine Pamoate for Preventing Infusion Reactions to the First Dose of Rituximab in Patients With Non-Hodgkin Lymphoma: Protocol for a Phase II, Double-Blind, Multicenter Randomized Trial", journal="JMIR Res Protoc", year="2024", month="Feb", day="22", volume="13", pages="e54882", keywords="non-Hodgkin lymphoma", keywords="rituximab", keywords="infusion reactions", keywords="bepotastine besilate", keywords="histamine H1-receptor antagonist", keywords="hydroxyzine pamoate", keywords="drowsiness", abstract="Background: Rituximab, an anti-CD20 monoclonal antibody, can cause infusion reactions (IRs), especially during the initial rituximab infusion therapy. Generally, patients are administered a histamine H1-receptor antagonist before the rituximab infusion, along with an antipyretic analgesic, to prevent or reduce IRs. Multiple retrospective case-control studies indicate that the second generation of histamine H1-receptor antagonists might be more effective than the first generation in suppressing IRs caused by the rituximab infusion. Objective: This study aimed to assess the efficacy of first- and second-generation histamine H1-receptor antagonists for preventing IRs resulting from the initial infusion of rituximab in patients diagnosed with non-Hodgkin lymphoma. Methods: This is a phase II, double-blind, active-controlled randomized trial. It will be a multicenter study conducted across 3 facilities that aims to enroll a total of 40 patients diagnosed with non-Hodgkin lymphoma who will receive their initial rituximab infusion. Participating patients will be administered hydroxyzine pamoate or bepotastine besilate, representing first- or second-generation histamine H1-receptor antagonists, respectively. This will be combined with 400-mg acetaminophen tablets taken approximately 30 minutes before the first infusion of rituximab. The primary end point of this trial is to assess severe IRs, equivalent to grade 2 or higher as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, that occur within a 4-hour period after the initiation of rituximab infusion. The secondary end points include assessing the severity of the initial IR, the maximum severity of the IR, and the duration between rituximab infusion initiation and the onset of the first IR within a 4-hour period. Additionally, the trial will evaluate histamine H1-receptor antagonist--induced drowsiness using the visual analogue scale, with each patient providing their individual response. Results: This study began with patient recruitment in April 2023, with 17 participants enrolled as of November 12, 2023. The anticipated study completion is set for February 2026. Conclusions: This study is the first randomized controlled trial comparing the effects of oral first- and second-generation histamine H1-receptor antagonists in preventing IRs induced by the initial administration of rituximab. The findings from this study hold the potential to establish the rationale for a phase III study aimed at determining the standard premedication protocol for rituximab infusion. Trial Registration: Japan Registry of Clinical Trials jRCTs051220169; https://jrct.niph.go.jp/latest-detail/jRCTs051220169 International Registered Report Identifier (IRRID): DERR1-10.2196/54882 ", doi="10.2196/54882", url="https://www.researchprotocols.org/2024/1/e54882", url="http://www.ncbi.nlm.nih.gov/pubmed/38386393" } @Article{info:doi/10.2196/54217, author="Olsson, Eva Sofia and Sreepad, Bhavana and Lee, Trevor and Fasih, Manal and Fijany, Arman", title="Public Interest in Acetyl Hexapeptide-8: Longitudinal Analysis", journal="JMIR Dermatol", year="2024", month="Feb", day="20", volume="7", pages="e54217", keywords="acetyl-hexapeptide-8", keywords="anti-aging", keywords="anti-wrinkle", keywords="Argireline", keywords="BoNT", keywords="botox", keywords="botulinum neurotoxin", keywords="cosmetic dermatology", keywords="cosmetic", keywords="dermatologist", keywords="dermatology", keywords="injectable neurotoxin", keywords="neurotoxin", keywords="skin specialist", keywords="topical agent", keywords="topical", abstract="Background: Acetyl hexapeptide-8, also known as Argireline, is a topical, short-acting, synthetic peptide that has recently gained popularity for its antiwrinkle effects. This agent has emerged as a more accessible alternative to botulinum neurotoxin. Objective: This study evaluates the public interest in acetyl hexapeptide-8 in the United States from 2013 to 2023, as described by search volume on Google, the most-used search engine. Methods: We analyzed the longitudinal relative monthly search volume from January 1, 2013, to January 1, 2023, for acetyl hexapeptide--related terms. We compared the internet search trends for ``Botox'' during this period to ``Argireline.'' Results: The terms ``Argireline'' and ``Botox in a Bottle'' both had substantial increases in search volume in 2022. Although its search volume is drastically increasing, ``Argireline'' was less searched than ``Botox,'' which had a stable, up-trending search volume over the past decade. Conclusions: The increasing interest in acetyl hexapeptide-8 may be due to its cost-effectiveness and use as a botulinum neurotoxin alternative. Affordability, over-the-counter availability, and ease of self-application of the agent suggest its potential to enhance accessibility to cosmetic dermatologic care. ", doi="10.2196/54217", url="https://derma.jmir.org/2024/1/e54217", url="http://www.ncbi.nlm.nih.gov/pubmed/38376906" } @Article{info:doi/10.2196/49755, author="Jeon, Min Soo and Lim, HyunJoo and Cheon, Hyo-bin and Ryu, Juhee and Kwon, Jin-Won", title="Assessing the Labeling Information on Drugs Associated With Suicide Risk: Systematic Review", journal="JMIR Public Health Surveill", year="2024", month="Jan", day="30", volume="10", pages="e49755", keywords="suicide", keywords="adverse drug events", keywords="review", keywords="drug", keywords="mental health", keywords="systematic review", keywords="drug induced suicide", keywords="drug reaction", keywords="substance use", keywords="suicidal", keywords="medication", keywords="suicide symptoms", keywords="suicidal risk", keywords="drugs", keywords="adverse drug event", abstract="Background: Drug-induced suicide (DIS) is a severe adverse drug reaction (ADR). Although clinical trials have provided evidence on DIS, limited investigations have been performed on rare ADRs, such as suicide. Objective: We aimed to systematically review case reports on DIS to provide evidence-based drug information. Methods: We searched PubMed to obtain case reports regarding DIS published until July 2021. Cases resulting from drugs that are no longer used or are nonapproved, substance use, and suicidal intentions were excluded. The quality of each case report was assessed using the CASE (Case Reports) checklist. We extracted data regarding demographics, medication history, suicide symptoms, and symptom improvement and evaluated the causality of DIS using the Naranjo score. Furthermore, to identify the potential suicidal risk of the unknown drugs, we compared the results of the causality assessment with those of the approved drug labels. Results: In 83 articles, we identified 152 cases involving 61 drugs. Antidepressants were reported as the most frequent causative drugs of DIS followed by immunostimulants. The causality assessment revealed 61 cases having possible, 89 cases having probable, and 2 cases having definite relationships with DIS. For approximately 85\% of suspected drugs, the risk of suicidal ADRs was indicated on the approved label; however, the approved labels for 9 drugs, including lumacaftor/ivacaftor, doxycycline, clozapine, dextromethorphan, adalimumab, infliximab, piroxicam, paclitaxel, and formoterol, did not provide information about these risks. Conclusions: We found several case reports involving drugs without suicide risk information on the drug label. Our findings might provide valuable insights into drugs that may cause suicidal ADRs. ", doi="10.2196/49755", url="https://publichealth.jmir.org/2024/1/e49755", url="http://www.ncbi.nlm.nih.gov/pubmed/38289650" } @Article{info:doi/10.2196/50110, author="Ben-Aharon, Irit and Rotem, Ran and Melzer-Cohen, Cheli and Twig, Gilad and Cercek, Andrea and Half, Elizabeth and Goshen-Lago, Tal and Chodik, Gabriel and Kelsen, David", title="Pharmaceutical Agents as Potential Drivers in the Development of Early-Onset Colorectal Cancer: Case-Control Study", journal="JMIR Public Health Surveill", year="2023", month="Dec", day="13", volume="9", pages="e50110", keywords="early onset colorectal cancer", keywords="pharmaceutical agents", keywords="increased risk", keywords="colorectal cancer", keywords="health provider", keywords="Israel", keywords="machine learning", keywords="decision tree", keywords="gradient boosting", keywords="risk factors", keywords="decision support", keywords="risk", keywords="risks", keywords="colorectal", keywords="cancer", keywords="oncology", keywords="internal medicine", keywords="gastroenterology", keywords="gastrointestinal", keywords="pharmaceutical", keywords="pharmaceuticals", keywords="drug", keywords="drugs", abstract="Background: The incidence of early-onset colorectal cancer (EOCRC) rose abruptly in the mid 1990s, is continuing to increase, and has now been noted in many countries. By 2030, 25\% of American patients diagnosed with rectal cancer will be 49 years or younger. The large majority of EOCRC cases are not found in patients with germline cancer susceptibility mutations (eg, Lynch syndrome) or inflammatory bowel disease. Thus, environmental or lifestyle factors are suspected drivers. Obesity, sedentary lifestyle, diabetes mellitus, smoking, alcohol, or antibiotics affecting the gut microbiome have been proposed. However, these factors, which have been present since the 1950s, have not yet been conclusively linked to the abrupt increase in EOCRC. The sharp increase suggests the introduction of a new risk factor for young people. We hypothesized that the driver may be an off-target effect of a pharmaceutical agent (ie, one requiring regulatory approval before its use in the general population or an off-label use of a previously approved agent) in a genetically susceptible subgroup of young adults. If a pharmaceutical agent is an EOCRC driving factor, regulatory risk mitigation strategies could be used. Objective: We aimed to evaluate the possibility that pharmaceutical agents serve as risk factors for EOCRC. Methods: We conducted a case-control study. Data including demographics, comorbidities, and complete medication dispensing history were obtained from the electronic medical records database of Maccabi Healthcare Services, a state-mandated health provider covering 26\% of the Israeli population. The participants included 941 patients with EOCRC (?50 years of age) diagnosed during 2001-2019 who were density matched at a ratio of 1:10 with 9410 control patients. Patients with inflammatory bowel disease and those with a known inherited cancer susceptibility syndrome were excluded. An advanced machine learning algorithm based on gradient boosted decision trees coupled with Bayesian model optimization and repeated data sampling was used to sort through the very high-dimensional drug dispensing data to identify specific medication groups that were consistently linked with EOCRC while allowing for synergistic or antagonistic interactions between medications. Odds ratios for the identified medication classes were obtained from a conditional logistic regression model. Results: Out of more than 800 medication classes, we identified several classes that were consistently associated with EOCRC risk across independently trained models. Interactions between medication groups did not seem to substantially affect the risk. In our analysis, drug groups that were consistently positively associated with EOCRC included beta blockers and valerian (Valeriana officinalis). Antibiotics were not consistently associated with EOCRC risk. Conclusions: Our analysis suggests that the development of EOCRC may be correlated with prior use of specific medications. Additional analyses should be used to validate the results. The mechanism of action inducing EOCRC by candidate pharmaceutical agents will then need to be determined. ", doi="10.2196/50110", url="https://publichealth.jmir.org/2023/1/e50110", url="http://www.ncbi.nlm.nih.gov/pubmed/37933755" } @Article{info:doi/10.2196/50894, author="Chen, Hongli and Hao, Jingjing and Hu, Jing and Song, Chang and Zhou, Yesheng and Li, Miaomiao and Chen, Jin and Liu, Xiu and Wang, Dong and Xu, Xiaoshan and Xin, Peixian and Zhang, Jiaxin and Liao, Lingjie and Feng, Yi and Li, Dan and Pan, W. Stephen and Shao, Yiming and Ruan, Yuhua and Xing, Hui", title="Pretreatment HIV Drug Resistance and the Molecular Transmission Network Among HIV-Positive Individuals in China in 2022: Multicenter Observational Study", journal="JMIR Public Health Surveill", year="2023", month="Nov", day="17", volume="9", pages="e50894", keywords="HIV", keywords="human immunodeficiency virus", keywords="mutation", keywords="pretreatment drug resistance", keywords="risk factors", keywords="molecular transmission network", abstract="Background: Emerging HIV drug resistance caused by increased usage of antiretroviral drugs (ARV) could jeopardize the success of standardized HIV management protocols in resource-limited settings. Objective: We aimed to characterize pretreatment HIV drug resistance (PDR) among HIV-positive individuals and risk factors in China in 2022. Methods: This cross-sectional study was conducted using 2-stage systematic sampling according to the World Health Organization's surveillance guidelines in 8 provincial-level administrative divisions in 2022. Demographic information and plasma samples were obtained from study participants. PDR was analyzed using the Stanford HIV drug resistance database, and the Tamura-Nei 93 model in HIV-TRACE was used to calculate pairwise matches with a genetic distance of 0.01 substitutions per site. Logistic regression was used to identify and estimate factors associated with PDR. Results: PDR testing was conducted on 2568 participants in 2022. Of the participants, 34.8\% (n=893) were aged 30-49 years, 81.4\% (n=2091) were male, and 3.2\% (n=81) had prior ARV exposure. The prevalence of PDR to protease and reverse transcriptase regions, nonnucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors were 7.4\% (n=190), 6.3\% (n=163), 1.2\% (n=32), and 0.2\% (n=5), respectively. Yunnan, Jilin, and Zhejiang had much higher PDR incidence than did Sichuan. The prevalence of nonnucleoside reverse transcriptase inhibitor--related drug resistance was 6.1\% (n=157) for efavirenz and 6.3\% (n=163) for nevirapine. Multivariable logistic regression models indicated that participants who had prior ARV exposure (odds ratio [OR] 7.45, 95\% CI 4.50-12.34) and the CRF55\_01B HIV subtype (OR 2.61, 95\% CI 1.41-4.83) were significantly associated with PDR. Among 618 (24.2\%) sequences (nodes) associated with 253 molecular transmission clusters (size range 2-13), drug resistance mutation sites included K103, E138, V179, P225, V106, V108, L210, T215, P225, K238, and A98. Conclusions: The overall prevalence of PDR in China in 2022 was modest. Targeted genotypic PDR testing and medication compliance interventions must be urgently expanded to address PDR among newly diagnosed people living with HIV in China. ", doi="10.2196/50894", url="https://publichealth.jmir.org/2023/1/e50894", url="http://www.ncbi.nlm.nih.gov/pubmed/37976080" } @Article{info:doi/10.2196/48368, author="Estarreja, Jo{\~a}o and Caldeira, Gon{\c{c}}alo and Silva, In{\^e}s and Mendes, Priscila and Mateus, Vanessa", title="The Pharmacological Effect of Hemin in Inflammatory-Related Diseases: Protocol for a Systematic Review", journal="JMIR Res Protoc", year="2023", month="Nov", day="16", volume="12", pages="e48368", keywords="hemin", keywords="inflammation", keywords="animal models", keywords="nonclinical studies", keywords="in vivo", abstract="Background: Hemin is a commonly used drug in the treatment of acute attacks of porphyria, due to its capability of restoring normal levels of hemoproteins and respiratory pigments. In addition, this drug has demonstrated the capacity to induce the heme oxygenase (HO) enzyme. At the moment, there are 3 known HO isoenzymes in mammals: HO-1, HO-2, and HO-3. The first of these shows cytoprotective, antioxidant, and anti-inflammatory effects. Currently, medicines used in inflammatory disorders have increased toxicity, especially over longer time frames, which highlights the need to investigate new, safer options. Indeed, the current nonclinical evidence demonstrates the potential that hemin has a significant anti-inflammatory effect in several animal models of inflammation-related diseases, such as experimental colitis, without significant side effects. However, the underlying mechanism(s) are still not fully understood. In addition, past nonclinical studies have applied different therapeutic regimens, making it relatively difficult to understand which is optimal. According to the literature, there is a lack of review articles discussing this topic, highlighting the need for a summary and analysis of the available preclinical evidence to elucidate the abovementioned issues. Therefore, a qualitative synthesis of the current evidence is essential for the research and medical communities. Objective: This systematic review aims to summarize and analyze currently available nonclinical data to ascertain the potential anti-inflammatory effect of hemin in animal models. Methods: Throughout the development of this protocol, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The comprehensive search strategy will be carried out in MEDLINE (PubMed), Web of Science, and Scopus without any filters associated with publication date. Only in vivo, nonclinical studies that evaluated the potential anti-inflammatory effect of hemin will be included. The evaluated outcomes will be the observed clinical signs, inflammatory and other biochemical markers, and macroscopic and microscopic evaluations. To analyze the potential risk of bias, we will use the risk of bias tool developed by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE). Results: Currently, it is not possible to disclose any results since the project is still in initial steps. More specifically, we are currently engaged in the identification of eligible articles through the application of the inclusion and exclusion criteria. The work was initiated in April 2023, and it is expected to be finished at the end of 2023. Conclusions: Concerning the major gap in the literature regarding the underlying mechanism(s) and treatment-related properties, this systematic review will be essential to clearly summarize and critically analyze the nonclinical data available, promoting a clearer vision of the potential anti-inflammatory effect of hemin. Trial Registration: PROSPERO CRD42023406160; https://www.crd.york.ac.uk/prospero/display\_record.php?RecordID=406160 International Registered Report Identifier (IRRID): PRR1-10.2196/48368 ", doi="10.2196/48368", url="https://www.researchprotocols.org/2023/1/e48368", url="http://www.ncbi.nlm.nih.gov/pubmed/37971806" } @Article{info:doi/10.2196/45225, author="Lou, Pei and Fang, An and Zhao, Wanqing and Yao, Kuanda and Yang, Yusheng and Hu, Jiahui", title="Potential Target Discovery and Drug Repurposing for Coronaviruses: Study Involving a Knowledge Graph--Based Approach", journal="J Med Internet Res", year="2023", month="Oct", day="20", volume="25", pages="e45225", keywords="coronavirus", keywords="heterogeneous data integration", keywords="knowledge graph embedding", keywords="drug repurposing", keywords="interpretable prediction", keywords="COVID-19", abstract="Background: The global pandemics of severe acute respiratory syndrome, Middle East respiratory syndrome, and COVID-19 have caused unprecedented crises for public health. Coronaviruses are constantly evolving, and it is unknown which new coronavirus will emerge and when the next coronavirus will sweep across the world. Knowledge graphs are expected to help discover the pathogenicity and transmission mechanism of viruses. Objective: The aim of this study was to discover potential targets and candidate drugs to repurpose for coronaviruses through a knowledge graph--based approach. Methods: We propose a computational and evidence-based knowledge discovery approach to identify potential targets and candidate drugs for coronaviruses from biomedical literature and well-known knowledge bases. To organize the semantic triples extracted automatically from biomedical literature, a semantic conversion model was designed. The literature knowledge was associated and integrated with existing drug and gene knowledge through semantic mapping, and the coronavirus knowledge graph (CovKG) was constructed. We adopted both the knowledge graph embedding model and the semantic reasoning mechanism to discover unrecorded mechanisms of drug action as well as potential targets and drug candidates. Furthermore, we have provided evidence-based support with a scoring and backtracking mechanism. Results: The constructed CovKG contains 17,369,620 triples, of which 641,195 were extracted from biomedical literature, covering 13,065 concept unique identifiers, 209 semantic types, and 97 semantic relations of the Unified Medical Language System. Through multi-source knowledge integration, 475 drugs and 262 targets were mapped to existing knowledge, and 41 new drug mechanisms of action were found by semantic reasoning, which were not recorded in the existing knowledge base. Among the knowledge graph embedding models, TransR outperformed others (mean reciprocal rank=0.2510, Hits@10=0.3505). A total of 33 potential targets and 18 drug candidates were identified for coronaviruses. Among them, 7 novel drugs (ie, quinine, nelfinavir, ivermectin, asunaprevir, tylophorine, Artemisia annua extract, and resveratrol) and 3 highly ranked targets (ie, angiotensin converting enzyme 2, transmembrane serine protease 2, and M protein) were further discussed. Conclusions: We showed the effectiveness of a knowledge graph--based approach in potential target discovery and drug repurposing for coronaviruses. Our approach can be extended to other viruses or diseases for biomedical knowledge discovery and relevant applications. ", doi="10.2196/45225", url="https://www.jmir.org/2023/1/e45225", url="http://www.ncbi.nlm.nih.gov/pubmed/37862061" } @Article{info:doi/10.2196/45263, author="Thai-Van, Hung and Valnet-Rabier, Marie-Blanche and Anciaux, Ma{\"e}va and Lambert, Aude and Maurier, Ana{\"i}s and Cottin, Judith and Pietri, Tessa and Dest{\`e}re, Alexandre and Damin-Pernik, Marl{\`e}ne and Perrouin, Fanny and Bagheri, Haleh", title="Safety Signal Generation for Sudden Sensorineural Hearing Loss Following Messenger RNA COVID-19 Vaccination: Postmarketing Surveillance Using the French Pharmacovigilance Spontaneous Reporting Database", journal="JMIR Public Health Surveill", year="2023", month="Jul", day="14", volume="9", pages="e45263", keywords="mRNA COVID-19 vaccine", keywords="COVID-19", keywords="messenger RNA", keywords="tozinameran", keywords="elasomeran", keywords="sudden sensorineural hearing loss", keywords="audiogram", keywords="positive rechallenge", keywords="spontaneous reporting", keywords="postmarketing", keywords="surveillance", keywords="pharmacovigilance", abstract="Background: The World Health Organization recently described sudden sensorineural hearing loss (SSNHL) as a possible adverse effect of COVID-19 vaccines. Recent discordant pharmacoepidemiologic studies invite robust clinical investigations of SSNHL after COVID-19 messenger RNA (mRNA) vaccines. This postmarketing surveillance study, overseen by French public health authorities, is the first to clinically document postvaccination SSNHL and examine the role of potential risk factors. Objective: This nationwide study aimed to assess the relationship between SSNHL and exposure to mRNA COVID-19 vaccines and estimate the reporting rate (Rr) of SSNHL after mRNA vaccination per 1 million doses (primary outcome). Methods: We performed a retrospective review of all suspected cases of SSNHL after mRNA COVID-19 vaccination spontaneously reported in France between January 2021 and February 2022 based on a comprehensive medical evaluation, including the evaluation of patient medical history, side and range of hearing loss, and hearing recovery outcomes after a minimum period of 3 months. The quantification of hearing loss and assessment of hearing recovery outcomes were performed according to a grading system modified from the Siegel criteria. A cutoff of 21 days was used for the delay onset of SSNHL. The primary outcome was estimated using the total number of doses of each vaccine administered during the study period in France as the denominator. Results: From 400 extracted cases for tozinameran and elasomeran, 345 (86.3\%) spontaneous reports were selected. After reviewing complementary data, 49.6\% (171/345) of documented cases of SSNHL were identified. Of these, 83\% (142/171) of SSNHL cases occurred after tozinameran vaccination: Rr=1.45/1,000,000 injections; no difference for the rank of injections; complete recovery in 22.5\% (32/142) of cases; median delay onset before day 21=4 days (median age 51, IQR 13-83 years); and no effects of sex. A total of 16.9\% (29/171) of SSNHL cases occurred after elasomeran vaccination: Rr=1.67/1,000,000 injections; rank effect in favor of the first injection (P=.03); complete recovery in 24\% (7/29) of cases; median delay onset before day 21=8 days (median age 47, IQR 33-81 years); and no effects of sex. Autoimmune, cardiovascular, or audiovestibular risk factors were present in approximately 29.8\% (51/171) of the cases. SSNHL was more often unilateral than bilateral for both mRNA vaccines (P<.001 for tozinameran; P<.003 for elasomeran). There were 13.5\% (23/142) of cases of profound hearing loss, among which 74\% (17/23) did not recover a serviceable ear. A positive rechallenge was documented for 8 cases. Conclusions: SSNHL after COVID-19 mRNA vaccines are very rare adverse events that do not call into question the benefits of mRNA vaccines but deserve to be known given the potentially disabling impact of sudden deafness. Therefore, it is essential to properly characterize postinjection SSNHL, especially in the case of a positive rechallenge, to provide appropriate individualized recommendations. ", doi="10.2196/45263", url="https://publichealth.jmir.org/2023/1/e45263", url="http://www.ncbi.nlm.nih.gov/pubmed/37071555" } @Article{info:doi/10.2196/38167, author="Constance, E. Jonathan and McFarland, M. Mary and Casucci, Tallie and Deininger, W. Michael and Enioutina, Y. Elena and Job, Kathleen and Lemons, S. Richard and Lim, S. Carol and Ward, M. Robert and Yellepeddi, Venkata and Watt, M. Kevin", title="Mapping the Evidence for Opioid-Mediated Changes in Malignancy and Chemotherapeutic Efficacy: Protocol for a Scoping Review", journal="JMIR Res Protoc", year="2023", month="May", day="22", volume="12", pages="e38167", keywords="opioid", keywords="opioid receptor", keywords="drug", keywords="cocaine", keywords="crack", keywords="prescription opioid", keywords="opium", keywords="war on drug", keywords="cancer", keywords="chemotherapy", keywords="drug-drug interaction", keywords="malignancy", keywords="treatment", keywords="oncology", keywords="tumor", keywords="survival", keywords="antineoplastic", keywords="cancer cell", keywords="scoping", keywords="chemotherapeutic", keywords="librarian", keywords="library science", keywords="antineoplast", keywords="cancer cell survival", keywords="cancer cell growth", keywords="addict", keywords="addiction", abstract="Background: Numerous reports contend opioids can augment or inhibit malignancy. At present, there is no consensus on the risk or benefit posed by opioids on malignancy or chemotherapeutic activity. Distinguishing the consequences of opioid use from pain and its management is challenging. Additionally, opioid concentration data is often lacking in clinical studies. A scoping review approach inclusive of preclinical and clinical data will improve our understanding of the risk-benefit relationship concerning commonly prescribed opioids and cancer and cancer treatment. Objective: The aim of the study is to map diverse studies spanning from preclinical to clinical regarding opioids with malignancy and its treatment. Methods: This scoping review will use the Arksey six stages framework to (1) identify the research question; (2) identify relevant studies; (3) select studies meeting criteria; (4) extract and chart data; (5) collate, summarize, and report results; and (6) conduct expert consultation. An initial pilot study was undertaken to (1) parameterize the extent and scale of existing data for an evidence review, (2) identify key factors to be extracted in systematic charting efforts, and (3) assess opioid concentration as a variable for its relevance to the central hypothesis. Six databases will be searched with no filters: MEDLINE, Embase, CINAHL Complete, Cochrane Library, Biological Sciences Collection, and International Pharmaceutical Abstracts. Trial registries will include ClinicalTrials.gov, Cochrane CENTRAL, International Standard Randomised Controlled Trial Number Registry, European Union Clinical Trials Register, and World Health Organization International Clinical Trials Registry. Eligibility criteria will include preclinical and clinical study data on opioids effects on tumor growth or survival, or alteration on the antineoplastic activity of chemotherapeutics. We will chart data on (1) opioid concentration from human subjects with cancer, yielding a ``physiologic range'' to better interpret available preclinical data; (2) patterns of opioid exposure with disease and treatment-related patient outcomes; and (3) the influence of opioids on cancer cell survival, as well as opioid-related changes to cancer cell susceptibility for chemotherapeutics. Results: This scoping review will present results in narrative forms as well as with the use of tables and diagrams. Initiated in February 2021 at the University of Utah, this protocol is anticipated to generate a scoping review by August 2023. The results of the scoping review will be disseminated through scientific conference proceedings and presentations, stakeholder meetings, and by publication in a peer-reviewed journal. Conclusions: The findings of this scoping review will provide a comprehensive description of the consequences of prescription opioids on malignancy and its treatment. By incorporating preclinical and clinical data, this scoping review will invite novel comparisons across study types that could inform new basic, translational, and clinical studies regarding risks and benefits of opioid use among patients with cancer. International Registered Report Identifier (IRRID): PRR1-10.2196/38167 ", doi="10.2196/38167", url="https://www.researchprotocols.org/2023/1/e38167", url="http://www.ncbi.nlm.nih.gov/pubmed/37213193" } @Article{info:doi/10.2196/34533, author="Abdel-Hafez, Ahmad and Scott, A. Ian and Falconer, Nazanin and Canaris, Stephen and Bonilla, Oscar and Marxen, Sven and Van Garderen, Aaron and Barras, Michael", title="Predicting Therapeutic Response to Unfractionated Heparin Therapy: Machine Learning Approach", journal="Interact J Med Res", year="2022", month="Sep", day="19", volume="11", number="2", pages="e34533", keywords="heparin", keywords="activated partial thromboplastin time", keywords="aPTT", keywords="predictive modeling", keywords="machine learning", keywords="personalized medicine", abstract="Background: Unfractionated heparin (UFH) is an anticoagulant drug that is considered a high-risk medication because an excessive dose can cause bleeding, whereas an insufficient dose can lead to a recurrent embolic event. Therapeutic response to the initiation of intravenous UFH is monitored using activated partial thromboplastin time (aPTT) as a measure of blood clotting time. Clinicians iteratively adjust the dose of UFH toward a target, indication-defined therapeutic aPTT range using nomograms, but this process can be imprecise and can take ?36 hours to achieve the target range. Thus, a more efficient approach is required. Objective: In this study, we aimed to develop and validate a machine learning (ML) algorithm to predict aPTT within 12 hours after a specified bolus and maintenance dose of UFH. Methods: This was a retrospective cohort study of 3019 patient episodes of care from January 2017 to August 2020 using data collected from electronic health records of 5 hospitals in Queensland, Australia. Data from 4 hospitals were used to build and test ensemble models using cross-validation, whereas data from the fifth hospital were used for external validation. We built 2 ML models: a regression model to predict the aPTT value after a UFH bolus dose and a multiclass model to predict the aPTT, classified as subtherapeutic (aPTT <70 seconds), therapeutic (aPTT 70-100 seconds), or supratherapeutic (aPTT >100 seconds). Modeling was performed using Driverless AI (H2O), an automated ML tool, and 17 different experiments were iteratively conducted to optimize model accuracy. Results: In predicting aPTT, the best performing model was an ensemble with 4x LightGBM models with a root mean square error of 31.35 (SD 1.37). In predicting the aPTT class using a repurposed data set, the best performing ensemble model achieved an accuracy of 0.599 (SD 0.0289) and an area under the receiver operating characteristic curve of 0.735. External validation yielded similar results: root mean square error of 30.52 (SD 1.29) for the aPTT prediction model, and accuracy of 0.568 (SD 0.0315) and area under the receiver operating characteristic curve of 0.724 for the aPTT multiclassification model. Conclusions: To the best of our knowledge, this is the first ML model applied to intravenous UFH dosing that has been developed and externally validated in a multisite adult general medical and surgical inpatient setting. We present the processes of data collection, preparation, and feature engineering for replication. ", doi="10.2196/34533", url="https://www.i-jmr.org/2022/2/e34533", url="http://www.ncbi.nlm.nih.gov/pubmed/35993617" } @Article{info:doi/10.2196/20168, author="Hatem, Reem and Nawaz, A. Faisal and Al-Sharif, A. Ghadah and Almoosa, Mohammad and Kattan, Wid and Tzivinikos, Christos and Amirali, Lila E. and Albanna, Ammar", title="Nonalcoholic Fatty Liver Disease in Children and Adolescents Taking Atypical Antipsychotic Medications: Protocol for a Systematic Review and Meta-analysis", journal="JMIR Res Protoc", year="2022", month="Mar", day="21", volume="11", number="3", pages="e20168", keywords="nonalcoholic fatty liver disease", keywords="psychopharmacology", keywords="antipsychotics", keywords="children", keywords="adolescents", keywords="overprescribing", keywords="pharmaceuticals", keywords="antipsychotic medications", keywords="medication", keywords="pediatric psychopharmacology", keywords="pharmacology", keywords="child and adolescent psychiatry", abstract="Background: Atypical antipsychotics (AAP) are commonly prescribed to children and adolescents and are associated with important adverse effects including weight gain and metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is not only the most common pediatric liver disease but is also associated with serious complications including liver cirrhosis. Objective: Given that NAFLD and AAP are associated with metabolic syndrome, we aim to comprehensively examine the association between AAP and NAFLD in children and adolescents. Methods: We will conduct a systematic review of studies exploring NAFLD in subjects younger than 18 years on AAP published in English between 1950 and 2020 following the PRISMA (Preferred Reporting items for Systematic Reviews and Meta-Analysis) guidelines. Results: A PRISMA flowchart will be used present the study results after comprehensively reviewing studies on NAFLD in children and adolescents taking AAP. The first and second systematic searches will be conducted during December 2021. The results are expected to be published in June 2022. Conclusions: This research project will serve as a foundation for future studies and assist in devising interventions and reforming clinical guidelines for using AAP to ensure improved patient safety. International Registered Report Identifier (IRRID): PRR1-10.2196/20168 ", doi="10.2196/20168", url="https://www.researchprotocols.org/2022/3/e20168", url="http://www.ncbi.nlm.nih.gov/pubmed/35311689" } @Article{info:doi/10.2196/25855, author="Penley, Benjamin and Minshew, Lana and Chen, Hui-Han and Eckel, Stephen and Ozawa, Sachiko", title="Accessibility of Low-cost Insulin From Illegitimate Internet Pharmacies: Cross-sectional Study", journal="J Med Internet Res", year="2022", month="Feb", day="14", volume="24", number="2", pages="e25855", keywords="insulin", keywords="diabetes", keywords="internet", keywords="online", keywords="pharmacy", keywords="medication", keywords="cost", abstract="Background: There is much public debate regarding the high cost of insulin. With 1-in-4 patients in the United States with type 1 diabetes reporting difficulties affording insulin, there is concern that some of these patients might look for cost savings on the internet, unaware that 96\% of internet pharmacies are illegitimate. Patients who purchase insulin from illegitimate internet pharmacies remove themselves from traditional health care systems that ensure safe, quality-assured, and effective medication use. Objective: This study aims to determine the accessibility of Humalog and NovoLog insulin from internet pharmacies and characterize how these sites approached patient safety, and priced as well as marketed their products. Methods: From September to December 2019, we queried the phrases buy insulin online, buy Humalog online, and buy NovoLog online in common search engines. The first 100 search results from Google and Bing, and the first 50 search results from Yahoo! and DuckDuckGo were screened. Websites were included if they claimed to sell Humalog or NovoLog insulin, were active, free access, in the English language, and had a unique URL. The legitimacy of websites was classified using LegitScript. Safety and marketing characteristics were compared across the legitimacy of internet pharmacies. Internet pharmacy prices were compared with the prices offered through brick-and-mortar pharmacies using GoodRx. Results: We found that 59\% (n=29) of the 49 internet pharmacies in our analysis were illegitimate, whereas only 14\% (n=7) were legitimate and 27\% (n=13) were unclassified. Across illegitimate internet pharmacies, Humalog and NovoLog insulin were 2 to 5 times cheaper as compared with both legitimate internet pharmacies and brick-and-mortar stores. Risks associated with the use of illegitimate internet pharmacies by American consumers were evident: 57\% (8/14) did not require a prescription, 43\% (6/14) did not display medication information or warnings, and only 21\% (3/14) offered access to purported pharmacists. This included 9 rogue internet pharmacies that sold Humalog and NovoLog insulin within the United States, where 11\% (1/9) required a prescription, 11\% (1/9) placed quantity limits per purchase, and none offered pharmacist services. Rogue internet pharmacies often offered bulk discounts (11/18, 61\%), assured privacy (14/18, 78\%), and promoted other products alongside insulin (13/18, 72\%). The marketing language of illegitimate internet pharmacies appealed more to quality, safety, and customer service as compared with legitimate sites. Conclusions: The ease of access to low-cost insulin through illegitimate internet pharmacies calls for urgent attention. Illegitimate internet pharmacies place patients at risk of poor-quality medications and subpar pharmacy services, resulting in adverse events and poor diabetes control. A multifaceted approach is needed to close illegitimate internet pharmacies through legal and regulatory measures, develop better search engine filters, raise public awareness of the dangers of illegitimate internet pharmacies, and address the high costs of insulin. ", doi="10.2196/25855", url="https://www.jmir.org/2022/2/e25855", url="http://www.ncbi.nlm.nih.gov/pubmed/35156937" } @Article{info:doi/10.2196/25200, author="Tremblay, Zo{\"e} and Mumbere, David and Laurin, Danielle and Sirois, Caroline and Furrer, Daniela and Poisblaud, Lise and Carmichael, Pierre-Hugues and Farrell, Barbara and Tourigny, Andr{\'e} and Giguere, Anik and Vedel, Isabelle and Morais, Jos{\'e} and Kr{\"o}ger, Edeltraut", title="Health Impacts and Characteristics of Deprescribing Interventions in Older Adults: Protocol for a Systematic Review and Meta-analysis", journal="JMIR Res Protoc", year="2021", month="Dec", day="9", volume="10", number="12", pages="e25200", keywords="deprescribing", keywords="older adult", keywords="aging", keywords="medication use", keywords="inappropriate prescribing", keywords="potentially inappropriate medication", keywords="polypharmacy", keywords="comorbidity", keywords="multimorbidity", keywords="systematic review", abstract="Background: Deprescribing, a relatively recent concept, has been proposed as a promising solution to the growing issues of polypharmacy and use of medications of questionable benefit among older adults. However, little is known about the health outcomes of deprescribing interventions. Objective: This paper presents the protocol of a study that aims to contribute to the knowledge on deprescribing by addressing two specific objectives: (1) describe the impact of deprescribing in adults ?60 years on health outcomes or quality of life; and (2) determine the characteristics of effective interventions in deprescribing. Methods: Primary studies targeting three concepts (older adults, deprescribing, and health or quality of life outcomes) will be included in the review. The search will be performed using key international databases (MEDLINE, EMBASE, CINAHL, Ageline, PsycInfo), and a special effort will be made to identify gray literature. Two reviewers will independently screen the articles, extract the information, and evaluate the quality of the selected studies. If methodologically feasible, meta-analyses will be performed for groups of intervention studies reporting on deprescribing interventions for similar medications, used for similar or identical indications, and reporting on similar outcomes (eg, benzodiazepines used against insomnia and studies reporting on quality of sleep or quality of life). Alternatively, the results will be presented in bottom-line statements (objective 1) and a matrix outlining effective interventions (objective 2). Results: The knowledge synthesis may be limited by the availability of high-quality clinical trials on deprescribing and their outcomes in older adults. Additionally, analyses will likely be affected by studies on the deprescribing of different types of molecules within the same indication (eg, different pharmacological classes and medications to treat hypertension) and different measures of health and quality of life outcomes for the same indication. Nevertheless, we expect the review to identify which deprescribing interventions lead to improved health outcomes among seniors and which of their characteristics contribute to these outcomes. Conclusions: This systematic review will contribute to a better understanding of the health outcomes of deprescribing interventions among seniors. Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42015020866; https://www.crd.york.ac.uk/prospero/display\_record.php?ID=CRD42015020866 International Registered Report Identifier (IRRID): PRR1-10.2196/25200 ", doi="10.2196/25200", url="https://www.researchprotocols.org/2021/12/e25200", url="http://www.ncbi.nlm.nih.gov/pubmed/34889771" } @Article{info:doi/10.2196/23571, author="M{\"u}ller, Lars and Srinivasan, Aditya and Abeles, R. Shira and Rajagopal, Amutha and Torriani, J. Francesca and Aronoff-Spencer, Eliah", title="A Risk-Based Clinical Decision Support System for Patient-Specific Antimicrobial Therapy (iBiogram): Design and Retrospective Analysis", journal="J Med Internet Res", year="2021", month="Dec", day="3", volume="23", number="12", pages="e23571", keywords="antimicrobial resistance", keywords="clinical decision support", keywords="antibiotic stewardship", keywords="data visualization", abstract="Background: There is a pressing need for digital tools that can leverage big data to help clinicians select effective antibiotic treatments in the absence of timely susceptibility data. Clinical presentation and local epidemiology can inform therapy selection to balance the risk of antimicrobial resistance and patient risk. However, data and clinical expertise must be appropriately integrated into clinical workflows. Objective: The aim of this study is to leverage available data in electronic health records, to develop a data-driven, user-centered, clinical decision support system to navigate patient safety and population health. Methods: We analyzed 5 years of susceptibility testing (1,078,510 isolates) and patient data (30,761 patients) across a large academic medical center. After curating the data according to the Clinical and Laboratory Standards Institute guidelines, we analyzed and visualized the impact of risk factors on clinical outcomes. On the basis of this data-driven understanding, we developed a probabilistic algorithm that maps these data to individual cases and implemented iBiogram, a prototype digital empiric antimicrobial clinical decision support system, which we evaluated against actual prescribing outcomes. Results: We determined patient-specific factors across syndromes and contexts and identified relevant local patterns of antimicrobial resistance by clinical syndrome. Mortality and length of stay differed significantly depending on these factors and could be used to generate heuristic targets for an acceptable risk of underprescription. Combined with the developed remaining risk algorithm, these factors can be used to inform clinicians' reasoning. A retrospective comparison of the iBiogram-suggested therapies versus the actual prescription by physicians showed similar performance for low-risk diseases such as urinary tract infections, whereas iBiogram recognized risk and recommended more appropriate coverage in high mortality conditions such as sepsis. Conclusions: The application of such data-driven, patient-centered tools may guide empirical prescription for clinicians to balance morbidity and mortality with antimicrobial stewardship. ", doi="10.2196/23571", url="https://www.jmir.org/2021/12/e23571", url="http://www.ncbi.nlm.nih.gov/pubmed/34870601" } @Article{info:doi/10.2196/32327, author="Tait, Margaret-Ann and Costa, J. Daniel S. and Campbell, Rachel and Norman, Richard and Schug, Stephan and Rutherford, Claudia", title="A Quality-of-Life Evaluation Study Assessing Health-Related Quality of Life in Patients Receiving Medicinal Cannabis (the QUEST Initiative): Protocol for a Longitudinal Observational Study", journal="JMIR Res Protoc", year="2021", month="Nov", day="24", volume="10", number="11", pages="e32327", keywords="medicinal cannabis", keywords="patient-reported outcomes", keywords="quality of life", keywords="chronic pain", keywords="pain management", keywords="mental health", keywords="depression", keywords="anxiety", keywords="cannabis oil", abstract="Background: Evidence supports several countries introducing legislation to allow cannabis-based medicine as an adjunctive treatment for the symptomatic relief of chronic pain, chemotherapy-induced nausea, spasticity in multiple sclerosis (MS), epileptic seizures, depression, and anxiety. However, clinical trial participants do not represent the entire spectrum of disease and health status seen in patients currently accessing medicinal cannabis in practice. Objective: This study aims to collect real-world data to evaluate health-related quality of life in patients prescribed medicinal cannabis oil and describe any differences over time, from before starting therapy to after 3 and 12 months of therapy. Methods: Adult patients newly prescribed medicinal cannabis oil by authorized prescribers and under the Special Access Schemes across Australia will be screened for eligibility and invited to participate. A sample size of 2142 is required, with a 3-month follow-up. All participants will complete the EuroQol 5-Dimension; European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-30; Depression, Anxiety, and Stress Scale-21; Patients' Global Impression of Change; Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form (SF) version 1.0: Sleep Disturbance 8b; and PROMIS SF Fatigue 13a questionnaires. Patients with chronic pain conditions will also complete the PROMIS SF version 1.0: Pain Intensity 3a and PROMIS SF version 1.0: Pain Interference 8a. Patients with movement disorders will also complete Quality of Life in Neurological Disorders (Neuro-QoL) SF version 1.0: Upper Extremity Function (Fine Motor and Activities of Daily Living) and if chorea is indicated, the Neuro-QoL SF version 2.0: Huntington's Disease health-related Quality of LIFE-Chorea 6a. All questionnaires will be administered at baseline, 2 weeks (titration), monthly up to 3 months, and then every 2 months up to 1 year. Results: Recruitment commenced in November 2020. By June 2021, 1095 patients were screened for the study by 69 physicians in centers across 6 Australian states: Australian Capital Territory, New South Wales, Queensland, South Australia, Victoria, and Western Australia. Of the patients screened, 833 (39\% of the target sample size) provided consent and completed baseline questionnaires. Results are expected to be published in 2022. Results of this study will show whether patient-reported outcomes improve in patients accessing prescribed medicinal cannabis from baseline to 3 months and whether any changes are maintained over a 12-month period. This study will also identify differences in improvements in patient-reported outcomes among patients with different chronic conditions (eg, chronic pain, MS, epilepsy, Parkinson disease, or cancer). Conclusions: This protocol contains detailed methods that will be used across multiple sites in Australia. The findings from this study have the potential to be integral to treatment assessment and recommendations for patients with chronic pain and other health indicators for accessing medicinal cannabis. Trial Registration: Australian New Zealand Clinical Trials Registry: ANZCTRN12621000063819; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380807\&isReview=true International Registered Report Identifier (IRRID): DERR1-10.2196/32327 ", doi="10.2196/32327", url="https://www.researchprotocols.org/2021/11/e32327", url="http://www.ncbi.nlm.nih.gov/pubmed/34821570" } @Article{info:doi/10.2196/33151, author="Liu, W. Jenny J. and Nazarov, Anthony and Easterbrook, Bethany and Plouffe, A. Rachel and Le, Tri and Forchuk, Callista and Brandwood, Alec and St Cyr, Kate and Auger, Edouard and Balderson, Ken and Bilodeau, Mathieu and Burhan, M. Amer and Enns, W. Murray and Smith, Patrick and Hosseiny, Fardous and Dupuis, Gabrielle and Roth, Maya and Mota, Natalie and Lavoie, Vicky and Richardson, Don J.", title="Four Decades of Military Posttraumatic Stress: Protocol for a Meta-analysis and Systematic Review of Treatment Approaches and Efficacy", journal="JMIR Res Protoc", year="2021", month="Oct", day="25", volume="10", number="10", pages="e33151", keywords="military personnel", keywords="psychotherapy", keywords="pharmacotherapy", keywords="stress disorders", keywords="posttraumatic", keywords="meta-analysis", keywords="systematic review", keywords="therapy", keywords="stress", keywords="disorder", keywords="posttraumatic stress disorder", keywords="review", keywords="treatment", keywords="efficacy", keywords="military", keywords="Canada", keywords="veteran", abstract="Background: Over 85\% of active members of the Canadian Armed Forces have been exposed to potentially traumatic events linked to the development of posttraumatic stress disorder (PTSD). At the time of transition to civilian life, as high as 1 in 8 veterans may be diagnosed with PTSD. Given the high prevalence of PTSD in military and veteran populations, the provision of effective treatment considering their unique challenges and experiences is critical for mental health support and the well-being of these populations. Objective: This paper presents the protocol for a meta-analysis and systematic review that will examine the effectiveness of treatment approaches for military-related PTSD. Methods: This PROSPERO-preregistered meta-analysis is being conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and Cochrane guidelines. A comprehensive search of the literature was conducted using the databases PsycInfo, Medline, Embase, CINAHL, and ProQuest Dissertation \& Theses. Effect sizes will be computed based on changes in PTSD symptom scores over time across studies using validated PTSD scales. A multilevel meta-analysis will examine the overall effects, between-study effects, and within-study effects of available evidence for PTSD treatments in military populations. Effect sizes will be compared between pharmacotherapeutic, psychotherapeutic, and alternative/emerging treatment interventions. Finally, meta-regression and subgroup analyses will explore the moderating roles of clinical characteristics (eg, PTSD symptom clusters), treatment approaches (eg, therapeutic orientations in psychotherapy and alternative therapies and classifications of drugs in pharmacotherapy), as well as treatment characteristics (eg, length of intervention) on treatment outcomes. Results: The literature search was completed on April 14, 2021. After the removal of duplicates, a total of 12,002 studies were screened for inclusion. As of July 2021, title and abstract screening has been completed, with 1469 out of 12,002 (12.23\%) studies included for full-text review. Full review is expected to be completed in the summer of 2021, with initial results expected for publication by early winter of 2021. Conclusions: This meta-analysis will provide information on the current state of evidence on the efficacy and effectiveness of various treatment approaches for military-related PTSD and identify factors that may influence treatment outcomes. The results will inform clinical decision-making for service providers and service users. Finally, the findings will provide insights into future treatment development and practice recommendations to better support the well-being of military and veteran populations. Trial Registration: PROSPERO CRD42021245754; https://tinyurl.com/y9u57c59 International Registered Report Identifier (IRRID): DERR1-10.2196/33151 ", doi="10.2196/33151", url="https://www.researchprotocols.org/2021/10/e33151", url="http://www.ncbi.nlm.nih.gov/pubmed/34694228" } @Article{info:doi/10.2196/24969, author="Maltby, E. Vicki and Lea, A. Rodney and Monif, Mastura and Fabis-Pedrini, J. Marzena and Buzzard, Katherine and Kalincik, Tomas and Kermode, G. Allan and Taylor, Bruce and Hodgkinson, Suzanne and McCombe, Pamela and Butzkueven, Helmut and Barnett, Michael and Lechner-Scott, Jeannette", title="Efficacy of Cladribine Tablets as a Treatment for People With Multiple Sclerosis: Protocol for the CLOBAS Study (Cladribine, a Multicenter, Long-term Efficacy and Biomarker Australian Study)", journal="JMIR Res Protoc", year="2021", month="Oct", day="19", volume="10", number="10", pages="e24969", keywords="multiple sclerosis", keywords="cladribine", keywords="biomarkers", abstract="Background: Cladribine tablets (marketed as Mavenclad) are a new oral therapy, which has recently been listed on the pharmaceutical benefits scheme in Australia for the treatment of relapsing multiple sclerosis (MS). The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS for up to 4 years in 75\% of patients (based on annualized relapse rate). However, the reinitiation of therapy after year 4 has not been studied. Objective: This study aims to evaluate the safety and efficacy of cladribine tablets over a 6-year period, according to no evidence of disease activity 3. Methods: This will be a multicenter, 6-year, phase IV, low interventional, observational study that incorporates clinical, hematological, biochemical, epigenetic, radiological and cognitive biomarkers of disease. Participants considered for treatment with cladribine as part of their routine clinical care will be consented to take part in the study. They will be monitored at regular intervals during the initial course of medication administration in years 1 and 2. After year 3, patients will have the option of redosing, if clinically indicated, or to switch to another disease-modifying therapy. Throughout the duration of the study, we will assess blood-based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation, and RNA analysis as well as magnetic resonance imaging findings (brain volume and/or lesion load) and cognitive performance. Results: This study has been approved by the Hunter New England Local Health District Human Research Ethics Committee. Recruitment began in March of 2019 and was completed by June 2021. Conclusions: This will be the first long-term efficacy trial of cladribine, which offers reinitiation of therapy in the 3rd year, based on disease activity, after the initial 2 courses. We expect that this study will indicate whether any of the assessed biomarkers can be used to predict treatment efficacy or the need for future reinitiation of cladribine in people with MS. Trial Registration: This study is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12619000257167) with Universal Trial Number (U1111-1228-2165). International Registered Report Identifier (IRRID): DERR1-10.2196/24969 ", doi="10.2196/24969", url="https://www.researchprotocols.org/2021/10/e24969", url="http://www.ncbi.nlm.nih.gov/pubmed/34665152" } @Article{info:doi/10.2196/31281, author="Mansell, Holly and Quinn, Declan and Kelly, E. Lauren and Szafron, Michael and Alcorn, Jane", title="Pharmacokinetics and Perceptions of Children and Young Adults Using Cannabis for Attention-Deficit/Hyperactivity Disorder and Oppositional Defiant Disorder: Protocol for a Mixed Methods Proof-of-Concept Study", journal="JMIR Res Protoc", year="2021", month="Oct", day="18", volume="10", number="10", pages="e31281", keywords="attention-deficit/hyperactivity disorder", keywords="ADHD", keywords="oppositional defiant disorder", keywords="cannabis", keywords="cannabidiol", keywords="young adults", keywords="youths", keywords="pharmacokinetics", keywords="marijuana", abstract="Background: Despite the lack of evidence on the use of cannabis for the treatment of attention-deficit/hyperactivity disorder (ADHD), the growing perception that cannabis is safe has led more patients and caregivers to self-medicate. Some psychiatrists now authorize medicinal cannabis for patients with ADHD with features of oppositional defiant disorder (ODD) to curtail the unregulated (ie, self-medicated) use of recreational cannabis or to offer a therapeutic option to those who continue to experience symptoms after exhausting all other treatment options. Objective: This protocol aims to explore the perceived effectiveness and pharmacokinetics of cannabis in youth and young adults, who are currently taking it as part of their treatment plan for ADHD with features of ODD, under the supervision of a psychiatrist. Methods: Patients between the ages of 12 and 25 years with a diagnosis of ADHD and features of ODD, who are currently taking cannabis herbal extract (at a $\Delta$9-tetrahydrocannabinol [THC]:cannabidiol [CBD] ratio of 1:20) as a treatment adjunct to stimulant pharmacotherapy will be recruited. A sample size of 10-20 individuals is estimated. The study interview will consist of (1) validated symptom rating scales (Swanson,?Nolan, and Pelham-IV Questionnaire [SNAP-IV], 90-item; Patient Health Questionnaire, 9-item [PHQ-9]; and Screen for Child Anxiety Related Emotional Disorders [SCARED] tool to measure symptoms of ADHD and ODD, depression, and anxiety, respectively); (2) a semistructured interview to probe the experiences of using cannabis; and (3) a cannabis side effects survey. A cannabis product sample as well as 2 blood samples (a trough level and 2-hour postdose level) will be collected to measure plasma concentrations of cannabinoids and relevant metabolites (THC, CBD, 11-hydroxy-THC, 7-hydroxy-CBD, cannabichromene, and 11-nor-9-carboxy-THB) using liquid chromatography--tandem mass spectrometry (LC--MS/MS). Self-report rating scales (SNAP-IV, SCARED, and PHQ-9) will be scored in accordance with standard protocols and compared to retrospective scores obtained from the participant's chart. Demographic variables (age, weight, and race), symptom scores, and blood levels (peaks and troughs) of THC, CBD, cannabichromene (CBC), and metabolites will be summarized using descriptive statistics. Relationships between plasma concentrations and symptom scores will be determined using analysis of variance, and multiple regression analysis will be performed to determine associations between plasma concentrations and demographic variables (age, weight, and ethnicity). The qualitative data will be audio-recorded and transcribed and organized into themes. Results: The protocol was approved by the Biomedical Research Ethics Board at the University of Saskatchewan (protocol \#1726), and recruitment began in May 2021. Conclusions: This proof-of-concept study will explore the potential treatment effectiveness of medical cannabis in participants with ADHD and ODD through a mixed methods approach to inform future research in this area. International Registered Report Identifier (IRRID): DERR1-10.2196/31281 ", doi="10.2196/31281", url="https://www.researchprotocols.org/2021/10/e31281", url="http://www.ncbi.nlm.nih.gov/pubmed/34661540" } @Article{info:doi/10.2196/31150, author="Alshammari, O. Fatemah O. F. and Al-saraireh, M. Yousef and Youssef, M. Ahmed M. and Al-Sarayra, M. Yahya and Alrawashdeh, Mohammad Hamzeh", title="Cytochrome P450 1B1 Overexpression in Cervical Cancers: Cross-sectional Study", journal="Interact J Med Res", year="2021", month="Oct", day="12", volume="10", number="4", pages="e31150", keywords="cancer", keywords="cervical cancer", keywords="cytochrome P450", keywords="cytochrome 1B1", keywords="immunohistochemistry", keywords="toxicity", keywords="therapies", keywords="molecular", keywords="tumor", keywords="cytochrome", keywords="cervix", abstract="Background: Current standard treatments for patients with recurrent cervical cancer are not very effective and are associated with severe toxicity. Recently, the rational approach for the discovery of new therapies for cervical cancer is based on the alterations in the molecular biology of cancer cells. One of the emerging molecular changes in cancer cells is the aberrant expression of cytochrome P450 1B1 (CYP1B1). This unique enzyme has been reported to be selectively overexpressed in several cancers. Objective: The aim of this study was to examine CYP1B1 expression in cervical cancers and to assess the enzyme's relationship with several clinicopathological features. Methods: Immunohistochemistry was performed to examine CYP1B1 expression in 100 patient samples with cervical cancer and 10 patient samples with normal healthy cervical tissues. Results: CYP1B1 was expressed in the majority of the cervical cancer samples (91/100, 91.0\%) but not in normal healthy cervical samples. The difference in the expression of CYP1B1 between healthy and tumorous cervical tissues was significant (P=.01). Moreover, the frequency of CYP1B1 expression was found to be significantly higher in patients with advanced grades of the disease (P=.03) and in patients having metastasis to the lymph nodes (P=.01). Surprisingly, there was a significantly higher expression of CYP1B1 in patients with a high prevalence of human papilloma virus 16/18 (P=.04). Conclusions: The differential profile of CYP1B1 expression between cervical cancer tissues and normal cervical tissues suggests that CYP1B1 may be used as a target for future therapeutic exploitations. ", doi="10.2196/31150", url="https://www.i-jmr.org/2021/4/e31150", url="http://www.ncbi.nlm.nih.gov/pubmed/34636736" } @Article{info:doi/10.2196/24542, author="Wang, Yi-Chen and Tsan, Chin-Yuan and Chen, Meng-Chun", title="Implementation of an Automated Dispensing Cabinet System and Its Impact on Drug Administration: Longitudinal Study", journal="JMIR Form Res", year="2021", month="Sep", day="17", volume="5", number="9", pages="e24542", keywords="automated dispensing cabinets", keywords="medication administration system", keywords="medication errors", keywords="dispensing", keywords="medication", keywords="nursing", keywords="Taiwan", abstract="Background: A technology that has been widely implemented in hospitals in the United States is the automated dispensing cabinet (ADC), which has been shown to reduce nurse drug administration errors and the time nurses spend administering drugs. Objective: This study aimed to determine the impact of an ADC system on medication administration by nurses as well as safety before and after ADC implementation. Methods: We conducted a 24-month-long longitudinal study at the National Taiwan University Hospital in Taipei, Taiwan. Clinical observations and questionnaires were used to evaluate the time differences in drug preparation, delivery, and returns in the inpatient ward by nurses before and after using the ADC. Drug errors recorded in the Medical Incident Events system were assessed the year before and after ADC implementation. Results: The drug preparation time of the wards increased significantly (all P<.005). On average, 2 minutes of preparation time is needed for each patient. Only 1 unit showed an increase in the drug return time, but this was not significant. There were 9 (45\%) adverse events during the drug administration phase, and 11 (55\%) events occurred during the drug-dispensing phase. Although a decrease in the mean number of events reported was observed during the ADC implementation period, this difference was not significant. As for the questionnaire that were administered to the nurses, the overall mean score was 3.90; the highest score was for the item ``I now spend less time waiting for medications that come from the pharmacy than before the ADC was implemented'' (score=4.24). The item with the lowest score was ``I have to wait in line to get my patient medications'' (score=3.32). Conclusions: The nurses were generally satisfied with ADC use over the 9 months following complete implementation and integration of the system. It was acknowledged that the ADC offers benefits in terms of pharmaceutical stock management; however, this comes at the cost of increased nursing time. In general, the nurses remained supportive of the benefits for their patients, despite consequences to their workflows. Their acceptance of the ADC system in this study demonstrates this. ", doi="10.2196/24542", url="https://formative.jmir.org/2021/9/e24542", url="http://www.ncbi.nlm.nih.gov/pubmed/34533467" } @Article{info:doi/10.2196/27855, author="Wharton-Smith, Alexandra and Baker, Kevin and Roca-Feltrer, Arantxa and Rodrigues, Maria and Richardson, Sol and Bonnington, A. Craig and Rassi, Christian and Marasciulo, Madeleine and Enosse, Sonia and Saute, Francisco and Aide, Pedro and Macete, Eusebio and Candrinho, Baltazar", title="Assessment of the Feasibility, Acceptability, and Impact of Implementing Seasonal Malaria Chemoprevention in Nampula Province, Mozambique: Protocol for a Hybrid Effectiveness-Implementation Study", journal="JMIR Res Protoc", year="2021", month="Sep", day="15", volume="10", number="9", pages="e27855", keywords="malaria", keywords="seasonal malaria chemoprevention", keywords="sulfadoxine-pyrimethamine amodiaquine", keywords="resistance", keywords="children under five", keywords="implementation research", keywords="Mozambique", keywords="Africa", keywords="mobile phone", abstract="Background: Malaria is a significant cause of morbidity and mortality in children aged under 5 years in Mozambique. The World Health Organization recommends seasonal malaria chemoprevention (SMC), the administration of four monthly courses of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ), to children aged 3-59 months during rainy season. However, as resistance to SP is widespread in East and Southern Africa, SMC has so far only been implemented across the Sahel in West Africa. Objective: This protocol describes the first phase of a pilot project that aims to assess the protective effect of SP and AQ when used for SMC and investigate the levels of molecular markers of resistance of Plasmodium falciparum to antimalarial medicines in the study districts. In addition, it is important to understand whether SMC is a feasible and acceptable intervention in the context of Nampula Province, Mozambique. Methods: This study will adopt a hybrid effectiveness-implementation design to conduct a mixed methods evaluation with six objectives: a molecular marker study, a nonrandomized controlled trial, an analysis of reported malaria morbidity indicators, a documentation exercise of the contextual SMC adaptation, an acceptability and feasibility assessment, and a coverage and quality assessment. Results: Ethical approval for this study was granted by the Mozambican Ministry of Health National Bioethics Committee on September 15, 2020. Data collection began in October 2020, and data analysis is expected to be completed by August 2021. Conclusions: This research will make a unique contribution to our understanding of whether the combination of SP and AQ, when used for SMC, can confer a protective effect against malaria in children aged 3-59 months in a region where malaria transmission is seasonal and SP resistance is expected to be high. If the project is successful, subsequent phases are expected to provide a more comprehensive assessment of the effectiveness and sustainability of SMCs. International Registered Report Identifier (IRRID): DERR1-10.2196/27855 ", doi="10.2196/27855", url="https://www.researchprotocols.org/2021/9/e27855", url="http://www.ncbi.nlm.nih.gov/pubmed/34524109" } @Article{info:doi/10.2196/26350, author="De Vos, Ruth and Brown, Thomas and Longstaff, Jayne and Lomax, Mitch and Mackenzie, Heather and Hicks, Alexander and Rupani, Hitasha and Gates, Jessica and Fox, Lauren and Wiffen, Laura and Chauhan, J. Anoop", title="A Study to Investigate the Prevalence of Device-Specific Errors in Inhaler Technique in Adults With Airway Disease (The SCORES Study): Protocol for a Single Visit Prevalence Study", journal="JMIR Res Protoc", year="2021", month="Aug", day="27", volume="10", number="8", pages="e26350", keywords="inhaler", keywords="inhaler technique", keywords="inhaler technique error", keywords="asthma", keywords="COPD", abstract="Background: It is a recurring theme in clinical practice that patients using inhaled medications via an inhaler do not use their device to a standard that allows for optimum therapeutic effect, and some studies have shown that up to 90\% of people do not use their inhalers properly. Observation and correction of the inhaler technique by health care professionals is advised by both national and international guidelines and should be performed at every opportunity to ensure that the optimum inhaler technique is achieved by the user. This study will provide a greater understanding of the most frequent technique errors made by people using 13 different inhaler types. Objective: This study aims to identify and compare inhaler technique errors and their prevalence in adults, using device-specific checklists in accordance with manufacturers' guidelines, for 13 specific inhaler types across all lung conditions and to correlate these errors with possible determinants of poor technique. It also aims to assess the error frequency at each step in the device-specific questionnaires and compare the error rates among device types. Methods: In a single visit, participants using an inhaler included in the inclusion criteria will have their inhaler technique observed using an identical placebo device, which will be recorded using device-specific checklists, and technique-optimized, or switched to a suitable inhaler. Results: The study is already underway, and it is anticipated that the results will be available by 2022. Conclusions: The SCORES (Study to Investigate the Prevalence of Device-Specific Errors in Inhaler Technique in Adults With Airway Disease) study will ascertain the prevalence of device-specific inhaler technique errors at each step in the device-specific checklists, compare error rates among 13 device types, and correlate these errors with possible determinants of poor technique. Future work will involve the clarification and classification of these errors into critical and noncritical categories. Trial Registration: ClinicalTrials.gov NCT04262271; https://clinicaltrials.gov/ct2/show/NCT04262271 International Registered Report Identifier (IRRID): DERR1-10.2196/26350 ", doi="10.2196/26350", url="https://www.researchprotocols.org/2021/8/e26350", url="http://www.ncbi.nlm.nih.gov/pubmed/34448728" } @Article{info:doi/10.2196/30090, author="Bandiera, Carole and Cardoso, Evelina and Locatelli, Isabella and Digklia, Antonia and Zaman, Khalil and Diciolla, Antonella and Cristina, Val{\'e}rie and Stravodimou, Athina and Veronica, Lopez Aedo and Dolcan, Ana and Sarivalasis, Apostolos and Liapi, Aikaterini and Bouchaab, Hasna and Orcurto, Angela and Dotta-Celio, Jennifer and Peters, Solange and Decosterd, Laurent and Widmer, Nicolas and Wagner, Dorothea and Csajka, Chantal and Schneider, Paule Marie", title="Optimizing Oral Targeted Anticancer Therapies Study for Patients With Solid Cancer: Protocol for a Randomized Controlled Medication Adherence Program Along With Systematic Collection and Modeling of Pharmacokinetic and Pharmacodynamic Data", journal="JMIR Res Protoc", year="2021", month="Jun", day="29", volume="10", number="6", pages="e30090", keywords="neoplasms", keywords="medication adherence", keywords="oral anticancer therapies", keywords="interprofessional program", keywords="adherence electronic measure", keywords="pharmacokinetics", keywords="pharmacodynamics", keywords="NONMEM", keywords="motivational interviewing", abstract="Background: The strengthening or substitution of intravenous cytotoxic chemotherapy cycles by oral targeted anticancer therapies, such as protein kinase inhibitors (PKIs), has provided impressive clinical benefits and autonomy as well as a better quality of life for patients with cancer. Despite these advances, adverse event management at home and medication adherence remain challenging. In addition, PKI plasma concentrations vary significantly among patients with cancer receiving the same dosage, which could explain part of the observed variability in the therapeutic response. Objective: The aim of this optimizing oral targeted anticancer therapies (OpTAT) study is to optimize and individualize targeted anticancer treatments to improve patient care and self-monitoring through an interprofessional medication adherence program (IMAP) combined with measurement PKI plasma concentrations. Methods: The OpTAT study has two parts: (1) a 1:1 randomized medication adherence program, in which the intervention consists of regular motivational interviewing sessions between the patient and the pharmacist, along with the delivery of PKIs in electronic monitors, and (2) a systematic collection of blood samples and clinical and biological data for combined pharmacokinetic and pharmacodynamic analysis. On the basis of the electronic monitor data, medication adherence will be compared between groups following the three operational definitions: implementation of treatment during the persistent period, persistence with treatment and longitudinal adherence. The implementation will be described using generalized estimating equation models. The persistence of PKI use will be represented using a Kaplan-Meier survival curve. Longitudinal adherence is defined as the product of persistence and implementation. PKI pharmacokinetics will be studied using a population approach. The relationship between drug exposure and efficacy outcomes will be explored using Cox regression analysis of progression-free survival. The relationship between drug exposure and toxicity will be analyzed using a pharmacokinetic-pharmacodynamic model and by logistic regression analysis. Receiver operating characteristic analyses will be applied to evaluate the best exposure threshold associated with clinical benefits. Results: The first patient was included in May 2015. As of June 2021, 262 patients had participated in at least one part of the study: 250 patients gave at least one blood sample, and 130 participated in the adherence study. Data collection is in process, and the final data analysis is planned to be performed in 2022. Conclusions: The OpTAT study will inform us about the effectiveness of the IMAP program in patients with solid cancers treated with PKIs. It will also shed light on PKI pharmacokinetic and pharmacodynamic properties, with the aim of learning how to adapt the PKI dosage at the individual patient level to increase PKI clinical suitability. The IMAP program will enable interprofessional teams to learn about patients' needs and to consider their concerns about their PKI self-management, considering the patient as an active partner. Trial Registration: ClinicalTrials.gov NCT04484064; https://clinicaltrials.gov/ct2/show/NCT04484064. International Registered Report Identifier (IRRID): DERR1-10.2196/30090 ", doi="10.2196/30090", url="https://www.researchprotocols.org/2021/6/e30090", url="http://www.ncbi.nlm.nih.gov/pubmed/34185020" } @Article{info:doi/10.2196/29208, author="Edelman, Alison and Hemon, Agnes and Creinin, Mitchell and Borensztein, Pascale and Scherrer, Bruno and Glasier, Anna", title="Assessing the Pregnancy Protective Impact of Scheduled Nonadherence to a Novel Progestin-Only Pill: Protocol for a Prospective, Multicenter, Randomized, Crossover Study", journal="JMIR Res Protoc", year="2021", month="Jun", day="8", volume="10", number="6", pages="e29208", keywords="protocol", keywords="missed pill", keywords="progestin-only pills", keywords="contraception", keywords="pharmacokinetics", abstract="Background: Progestin-only contraceptive pills (POP) are commonly reserved for women with medical comorbidities but in actuality, POPs can be safely used by anyone wanting to prevent pregnancy. This wide safety profile makes them an ideal candidate for being available over the counter without a prescription, but adherence issues may be more common with over-the-counter use. We need a better understanding of the ability of POPs to prevent pregnancy when adherence issues occur in the form of a missed or delayed pill. Objective: This study aims to determine cervical mucus characteristics following a 6-hour delayed pill intake or after one missed pill as compared to typical daily use of norgestrel 75 mcg. Methods: This prospective, multicenter, randomized, crossover study assesses the effect of norgestrel 75 mcg (Opill) on cervical mucus and ovarian activity during reported compliant daily use, after a 6-hour delayed intake mid cycle, and after a mid-cycle missed pill. Subject participation will last approximately 4.5 months. We will recruit at 2 US sites: Oregon Health \& Science University, Portland, Oregon and University of California Davis Health, Sacramento, California. Reproductive-aged subjects with regular menstrual cycles (21-35 days), BMI <32 kg/m2, and proven ovulation (screening luteal phase progesterone >3 ng/mL [>10 nmol/L]) are eligible to enroll. Participants cannot be at risk for pregnancy during the study period and not use other hormonal methods. Norgestrel 75 mcg will be taken at the same time daily except for one day in each of treatment periods 2 and 3, when the pill will be taken either 6 hours late (delayed pill) or omitted completely (missed pill). Every 3-4 days, we will monitor subjects for follicular activity with transvaginal ultrasound (TVUS) examination, cervical mucus, and blood sampling for ovarian hormones and gonadotropins. Subjects will undergo serial cervical mucus sampling on the days with missed and delayed pill intake at 8 hours after pill intake on the day before the delayed or missed pill, 3 hours following the scheduled time of pill intake if intake was delayed, 6 hours after the scheduled time if intake was omitted, and on the next day 30 minutes before the time of scheduled pill intake. The primary objective of the study is to determine the effect of a delayed or omitted pill intake on cervical mucus characteristics based on a modified Insler score compared to reported daily use. Results: Our protocol was successfully approved by a central institutional review board (Advarra, Columbia, MD), received ethical approval on March 23, 2018, and was registered with ClinicalTrials.gov (NCT03585712). As of January 2020, the study completed enrollment of 52 subjects. Analyses are pending. Conclusions: Our protocol was approved by a central review board, and study procedures were successfully executed with completed proposed enrollment. Trial Registration: ClinicalTrials.gov NCT03585712; https://clinicaltrials.gov/ct2/show/NCT03585712 International Registered Report Identifier (IRRID): DERR1-10.2196/29208 ", doi="10.2196/29208", url="https://www.researchprotocols.org/2021/6/e29208", url="http://www.ncbi.nlm.nih.gov/pubmed/33970869" } @Article{info:doi/10.2196/22533, author="Dabner, Lucy and Pieles, E. Guido and Steward, G. Colin and Hamilton-Shield, P. Julian and Ness, R. Andrew and Rogers, A. Chris and Bucciarelli-Ducci, Chiara and Greenwood, Rosemary and Ellis, Lucy and Sheehan, Karen and Reeves, C. Barnaby", title="Treatment of Barth Syndrome by Cardiolipin Manipulation (CARDIOMAN) With Bezafibrate: Protocol for a Randomized Placebo-Controlled Pilot Trial Conducted in the Nationally Commissioned Barth Syndrome Service", journal="JMIR Res Protoc", year="2021", month="May", day="31", volume="10", number="5", pages="e22533", keywords="randomized controlled trial", keywords="Barth syndrome", keywords="cardiomyopathies", keywords="inherited cardiomyopathy", keywords="bezafibrate", keywords="placebo controlled", keywords="rare disease", keywords="resveratrol", keywords="cardiomyopathy", keywords="metabolism", keywords="lipid", keywords="genetic diseases", keywords="x-linked", keywords="genes", keywords="mitochondrial", keywords="controlled clinical trial", keywords="placebos", keywords="mitochondrial diseases", keywords="metabolic diseases", keywords="lipid metabolism", keywords="lipid metabolism disorders", keywords="cross-over studies", abstract="Background: Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. Objective: The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. Methods: The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. Results: A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. Conclusions: This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579 International Registered Report Identifier (IRRID): DERR1-10.2196/22533 ", doi="10.2196/22533", url="https://www.researchprotocols.org/2021/5/e22533", url="http://www.ncbi.nlm.nih.gov/pubmed/34057417" } @Article{info:doi/10.2196/21909, author="Mohiuddin, Mohammed and Park, Rex and Wesselmann, Ursula and Pukall, Caroline and Jarvi, Keith and Nickel, Curtis and Doiron, Christopher and Gilron, Ian", title="Efficacy and Safety of Drug Combinations for Chronic Pelvic Pain: Protocol for a Systematic Review", journal="JMIR Res Protoc", year="2021", month="May", day="17", volume="10", number="5", pages="e21909", keywords="chronic pelvic pain", keywords="combination therapy", keywords="clinical studies", keywords="systematic review", keywords="chronic prostatitis", keywords="chronic pelvic pain syndrome", keywords="CPPS", keywords="interstitial cystitis", keywords="bladder pain syndrome", keywords="efficacy", keywords="safety", keywords="drug", keywords="pain", keywords="pelvis", keywords="chronic pain", keywords="protocol", keywords="therapy", keywords="treatment", keywords="combination", abstract="Background: Chronic pelvic pain with various etiologies and mechanisms affects men and women and is a major challenge. Monotherapy is often unsuccessful for chronic pelvic pain, and combinations of different classes of medications are frequently prescribed, with the expectation of improved outcomes. Although a number of combination trials for chronic pelvic pain have been reported, we are not aware of any systematic reviews of the available evidence on combination drug therapy for chronic pelvic pain. Objective: We have developed a protocol for a systematic review to evaluate available evidence of the efficacy and safety of drug combinations for chronic pelvic pain. Methods: This systematic review will involve a detailed search of randomized controlled trials investigating drug combinations to treat chronic pelvic pain in adults. The databases searched will include the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from their inception until the date the searches are run to identify relevant studies. The primary outcome will be pain relief measured using validated scoring tools. Secondary outcomes, where reported, will include the following: adverse events, serious adverse events, sexual function, quality of life, and depression and anxiety. Methodological quality of each included study will be assessed using the Cochrane Risk of Bias Tool. Results: The systematic review defined by this protocol is expected to synthesize available good quality evidence on combination drug therapy in chronic pelvic pain, which may help guide future research and treatment choices for patients and their health care providers. Conclusions: This review will provide a clearer understanding of the efficacy and safety of combination pharmacological therapy for chronic pelvic pain. Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42020192231; https://www.crd.york.ac.uk/prospero/display\_record.php?RecordID=192231 International Registered Report Identifier (IRRID): PRR1-10.2196/21909 ", doi="10.2196/21909", url="https://www.researchprotocols.org/2021/5/e21909", url="http://www.ncbi.nlm.nih.gov/pubmed/33999006" } @Article{info:doi/10.2196/29161, author="Leitch, Sharon and Smith, Alesha and Zeng, Jiaxu and Stokes, Tim", title="Using an Information Package to Reduce Patients' Risk of Renal Damage: Protocol for a Randomized Feasibility Trial", journal="JMIR Res Protoc", year="2021", month="Apr", day="30", volume="10", number="4", pages="e29161", keywords="triple whammy", keywords="medication safety", keywords="patient education", keywords="general practice", keywords="NSAID", keywords="digital intervention", keywords="primary care", keywords="safety", keywords="protocol", keywords="feasibility", keywords="randomized controlled trial", keywords="risk", keywords="kidney", keywords="renal", keywords="information", keywords="acceptability", abstract="Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are a common cause of renal damage, especially when taken together with angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin II receptor blockers (ARBs) plus a diuretic --- a combination known as the ``triple whammy.'' New Zealand patients are at high risk of the ``triple whammy'' because they can easily purchase NSAIDs without a prescription and in nonpharmacy retail settings (eg, the supermarket), there is no legal requirement to include patient information sheets with medication, and direct-to-consumer drug advertising is permitted. A patient information package has been developed for those at greatest risk of the ``triple whammy,'' consisting of a printable PDF and an interactive online learning activity. This information package aims to inform patients about their elevated risk of harm from NSAIDS and discourage use of NSAIDs. A randomized control trial was planned to assess the effect of the information package. Objective: This study aims to pilot the trial procedures for recruiting patients and providing patient information online and to assess the acceptability of the patient information package. Methods: A two-armed randomized feasibility trial will be undertaken in Northland, New Zealand. We will recruit 50 patients who are at least 18 years old from those who have signed up to receive email alerts through their general practice. Patients eligible for this study have been prescribed an ACE-i or ARB plus a diuretic in the past 3 months. They will be randomly allocated to 2 study arms. The intervention arm will receive access to an information package plus usual care; the control arm will receive usual care alone. Online surveys will be used to assess NSAID knowledge and NSAID use at baseline and after 2 weeks for both arms. The intervention arm will also evaluate the information package in an additional survey based on Normalization Process Theory (NPT) concepts. We will report the number and proportion of participants who are eligible and consent to participate in the trial. Response and drop-out rates will be reported for each trial arm. The numbers of patients who interact with the education package will be reported together with the patient evaluation of it. Results: Funding has been obtained from the Health Research Council of New Zealand (HRC 18-031). The University of Otago Human Research Ethics Committee (H21/016) has approved this trial. Consultation has been undertaken with The Ngai Tahu research consultation committee. The trial commenced on April 12, 2021. Conclusions: This feasibility trial will test the study processes prior to commencing a randomized controlled trial and will determine the acceptability of the patient information package. We anticipate this work will provide useful information for other researchers attempting similar work. International Registered Report Identifier (IRRID): PRR1-10.2196/29161 ", doi="10.2196/29161", url="https://www.researchprotocols.org/2021/4/e29161", url="http://www.ncbi.nlm.nih.gov/pubmed/33929338" } @Article{info:doi/10.2196/25406, author="Rafiei, Ramin and Williams, Chelsea and Jiang, Jeannette and Aungst, Dy Timothy and Durrer, Matthias and Tran, Dao and Howald, Ralph", title="Digital Health Integration Assessment and Maturity of the United States Biopharmaceutical Industry: Forces Driving the Next Generation of Connected Autoinjectable Devices", journal="JMIR Mhealth Uhealth", year="2021", month="Mar", day="18", volume="9", number="3", pages="e25406", keywords="digital health", keywords="artificial intelligence", keywords="drug delivery", keywords="biopharma", keywords="autoinjector", keywords="injectable devices", keywords="disease management", keywords="autoimmune", keywords="oncology", keywords="rare diseases", doi="10.2196/25406", url="https://mhealth.jmir.org/2021/3/e25406", url="http://www.ncbi.nlm.nih.gov/pubmed/33621188" } @Article{info:doi/10.2196/14563, author="Bonet Olivencia, Samuel and Sasangohar, Farzan", title="Investigating the Food and Drug Administration Biotherapeutics Review and Approval Process: Narrative Review", journal="JMIR Form Res", year="2021", month="Mar", day="4", volume="5", number="3", pages="e14563", keywords="biotherapeutics", keywords="drug approval", keywords="drug review process", keywords="model-based systems engineering", abstract="Background: The development, review, and approval process of therapeutic biological products in the United States presents two primary challenges: time and cost. Advancing a biotherapeutic from concept to market may take an average of 12 years, with costs exceeding US \$1 billion, and the product may still fail the US Food and Drug Administration (FDA) approval process. Despite the FDA's practices to expedite the approval of new therapies, seeking FDA approval remains a long, costly, and risky process. Objective: The objective of this paper is to explore the factors and gaps related to the FDA review and approval process that contribute to process inefficiencies and complexities as well as proposed methods and solutions to address such gaps. This paper also aims to investigate the available modeling efforts for the FDA approval process of therapeutic biological products. Methods: A narrative review of literature was conducted to understand the scope of published knowledge about challenges, opportunities, and specific methods to address the factors and gaps related to the review and approval of new drugs, including therapeutic biological products. Relevant peer-reviewed journal articles, conference proceedings, book chapters, official reports from public policy professional centers, and official reports and guidelines from the FDA were reviewed. Results: Of the 23 articles identified in this narrative literature review, none modeled the current FDA review and approval process structure to address issues related to the robustness, reliability, and efficiency of its operations from an external point of view. Although several studies summarize the FDA approval process with clarity, in addition to bringing to light the problems and challenges faced by the regulatory agency, only a few attempts have been made to provide solutions for the problems and challenges identified. In addition, although several reform models have been discussed, these models lack the application of scientific methodologies and modeling techniques in understanding FDA as a complex sociotechnical system. Furthermore, tools and methods to assess the efficacy of the models before implementation are largely absent. Conclusions: The findings suggest the efficacy of model-based systems engineering approaches for identifying opportunities for significant improvements to the FDA review and approval process. Using this holistic approach will serve several investigative purposes: identify influential sources of variability that cause major delays, including individual, team, and organizational decision making; identify the human-system bottlenecks; identify areas of opportunity for design-driven improvements; study the effect of induced changes in the system; and assess the robustness of the structure of the FDA approval process in terms of enforcement and information symmetry. ", doi="10.2196/14563", url="https://formative.jmir.org/2021/3/e14563", url="http://www.ncbi.nlm.nih.gov/pubmed/33661119" } @Article{info:doi/10.2196/22511, author="Sharshar, Tarek and Ben Hadj Salem, Omar and Porcher, Rapha{\"e}l and Grimaldi-Bensouda, Lamiae and Heming, Nicholas and Clair, Bernard and Azabou, Eric and Mazeraud, Aur{\'e}lien and Rohaut, Benjamin and Outin, Herv{\'e}", title="Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus in Adults Admitted to Intensive Care Units: Protocol for a Double-Blind, Multicenter Randomized Controlled Trial", journal="JMIR Res Protoc", year="2021", month="Feb", day="24", volume="10", number="2", pages="e22511", keywords="generalized convulsive status epilepticus", keywords="intensive care unit", keywords="seizure", keywords="valproic acid", abstract="Background: Generalized convulsive status epilepticus (GCSE) is a frequent medical emergency. GCSE treatment focuses on the administration of benzodiazepines followed by a second-line antiepileptic drug (AED). Despite this stepwise strategy, GCSE is not controlled in one-quarter of patients and is associated with protracted hospitalization, high mortality, and long-term disability. Valproic acid (VPA) is an AED with good tolerability and neuroprotective properties. Objective: This study aims to demonstrate that administration of VPA as an adjuvant for first- and second-line treatment in GCSE can improve outcomes. Methods: A multicenter, double-blind, randomized controlled trial was conducted, comparing VPA with a placebo in adults admitted to intensive care units (ICUs) for GCSE in France. GCSE was diagnosed by specifically trained ICU physicians according to standard criteria. All patients received standard of care, including a benzodiazepine and a second-line AED (not VPA), at the discretion of the treating medical team. In the intervention arm, VPA was administered intravenously at a loading dose of 30 mg/kg over 15 minutes, followed by a continuous infusion of 1 mg/kg/hour over the next 12 hours. In the placebo group, an identical intravenous administration of 0.9\% saline was used. The primary outcome was the proportion of patients discharged alive from the hospital by day 15. Secondary outcomes were frequency of refractory and super refractory GCSE, ICU-related morbidity, adverse events related to VPA, and cognitive dysfunction at 3 months. Statistical analyses will be performed according to the intent-to-treat principle. Results: The first patient was randomized on February 18, 2013, and the last patient was randomized on July 7, 2018. Of 248 planned patients, 98.7\% (245/248) were enrolled across 20 ICUs. At present, data management is still ongoing, and all parties involved in the trial remain blinded. Conclusions: The Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus (VALSE) trial will evaluate whether the use of VPA as an adjuvant for first- and second-line treatment in GCSE improves outcomes. Trial Registration: ClinicalTrials.gov NCT01791868; https://clinicaltrials.gov/ct2/show/NCT01791868. International Registered Report Identifier (IRRID): DERR1-10.2196/22511 ", doi="10.2196/22511", url="https://www.researchprotocols.org/2021/2/e22511", url="http://www.ncbi.nlm.nih.gov/pubmed/33625371" } @Article{info:doi/10.2196/22905, author="Rizzo, N. Rodrigo R. and Ferraro, C. Michael and Wewege, A. Michael and Cashin, G. Aidan and Leake, B. Hayley and O'Hagan, T. Edel and Jones, D. Matthew and Gustin, M. Sylvia and McAuley, H. James", title="Efficacy and Safety of Medicines Targeting Neurotrophic Factors in the Management of Low Back Pain: Protocol for a Systematic Review and Meta-analysis", journal="JMIR Res Protoc", year="2021", month="Jan", day="22", volume="10", number="1", pages="e22905", keywords="back pain", keywords="analgesics", keywords="drug therapy", keywords="monoclonal antibodies", keywords="nerve growth factor", keywords="review", keywords="meta-analysis", keywords="antibodies", keywords="pain", keywords="back", keywords="growth factor", keywords="disability", keywords="sciatica", abstract="Background: Low back pain (LBP) is the leading cause of years lived with disability worldwide. Most people with LBP receive the diagnosis of nonspecific LBP or sciatica. Medications are commonly prescribed but have limited analgesic effects and are associated with adverse events. A novel treatment approach is to target neurotrophins such as nerve growth factor (NGF) to reduce pain intensity. NGF inhibitors have been tested in some randomized controlled trials (RCTs) in recent years, showing promise for the treatment of chronic LBP; however, their efficacy and safety need to be evaluated to guide regulatory actions. Objective: The aim of this study is to evaluate the efficacy and safety of medicines targeting neurotrophins in patients with LBP and sciatica. Methods: In this systematic review, we will include published and unpublished records of parallel RCTs and the first phase of crossover RCTs that compare the effects of medicines targeting neurotrophins with any control group. We will search the CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, EU Clinical Trials Register, and WHO International Clinical Registry Platform databases from inception. Pairs of authors will independently screen the records for eligibility, and we will independently extract data in duplicate. We will conduct a quantitative synthesis (meta-analysis) with the studies that report sufficient data and compare the medicines of interest versus placebo. We will use random-effects models and calculate estimates of effects and heterogeneity for each outcome. We will assess the risk of bias for each study using the Cochrane Collaboration tool, and form judgments of confidence in the evidence according to GRADE recommendations. We will use the PRISMA statement to report the findings. We plan to conduct subgroup analyses by condition, type of medication, and time point. We will also assess the impact of a potential new trial on an existing meta-analysis. Data from studies that meet inclusion criteria but cannot be included in the meta-analysis will be reported narratively. Results: The protocol was registered on the Open Science Framework on May 19, 2020. As of December 2020, we have identified 1932 records. Conclusions: This systematic review and meta-analysis will assess the evidence for the efficacy and safety of NGF inhibitors for pain in patients with nonspecific LBP and sciatica. The inclusion of new studies and unpublished data may improve the precision of the effect estimates and guide regulatory actions of the medications for LBP and sciatica. Trial Registration: Open Science Framework; https://osf.io/b8adn/ International Registered Report Identifier (IRRID): DERR1-10.2196/22905 ", doi="10.2196/22905", url="http://www.researchprotocols.org/2021/1/e22905/", url="http://www.ncbi.nlm.nih.gov/pubmed/33480861" } @Article{info:doi/10.2196/21648, author="Khan, Younus Junaed and Khondaker, Islam Md Tawkat and Hoque, Tazim Iram and Al-Absi, H. Hamada R. and Rahman, Saifur Mohammad and Guler, Reto and Alam, Tanvir and Rahman, Sohel M.", title="Toward Preparing a Knowledge Base to Explore Potential Drugs and Biomedical Entities Related to COVID-19: Automated Computational Approach", journal="JMIR Med Inform", year="2020", month="Nov", day="10", volume="8", number="11", pages="e21648", keywords="COVID-19", keywords="2019-nCoV", keywords="coronavirus", keywords="SARS-CoV-2", keywords="SARS", keywords="remdesivir", keywords="statin", keywords="statins", keywords="dexamethasone", keywords="ivermectin", keywords="hydroxychloroquine", abstract="Background: Novel coronavirus disease 2019 (COVID-19) is taking a huge toll on public health. Along with the non-therapeutic preventive measurements, scientific efforts are currently focused, mainly, on the development of vaccines and pharmacological treatment with existing drugs. Summarizing evidences from scientific literatures on the discovery of treatment plan of COVID-19 under a platform would help the scientific community to explore the opportunities in a systematic fashion. Objective: The aim of this study is to explore the potential drugs and biomedical entities related to coronavirus related diseases, including COVID-19, that are mentioned on scientific literature through an automated computational approach. Methods: We mined the information from publicly available scientific literature and related public resources. Six topic-specific dictionaries, including human genes, human miRNAs, diseases, Protein Databank, drugs, and drug side effects, were integrated to mine all scientific evidence related to COVID-19. We employed an automated literature mining and labeling system through a novel approach to measure the effectiveness of drugs against diseases based on natural language processing, sentiment analysis, and deep learning. We also applied the concept of cosine similarity to confidently infer the associations between diseases and genes. Results: Based on the literature mining, we identified 1805 diseases, 2454 drugs, 1910 genes that are related to coronavirus related diseases including COVID-19. Integrating the extracted information, we developed the first knowledgebase platform dedicated to COVID-19, which highlights potential list of drugs and related biomedical entities. For COVID-19, we highlighted multiple case studies on existing drugs along with a confidence score for their applicability in the treatment plan. Based on our computational method, we found Remdesivir, Statins, Dexamethasone, and Ivermectin could be considered as potential effective drugs to improve clinical status and lower mortality in patients hospitalized with COVID-19. We also found that Hydroxychloroquine could not be considered as an effective drug for COVID-19. The resulting knowledgebase is made available as an open source tool, named COVID-19Base. Conclusions: Proper investigation of the mined biomedical entities along with the identified interactions among those would help the research community to discover possible ways for the therapeutic treatment of COVID-19. ", doi="10.2196/21648", url="http://medinform.jmir.org/2020/11/e21648/", url="http://www.ncbi.nlm.nih.gov/pubmed/33055059" } @Article{info:doi/10.2196/20291, author="Kang, Hongyu and Li, Jiao and Wu, Meng and Shen, Liu and Hou, Li", title="Building a Pharmacogenomics Knowledge Model Toward Precision Medicine: Case Study in Melanoma", journal="JMIR Med Inform", year="2020", month="Oct", day="21", volume="8", number="10", pages="e20291", keywords="pharmacogenomics", keywords="knowledge model", keywords="BERT--CRF model", keywords="named entity recognition", keywords="melanoma", abstract="Background: Many drugs do not work the same way for everyone owing to distinctions in their genes. Pharmacogenomics (PGx) aims to understand how genetic variants influence drug efficacy and toxicity. It is often considered one of the most actionable areas of the personalized medicine paradigm. However, little prior work has included in-depth explorations and descriptions of drug usage, dosage adjustment, and so on. Objective: We present a pharmacogenomics knowledge model to discover the hidden relationships between PGx entities such as drugs, genes, and diseases, especially details in precise medication. Methods: PGx open data such as DrugBank and RxNorm were integrated in this study, as well as drug labels published by the US Food and Drug Administration. We annotated 190 drug labels manually for entities and relationships. Based on the annotation results, we trained 3 different natural language processing models to complete entity recognition. Finally, the pharmacogenomics knowledge model was described in detail. Results: In entity recognition tasks, the Bidirectional Encoder Representations from Transformers--conditional random field model achieved better performance with micro-F1 score of 85.12\%. The pharmacogenomics knowledge model in our study included 5 semantic types: drug, gene, disease, precise medication (population, daily dose, dose form, frequency, etc), and adverse reaction. Meanwhile, 26 semantic relationships were defined in detail. Taking melanoma caused by a BRAF gene mutation into consideration, the pharmacogenomics knowledge model covered 7 related drugs and 4846 triples were established in this case. All the corpora, relationship definitions, and triples were made publically available. Conclusions: We highlighted the pharmacogenomics knowledge model as a scalable framework for clinicians and clinical pharmacists to adjust drug dosage according to patient-specific genetic variation, and for pharmaceutical researchers to develop new drugs. In the future, a series of other antitumor drugs and automatic relation extractions will be taken into consideration to further enhance our framework with more PGx linked data. ", doi="10.2196/20291", url="http://medinform.jmir.org/2020/10/e20291/", url="http://www.ncbi.nlm.nih.gov/pubmed/33084582" } @Article{info:doi/10.2196/17684, author="Milne-Ives, Madison and Lam, Ching and van Velthoven, Michelle and Meinert, Edward", title="The Impact of Brexit on the Pharmaceutical Supply Chain of the United Kingdom: Scoping Review Protocol", journal="JMIR Res Protoc", year="2020", month="Sep", day="23", volume="9", number="9", pages="e17684", keywords="Brexit", keywords="drug industry", keywords="pharmaceutical supply", abstract="Background: The continuing uncertainty around Brexit has caused concern in the pharmaceutical industry and among health care professionals and patients. The exact consequences of Brexit on the pharmaceutical supply chain in the United Kingdom will depend on whether a deal is reached and what it entails, but it is likely to be affected by the withdrawal of the United Kingdom from the European Union. Regulatory issues and delays in supply have the potential to negatively affect the ability of UK residents to receive an adequate and timely supply of necessary medicines. Objective: The purpose of this protocol is to provide an overview and critical analysis of current perspectives on the effect of Brexit on the UK pharmaceutical supply chain. Methods: The PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) guidelines will be used to structure this protocol. A systematic search of MEDLINE, EMBASE, PsycINFO, Healthcare Management Information Consortium (HMIC), Cochrane, Web of Science, Business Source Complete, EconLit, and Economist Intelligence Unit will be conducted, as well as a Google and Nexis.UK search for grey literature such as reports, opinion pieces, and press releases. Two reviewers will independently screen the titles and abstracts of identified references and select studies according to the eligibility criteria. Any discrepancies will then be discussed and resolved. One reviewer will extract data from the included studies into a standardized form, which will be validated by a second reviewer. Risk of bias will be assessed using the Cochrane Collaboration Risk of Bias tool for any randomized controlled trials; quality will be assessed using the relevant Critical Appraisal Skills Programme (CASP) checklists; and grey literature will be assessed using the Authority, Accuracy, Coverage, Objectivity, Date, Significance (AACODS) checklist. Outcomes include the agreement between sources on the potential, likelihood, and severity of the consequences of Brexit on the UK pharmaceutical supply chain. Results: Results will be included in the scoping review, which will be published in 2020. Conclusions: This scoping review will summarize the currently expected consequences of Brexit on the UK pharmaceutical supply chain. International Registered Report Identifier (IRRID): PRR1-10.2196/17684 ", doi="10.2196/17684", url="http://www.researchprotocols.org/2020/9/e17684/", url="http://www.ncbi.nlm.nih.gov/pubmed/32965239" } @Article{info:doi/10.2196/20007, author="Michelson, Matthew and Chow, Tiffany and Martin, A. Neil and Ross, Mike and Tee Qiao Ying, Amelia and Minton, Steven", title="Artificial Intelligence for Rapid Meta-Analysis: Case Study on Ocular Toxicity of Hydroxychloroquine", journal="J Med Internet Res", year="2020", month="Aug", day="17", volume="22", number="8", pages="e20007", keywords="meta-analysis", keywords="rapid meta-analysis", keywords="artificial intelligence", keywords="drug", keywords="analysis", keywords="hydroxychloroquine", keywords="toxic", keywords="COVID-19", keywords="treatment", keywords="side effect", keywords="ocular", keywords="eye", abstract="Background: Rapid access to evidence is crucial in times of an evolving clinical crisis. To that end, we propose a novel approach to answer clinical queries, termed rapid meta-analysis (RMA). Unlike traditional meta-analysis, RMA balances a quick time to production with reasonable data quality assurances, leveraging artificial intelligence (AI) to strike this balance. Objective: We aimed to evaluate whether RMA can generate meaningful clinical insights, but crucially, in a much faster processing time than traditional meta-analysis, using a relevant, real-world example. Methods: The development of our RMA approach was motivated by a currently relevant clinical question: is ocular toxicity and vision compromise a side effect of hydroxychloroquine therapy? At the time of designing this study, hydroxychloroquine was a leading candidate in the treatment of coronavirus disease (COVID-19). We then leveraged AI to pull and screen articles, automatically extract their results, review the studies, and analyze the data with standard statistical methods. Results: By combining AI with human analysis in our RMA, we generated a meaningful, clinical result in less than 30 minutes. The RMA identified 11 studies considering ocular toxicity as a side effect of hydroxychloroquine and estimated the incidence to be 3.4\% (95\% CI 1.11\%-9.96\%). The heterogeneity across individual study findings was high, which should be taken into account in interpretation of the result. Conclusions: We demonstrate that a novel approach to meta-analysis using AI can generate meaningful clinical insights in a much shorter time period than traditional meta-analysis. ", doi="10.2196/20007", url="http://www.jmir.org/2020/8/e20007/", url="http://www.ncbi.nlm.nih.gov/pubmed/32804086" } @Article{info:doi/10.2196/ijmr.5231, author="Lombardo, Simona and Cosentino, Marco", title="Internet Use for Searching Information on Medicines and Disease: A Community Pharmacy--Based Survey Among Adult Pharmacy Customers", journal="Interact J Med Res", year="2016", month="Jul", day="13", volume="5", number="3", pages="e22", keywords="Internet", keywords="health information", keywords="information searching behavior", keywords="medicines", keywords="diseases", keywords="survey", abstract="Background: The Internet is increasingly used as a source of health-related information, and a vast majority of Internet users are performing health-related searches in the United States and Europe, with wide differences among countries. Health information searching behavior on the Internet is affected by multiple factors, including demographics, socioeconomic factors, education, employment, attitudes toward the Internet, and health conditions, and their knowledge may help to promote a safer use of the Internet. Limited information however exists so far about Internet use to search for medical information in Italy. Objective: The objective of this study was to investigate the use of the Internet for searching for information on medicines and disease in adult subjects in Northern Italy. Methods: Survey in randomly selected community pharmacies, using a self-administered questionnaire, with open and multiple choices questions, was conducted. Results: A total of 1008 participants were enrolled (59.5\% women; median age: 43 years; range: 14-88 years). Previous use of the Internet to search for information about medicines or dietary supplements was reported by 26.0\% of respondents, more commonly by women (30.00\% vs 20.10\% men, P<.001), unmarried subjects (32.9\% vs 17.4\% widowed subjects, P=.022), and employed people (29.1\% vs 10.4\% retired people, P=.002). Use was highest in the age range of 26 to 35 (40.0\% users vs 19.6\% and 12.3\% in the age range ?25 and ?56, respectively, P<.001) and increased with years of education (from 5.3\% with 5 years, up to 41.0\% with a university degree, P<.001). Previous use of the Internet to search for information about disease was reported by 59.1\% of respondents, more commonly by women (64.5\% vs 51.0\% males, P<.001), unmarried subjects (64.2\% vs 58.5\% married or divorced subjects and 30.4\% widowed subjects, P=.012), unemployed people (66.7\% vs 64.0\% workers and 29.9\% retired people, P<.001). Use was highest in the age range of 26 to 35 (70.1\% vs 64.4\% in both 36-45 and 46-55 ranges and 35.1\% in ?56, P<.001) and increased with years of education (from 12.5\% with 5 years up to 66.7\% with 13 years and 68.6\% with a university degree, P<.001). Retrieved information was rated as satisfactory by about 87.5\% (88.1\% women and 86.2\% men, P=.562). Recent use of medicines or dietary supplements was associated with more frequent use of the Internet to search for disease and drugs. Conclusions: The study provides detailed information on the use of the Internet for searching for information on medicines and disease in the Italian population. Gender, age, social status and level of education, and the previous use of medicines, affect searching behaviors and use patterns. Results can support educational interventions to promote the retrieval of high-quality information by Internet users and health professionals advising patients about appropriate use of Internet for health-related purposes. ", doi="10.2196/ijmr.5231", url="http://www.i-jmr.org/2016/3/e22/", url="http://www.ncbi.nlm.nih.gov/pubmed/27417304" }