Staphylococcus aureus bacteraemia (SAB) is a common and severe infection, with a 90-day mortality of 24%–32%. Cloxacillin is regarded as a first-line antibiotic treatment in SAB in Sweden. However, exposure to cloxacillin in real-world hospitalised patients with SAB, most of whom are elderly patients treated outside the intensive care unit, is not well described. There are also limited data on the role of unbound cloxacillin exposure in relation to renal function or drug-induced toxicity.

This multicentre, prospective, observational clinical trial will include 95 adult patients with methicillin-susceptible S. aureus bacteraemia, treated with cloxacillin. Patients with endocarditis, polymicrobial bacteraemia or those considered unsuitable for cloxacillin treatment are excluded. Trough and peak total and unbound cloxacillin concentrations will be measured at steady state at days 2 and 7. Blood cultures will be obtained at days 2, 3, 4 and 7 to assess time to negative culture. Renal function will be assessed daily for plasma creatinine and at days 1 and 6 for cystatin C and for 12-hour urine creatinine clearance. In a novel approach to detecting nephrotoxicity, renal tubular damage biomarkers will be measured at days 1 and 6 (KIM-1, N-acetyl-β-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, urine cystatin C, alpha-1-microglobulin). Detection of neurologic symptoms such as confusion, tremor, hallucinations and convulsions, as well as consciousness, will be monitored daily using a structured evaluation form.

We aim to investigate to which extent target attainment (100% of the dosing interval during which the free (unbound) drug concentration exceeds the minimum inhibitory concentration) is achieved with standard dosing of cloxacillin in a real-world cohort of hospitalised patients with SAB, and whether initial renal function can predict who is at risk for underdosing or overdosing. We will also explore whether neurological or renal damage is prevalent and associated with cloxacillin levels.

Ethics approval has been granted by the Swedish Ethical Review Authority (EUCT 2023-505148-20-00) as part of a low-intervention clinical trial approval according to EU regulation 536/2014. Results will be disseminated in a peer-reviewed journal and at academic conferences.

EUCT 2023-505148-20-00.

While almost half of older adults admitted to hospital are prescribed potentially inappropriate medicines, less than 1% have a medicine proactively deprescribed during admission in the UK. The CompreHensive geriAtRician-led MEdication Review (CHARMER) intervention is designed to address geriatricians’ and pharmacists’ barriers and enablers to deprescribing. The CHARMER definitive trial will evaluate effectiveness, cost-effectiveness and safety.

A stepped-wedge cluster randomised controlled trial will be conducted in 20 hospitals in England, with four hospitals in reserve. All hospitals will collect baseline data. Every 3 months, five hospitals will be randomised to receive the intervention. The intervention, implemented by a local project manager, comprises a hospital action plan to set deprescribing as an organisational goal; workshops for pharmacists and geriatricians to change beliefs about deprescribing; weekly briefings between geriatricians and pharmacists to discuss opportunities for deprescribing; benchmarking reports to compare deprescribing performance across participating hospitals. With an average of 200 patients admitted and discharged during each step, the study will have 89.5% power at 5% significance level and intra-class correlation coefficient of 0.05 to detect a 3% difference in 90-day re-admission rate from 16.7% versus 13.7%. Anonymised routinely collected data, including readmissions, will be obtained for all patients admitted during the study period. Enhanced data collection periods of 1 month during control and intervention periods will be used to recruit patients and data for secondary outcomes and process evaluation.

A stepped-wedge design enabled a smaller number of hospitals and patients to be included than a traditional cluster-randomised design. The complexity of intervention implementation necessitated a project manager in addition to the principal investigator responsible for trial conduct. Using routinely collected data for the primary outcome measure should ensure that the trial has sufficient power on completion. Planned enhanced data collection for short periods of time improves trial efficiency.

ISRCTN13248281.

Equity, Diversity, Inclusion and Accessibility (EDIA) are recognised as core principles in higher education, yet their practical integration into pharmacy education remains underexplored. This review aims to identify the scope of existing research, highlight knowledge gaps and provide valuable insights for pharmacy educators, researchers and policymakers seeking to enhance EDIA integration within pharmacy education.

This protocol describes the methodology for a scoping review to systematically map the existing peer-reviewed literature on EDIA in pharmacy education, focusing on three critical areas: faculty development, curriculum content and teaching strategies. Using the Population, Concept and Context framework, the review will include studies examining faculty members, students and administrators within formal pharmacy education contexts worldwide. The scoping review will adhere to the Joanna Briggs Institute methodology and PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The search will include peer-reviewed academic studies, accessed through databases such as MEDLINE, Embase, CINAHL, APA PsycINFO, ERIC and Web of Science. Backward snowballing will also be employed. Data will be charted using a predefined extraction tool, and findings will be synthesised and presented in tabular and narrative formats. A pilot search took place in March 2025, and the final search, study selection and data extraction will be conducted from May to December 2025. The subsequent analysis, presentation and interpretation of results are planned thereafter.

Ethics approval is not required. We plan to share findings through a variety of means including professional networks, peer-reviewed journal publications, conference presentations, invited workshops and webinars, on the FPD-Include project website and on our research groups’ university websites.

To determine the prevalence of potentially inappropriate prescribing (PIP), potentially inappropriate medication (PIM), potential prescription omission (PPO), potentially harmful drug–drug interactions (PDDI) and identify associated factors among older Ethiopians.

Systematic review and meta-analysis

We searched PubMed, HINARI, Scopus and Web of Science databases to identify eligible studies published up to 31 October 2025.

Observational studies reported the prevalence of PIP, PIM, PPO and PDDI among older adults from any healthcare settings were screened.

Two independent reviewers selected studies, extracted data and assessed the risk of bias. The quality and risk of bias of the studies were assessed using the Newcastle-Ottawa scale and Hoy risk of bias tool, respectively, while the certainty of evidence of outcomes was assessed using Grading of Recommendations, Assessment, Development and Evaluation based on Cochrane recommendations. We used a random-effects model for analyses to estimate the pooled prevalence and associated factors. All data analyses were done using Stata V.17 software.

The national prevalence of PIP, PIM, PPO and PDDI was estimated as main outcomes. Variations were estimated based on regions, age groups, outcome evaluation tool, disease type and healthcare setting.

The review included 25 studies (n=5662 participants) for PIP or PIM, 14 studies (n=2706 participants) for PDDI and 6 studies (n=1342 participants) for PPO. The pooled prevalence estimate was 41% (95% CI 33% to 48%), I²=96.87% for PIP, 37% (95% CI 31% to 44%), I²=96.33% for PIM, 55% (95% CI 36% to 73%), I²=99.00% for PDDI and 14% (95% CI 6% to 24%), I²=95.07% for PPO. The majority of the studies have very good quality (very good=13, good=1, satisfactory=11 for PIP and PIM; very good=11, satisfactory=3 for PDDI; very good=6 for PPO) and low risk of bias (low risk=18, moderate risk=7 for PIP and PIM; low risk=12, moderate risk=2 for PDDI and low risk=6 for PPO), while all studies for each outcome have low certainty of evidence. Subgroup analyses revealed significant regional and contextual variations. Polypharmacy was significantly associated with PIP (OR=3.72, 95% CI 2.53 to 5.46, p2=69.56%), PIM (OR=4.20, 95% CI 2.91 to 6.06, p2=57.83%) and PDDI (OR=4.51, 95% CI 3.05 to 6.69, p2=0.00%), while hypertension (OR=2.46, 95% CI 1.38 to 4.36, p2=0.00%) was associated with PIP.

This review found a high prevalence of PIP, PIM, PDDI and PPO among older adults in Ethiopia, with notable heterogeneity across regions. Polypharmacy was associated with PIP, PIM and PDDI, while hypertension showed association with PIP. Despite generally good study quality, the certainty of evidence was low for the included studies due to the cross-sectional design nature, with high heterogeneity. Therefore, these findings should be interpreted cautiously. This study indicates a high burden of inappropriate medication prescribing and its associated factors, underscoring the importance of further robust studies to clarify prescribing practices and associated factors.

CRD42024556744.

Multimorbidity, defined as two or more chronic medical conditions, leads to the use of multiple medicines, including for cardiovascular conditions. This is associated with frailty and an increased risk of medication-related harm. Hospitalised adults have higher rates of multimorbidity and frailty compared with non-hospitalised adults. The aim of this study was to examine the use of medicines for hypertension, ischaemic heart disease and atrial fibrillation among patients with multimorbidity and frailty, who are generally not well represented in clinical trials.

A cross-sectional study was performed of adults aged ≥45 years with inpatient admissions during an 18-month period. Regular medications prescribed at discharge and coding data were obtained from the electronic medical record and hospital datasets.

The prevalence of multimorbidity (using coded chronic medical conditions or the RxRisk pharmaceutical comorbidity index), frailty (using hospital frailty risk score) and polypharmacy (defined as ≥5 medicines) were calculated. The uptake of medicines recommended by the Australian Therapeutic Guidelines for patients with coded hypertension, ischaemic heart disease and atrial fibrillation was also assessed.

Two large acute care, teaching hospitals in Adelaide, South Australia.

23 980 unique patients were identified.

69% (n=16 637) of patients had multimorbidity using the coding definition compared with 94% (n=22 620) using the pharmaceutical comorbidity score. 81% (n=19 366) had polypharmacy and 46% (n=11 091) had frailty. More than 85% of patients with hypertension were taking an antihypertensive. More than 75% of patients with ischaemic heart disease were taking an antithrombotic or a lipid-lowering agent and more than 50% were taking an agent acting on the renin-angiotensin system. Over 70% of patients with atrial fibrillation without a contraindication to anticoagulation were taking an anticoagulant. Patients with multimorbidity were 11–51% more likely to be taking an antihypertensive, antithrombotic or lipid-lowering medicine for the respective cardiovascular conditions, whereas those with frailty were 31–48% less likely to be taking guideline-directed medicines for all conditions studied.

Over two-thirds of hospitalised patients with these cardiovascular conditions were taking at least one guideline-directed medicine. Medication use was generally more common in multimorbidity and less common in frailty. Outcomes studies are needed to quantify the risks and benefits of cardiovascular medicines in these patients.

Meperidine, once viewed as relatively safe, is now discouraged in clinical settings due to its associated risks. Previous studies have identified a significant decrease in meperidine distribution across the USA from 2000 to 2021. Regional disparities accompanied this decline. The goal of this study was to investigate if the decrease in meperidine distribution has continued in recent years, 2019–2023, and if regional variations persist. This investigation also aimed to identify correlates of meperidine distribution, including adult obesity prevalence and annual income, to provide insight into the regional variation.

Retrospective observational study using data from the Automation of Reports and Consolidated Orders System Drug Retail Summary Reports by the Drug Enforcement Administration (DEA), the Centers for Disease Control and Prevention (CDC) and the US Census Bureau.

USA, including Puerto Rico.

US population.

The primary outcome was the meperidine distribution across the US between 2019 and 2023. Secondary outcomes included associations between meperidine distribution and adult obesity prevalence and median household income.

Total meperidine distribution across the USA dropped by 57.8% from 2019 to 2023. A substantial geographic variation was found with southern states accounting for the second, third and fourth highest in meperidine use per capita in 2023, only behind Puerto Rico. In contrast, northeastern states accounted for four of the five lowest states. A significant relationship was found between annual income and meperidine distribution in 2022 (r(49) = –0.38, p

Our study revealed a continued decrease in meperidine distribution and sustained presence of geographical variation from 2019 to 2023. Furthermore, novel relationships were identified between meperidine distribution, annual income and adult obesity prevalence.

We aimed to investigate the feasibility of a cluster randomised controlled trial (RCT) of the ADRe Profile in UK primary care. The ADRe Profile is a patient monitoring system to identify and address adverse drug reactions (ADR) and ADR-related issues to pre-empt clinical deterioration.

A preliminary study to test the feasibility of an RCT.

General practices (GPs) in South-West Wales, UK.

20 patients aged >64 and prescribed >4 long-term medicines.

Participants reported their health-related problems using the ADRe-Profile. Participants completed the profile independently initially, then with researcher support, capturing vital signs, clinical observations and patient-reported symptoms.

Feasibility was assessed based on recruitment, retention, adherence to protocols, potential for clinical impact and staff costs.

We recruited two GP practices (0.94% of 213 contacted), and 20 patients aged >64 (51.3% of those approached). Retention was 100%. ADRe Profiles had a 98.29% completion rate, identifying 289 clinical problems, including pain (16 of 20 patients), dyspnoea (10/20), dizziness (8/20), bleeding/bruising (7/20) and falls (4/20). Most problems (90%) and vital signs (78%) recorded on ADRe Profiles were absent from existing patient records. Researchers recommended further investigations (164 instances) and interventions (126 suggestions). Despite the potential for clinical benefits, engagement from clinicians was limited. Cost estimates for ADRe administration ranged from £40 to £73, within the funding available from Health and Care Research Wales.

An RCT of the ADRe Profile was feasible, despite gatekeeping by clinicians. Recruitment of GP practices was challenging, with

NCT04663360; Pre-Results.

To evaluate the impact of various antihypertensive drugs on secondary stroke prevention in a real-life setting.

Nationwide historic cohort study.

French healthcare system data (SNDS).

Adults hospitalised for ischaemic stroke between 2014 and 2015 were followed up until December 2021 and stratified based on the presence of atrial fibrillation (AF).

Risk of stroke recurrence was assessed using a time-dependent Cox cause-specific model accounting for changes in drug exposure. We also investigated the risk of major adverse cardiovascular events (MACE) or all-cause death. Models were adjusted on stroke characteristics, coprescriptions and co-morbidities, at inclusion and across follow-up.

Among 54 764 patients without AF (median age 71; 46% women) and 17 960 with AF (median age 79; 51% women), stroke recurrence occurred in 11% and 13%, respectively. In non-AF patients, reduced recurrence risk was associated only with use of calcium channel blockers (adjusted HR (aHR) 0.91, 95% CI 0.86 to 0.97), thiazide diuretics (aHR 0.90, 95% CI 0. 83 to 0.97), loop diuretics (aHR 0.86, 95% CI 0.77 to 0.95) and potassium-sparing agents (aHR 0.83, 95% CI 0.70 to 0.98). In AF patients, only potassium-sparing agents (aHR 0.82, 95% CI 0.69 to 0.99) were associated with reduced recurrence risk. All antihypertensive drugs, apart from loop diuretics, were associated with a reduced risk of MACE or all-cause death.

In this large cohort, only diuretics and calcium channel blockers were associated with a reduced risk of recurrent stroke. Most antihypertensive drugs, however, may be more effective in overall cardiovascular prevention.

To determine whether a biopsychosocial model of suicidality, specifically sleep, nutrition, physical exercise, mindfulness, social connectedness, lower socioeconomic status (SES) and sex are uniquely associated with increased suicidal ideation, longitudinally over adolescence.

Longitudinal, prospective cohort study.

A structured self-report questionnaire was collected as part of the Longitudinal Adolescent Brain Study at the University of the Sunshine Coast’s Thompson Institute (Queensland, Australia) from July 2018 to January 2024.

159 Australian adolescents (n=91 female; 68 male) aged 12 to 17 years.

Self-reported suicidal ideation was measured longitudinally. Data were also collected on self-reported lifestyle factors (sleep, nutrition, physical exercise, mindfulness and social connectedness), psychological distress, SES and sex. All measures were collected at 4-monthly intervals for each participant for up to 5 years (maximum of 15 time points).

Significant relationships were identified between increased suicidal ideation and poor sleep (OR 2.6, 95% CI 1.4 to 4.6, p=0.002), socioeconomic disadvantage (SES quintile 1: OR 6.3, 95% CI, 1.8 to 21.8, p=0.004; SES quintile 2: OR 8.7, 95% CI 1.4 to 56.2, p=0.022), psychological distress (OR 5.7, 95% CI 2.1 to 15.6, p≤0.001) and eating habits (β –0.08, 95% CI –0.2 to –0.0).

Poor sleep, socioeconomic disadvantage, psychological distress and eating habits were all found to be significantly associated with increased adolescent suicidal ideation over time. These biopsychosocial factors should be considered in targeted interventions and policies for reducing adolescent suicidality. Further research should employ multilevel modelling to examine factor interactions and rigorously evaluate interventions targeting lifestyle factors and socioeconomic inequalities through randomised controlled trials and quasi-experimental designs.

Preoperative administration of tranexamic acid (TXA) reduces perioperative blood loss and transfusion requirements in total hip arthroplasty (THA), but optimal dosing remains uncertain due to the narrow range of doses explored in prior studies. This study aims to define the dose–response of intravenous TXA in THA, focusing on perioperative haemoglobin drop to improve blood-sparing effect.

This monocentric, double-blind, placebo-controlled, parallel-group, dose-finding study will enrol 170 adults undergoing THA, aiming to randomise 150 patients. Participants will be allocated using a minimisation technique with a random component in equal proportions to receive either placebo or one of four intravenous TXA doses: 300 mg, 500 mg, 1000 mg or 3000 mg. Dose selection and sample size are based on a model-based meta-analysis that employed a maximum effect (Emax) model with a maximum effect of 40% and an ED50 (dose providing 50% of Emax) of 400 mg. The primary outcome will be the relative perioperative haemoglobin drop at postoperative day 3. Secondary outcomes include TXA exposure and perioperative fibrinolytic activity as measured by D-dimer levels. Only patients receiving the allocated study treatment will be analysed (modified intention-to-treat population). The dose–response relationship for the primary outcome will be analysed using non-linear mixed-effect models.

The study protocol was approved by the French ethics committee (Institutional Review Board Sud Méditerranée V) and the French National Agency for the Safety of Medicines and Health Products (ANSM). Results will be disseminated at conferences and published in peer-reviewed journals.

CTIS 2022-502532-38-01; NCT03822793.

Glioblastoma multiforme (GBM) is an aggressive primary brain tumour associated with a poor prognosis despite standard-of-care treatment, including surgical resection, radiotherapy and temozolomide (TMZ) chemotherapy. Certepetide (also known as LSTA1, CEND-1) is an investigational tumour-penetrating peptide that facilitates the extravascular delivery and intratumoural penetration of co-administered immune/chemotherapeutics; however, it has not yet been evaluated in clinical trials for the treatment of intracranial malignancies.

LSTA1-GBM-2A is an exploratory phase 2a, double-blind, placebo-controlled, randomised, proof-of-concept investigator-initiated trial assessing the safety, tolerability and preliminary efficacy of certepetide in combination with standard-of-care TMZ, compared with TMZ with a matching placebo, in subjects with newly diagnosed GBM.

The trial is funded by Lisata Therapeutics, sponsored by Tartu University Hospital and conducted at hospitals in Estonia and Latvia. Subjects are randomised in a 2:1 ratio. Following initial surgery and radiotherapy with concurrent TMZ, the subjects receive intravenous certepetide or placebo alongside six cycles of adjuvant TMZ treatment. The primary endpoint is overall survival. The target number of subjects is 30. The first subject was recruited in January 2024, and accrual is ongoing.

This study was approved by the Republic of Estonia State Agency of Medicines (17 October 2023) and the State Agency of Medicines of the Republic of Latvia (1 February 2024). The results of this study will be published in peer-reviewed journals and reported at academic conferences.

2023-506813-23-00.

Inappropriate medication use among surgical patients poses significant risks, including antibiotic resistance, complications, mortality, increased healthcare costs and challenges in pain management. This study aimed to assess the extent of inappropriate antibiotic and analgesic prescriptions, treatment adequacy and contributing factors.

A hospital-based cross-sectional study was conducted among patients admitted to surgical wards in three comprehensive specialised hospitals in northwest Ethiopia.

All eligible adult patients admitted to the surgical wards during the data collection period were included in the study.

The primary outcomes were the appropriateness of antibiotic and analgesic prescriptions. To assess patients’ pain perception and the effectiveness of pain management strategies, the American Pain Society Patient Outcome Questionnaire was used. The Pain Management Index was employed to evaluate the treatment adequacy. The RAND (Research and Development)-modified Delphi method was applied to reach expert consensus on best practices for antibiotic prescribing. Additionally, the national standard treatment guideline was used to benchmark prescribing practices. Binary logistic regression was used to identify factors associated with inappropriate prescriptions of antibiotics and analgesics.

The prevalence of inappropriate antibiotics use was 67.5% and 42.2% of patients received inappropriate analgesic prescriptions. Moreover, 51.6% of patients experienced inadequate pain management. Significant factors associated with inappropriate antibiotic prescription included the presence of comorbidities (adjsuted OR (AOR) 3.34, 95% CI 1.88 to 5.92), lack of laboratory tests (AOR 0.26, 95% CI 0.16 to 0.43, higher number of medications (AOR 2.71, 95% CI 1.62 to 4.52) and contaminated wound class (AOR 3.13, 95% CI 1.58 to 6.20). For inappropriate analgesic prescription, pain due to disease (AOR 8.69, 95% CI 1.73 to 4.62), mixed causes of pain (AOR 7.20, 95% CI 1.43 to 6.31), head and facial pain (AOR 0.14, 95% CI 0.05 to 0.39) and an increased number of medications (AOR 2.75, 95% CI 1.72 to 4.41) were significant factors.

The majority of the patients admitted to surgical wards were found to receive inappropriate antibiotic and analgesic medications. Prescribers should pay attention to patients with comorbid diseases, receiving multiple medications. Additionally, routine laboratory tests are essential for guiding antibiotic therapy and improving patient outcomes in surgical wards.

The glucose-lowering drug metformin has shown promise in non-diabetic conditions for improving endothelial dysfunction, but the literature of metformin’s effect on endothelial dysfunction and the biomarkers used to measure endothelial dysfunction have not yet been synthesised.

We aimed to map the extent and nature of the existing research related to metformin for endothelial dysfunction in non-diabetic non-communicable diseases (NCDs). This scoping review was conducted following the methodological framework by Arksey and O’Malley and the recommendations from the Joanna Briggs Institute, and was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews.

We considered any peer-reviewed studies in adult humans on the use of metformin for endothelial dysfunction in non-diabetic NCDs. Narrative reviews, expert opinion, preclinical studies and qualitative studies were excluded.

An unrestricted search was conducted on four electronic databases and three registries from inception to October 2024.

Data charting was performed using predetermined data extraction headings. We used a systematic charting method and narrative synthesis to organise, synthesise and report the data.

We identified 56 studies comprising 4620 participants (71.7% female). Polycystic ovarian syndrome was the most investigated NCD (57.1% of studies). 19 distinct biomarkers of endothelial dysfunction were identified, with flow-mediated dilation being the most frequently assessed (18 studies, 745 participants). Metformin showed a trend towards improvement for 7/19 (36.8%) biomarkers. Male participants were underrepresented in the literature and only five studies (9%) were conducted in the global south, potentially limiting the generalisability of repurposed metformin in diverse populations or settings. Studies with an active comparator reported a significant difference between the metformin and comparator groups in 20% (4/20), in contrast to studies without an active comparator (placebo or pre–post studies) reporting significant results favouring metformin in 83.3% (30/36). A knowledge gap also exists for metformin use in people with HIV, given that they are known to develop cardiovascular NCDs at a twofold higher rate than their HIV-negative counterparts.

While there is a growing evidence base supporting metformin as treatment for endothelial dysfunction in non-diabetic NCDs, our scoping review highlighted knowledge gaps in optimal biomarker selection and dosing strategies, and applications in a broader range of NCDs, including in people with HIV. More primary and secondary research using robust methodologies and study designs is needed to determine the quantitative effect of metformin on endothelial dysfunction.

Non-specific chronic low back pain is a leading cause of disability-adjusted life-years (DALYs) with a lifetime prevalence of 80%–85%. Although many modalities of treating chronic low back pain are available, pharmacotherapy remains a very important treatment modality, according to many recognised guidelines. Each of these pharmacological agents has evidence supporting its efficacy in treating chronic low back pain, and each of them is associated with side effects. At present, no study has unified these two outcomes or ranked them from the most effective to the least effective. Thus, this study aims to identify pharmacological agents that rank best by conducting multivariate bivariate network meta-analysis.

Four databases (Medline/Pubmed, Cochrane Central Register for Controlled Trials, Cochrane Database for Systematic Reviews and CINAHL) will be systematically searched from their inception to 31 July 2024 for randomised control trials that meet the inclusion criteria. Appropriate data will be extracted from the relevant studies, including the two outcomes of interest: the pain intensity score and the proportion of patients who withdrew from the study because of adverse events. A bivariate Bayesian network meta-analysis will be used to combine the two outcomes of interest to form a single probability that will rank the pharmacotherapy agents from the most effective and safe to the least. The studies will be assessed for risk of bias, and their evidence will be graded using the Grading of Recommendations Assessment, Development, and Evaluation assessment tool. Inconsistency, which is a key assumption of network meta-analysis, will be assessed using both local and global methods.

This systematic review is based on already published data, so it does not require ethical approval. The findings from the review, after completion, will be disseminated via peer-reviewed publications.

CRD42024569192.

Adolescence and youth are periods of significant maturational changes, which seem to involve greater susceptibility to disruptive events in the brain, such as binge drinking (BD). This pattern—characterised by repeated episodes of alcohol intoxication—is of particular concern, as it has been associated with significant alterations in the developing brain. Recent evidence indicates that alcohol may also induce changes in gut microbiota composition and that such disturbances can lead to impairments in both brain function and behaviour. Moreover, there is evidence suggesting that microbiota-targeted interventions (psychobiotics) may help mitigate alcohol-induced damage in individuals with chronic alcohol use, positively influencing cognitive and brain functioning. However, the triadic relationship between BD, gut microbiota and brain structure/function, as well as the therapeutic potential of gut microbiota-targeted interventions in young binge drinkers, remains largely unexplored.

This double-blind, parallel, randomised controlled study aims to evaluate whether a BD pattern disrupts gut microbiota diversity in young college students (primary outcome). Additionally, it seeks to determine whether alcohol-induced alterations in the microbial composition and function are associated with immunological, cognitive, neurostructural and neurofunctional impairments (secondary outcomes). A total of 82 college students (36 non/low drinkers and 46 binge drinkers (BDs)), matched for age and sex, will be recruited from the University of Minho (Portugal). During the pre-intervention phase, all participants will undergo a comprehensive assessment protocol, including gut microbiota profiling, measurement of inflammatory markers, neuropsychological testing and structural and functional MRI. BDs will then be randomly assigned to a 6-week intervention with either a prebiotic (inulin) or a placebo (maltodextrin). Post-intervention assessment will mirror the baseline protocol, and craving and alcohol use will be monitored for 3 months.

The present protocol was approved by the Ethics Committee for Social and Human Sciences of the University of Minho (CEICSH 078/2022), ensuring compliance with national and international ethical guidelines, including the Declaration of Helsinki. Participation is voluntary and preceded by informed consent, with confidentiality and data processing safeguarded in accordance with the General Data Protection Regulation. All procedures are safe and non-invasive, and the prebiotics used are recognised as food ingredients in Europe, hold Generally Recognized as Safe status in the USA and are classified as dietary fibres by the Food and Drug Administration. Findings will be disseminated in national and international scientific forums, with preference for publication in open-access, peer-reviewed journals.

NCT05946083

Drug–drug interactions (DDIs) are a significant concern for patients on complex therapeutic regimens, especially involving cardiovascular medications, which are frequently implicated in these interactions.

This study used a standardised interaction database to determine the frequency, severity and risk factors associated with potential DDIs (pDDIs) among cardiovascular disease (CVD) in-patients.

The prospective cross-sectional study was conducted at a tertiary care hospital in Nepal from April 2024 to October 2024. A total of 106 eligible CVD in-patients were evaluated for pDDIs using the Lexicomp DDI checker database, and the interactions were categorised based on severity and risk rating. Binary logistic regression identified factors associated with pDDIs.

The study identified 621 pDDIs using the Lexicomp database, with median values of 8 pDDIs per patient. Patients with at least one pDDI comprised 64.2% of the sample. Most pDDIs were of moderate severity (77.3%) with risk ratings of C (65.7%). The most common cardiovascular medications involved in the detected DDI pairs were diuretics (31.2%), antiplatelets and anticoagulants (23.8%) and calcium channel blockers (12.2%). Multivariate binary logistic regression revealed that patients who stayed longer (adjusted OR (AOR) 9.08, 95% CI 1.027 to 80.216, p=0.047), those receiving more medications (AOR 18.85, 95% CI 2.975 to 119.370, p=0.002) and those who were admitted to the intensive cardiac care unit (AOR 16.31, 95% CI 2.728 to 97.461, p=0.002) were significantly more likely to experience pDDIs.

This study found a higher prevalence of pDDIs. It is advisable to incorporate medication reviews into routine cardiac care and use a drug interaction checker to identify pDDIs.

Pharmacist prescribing has evolved to meet healthcare system needs, but the effectiveness, mechanisms and contextual factors influencing education programmes remain poorly understood. Realist approaches are fairly novel in pharmacy practice research. This realist synthesis aims to answer the question: to what extent do pharmacy prescribing education programs work (or not), for whom and under what circumstances, and why?

A realist methodology (realist synthesis) will be used to review the outcomes of programmes. Pawson’s key stages will be followed: (1) clarifying the scope; (2) determining the search strategy; (3) study selection; (4) extracting and analysing data; and (5) synthesising findings and drawing conclusions. The synthesis will follow Realist And Meta-narrative Evidence Syntheses–Evolving Standards publication guidelines. Data extracted will include the study characteristics, alongside the contexts, mechanisms and outcomes of varied pharmacy prescribing education programmes. The search strategy will include searching PubMed, Scopus, Web of Science and CINAHL Complete. An initial programme theory will use selected grey literature. Context-mechanism-outcome configurations will be identified, and recurring patterns will be synthesised to refine the initial programme theory.

Ethics approval is not required. Dissemination will be sought via peer-reviewed academic conferences and journals.

CRD420251056576.

Thrombopoietin receptor agonists (TPO-RAs) are widely used in thrombocytopenia, yet their association with thromboembolic events (TEEs) remains concerning. This study aimed to assess the real-world TEE risk associated with TPO-RAs.

Retrospective pharmacovigilance analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases.

Both FAERS and JADER were searched from January 2004 to March 2025.

Disproportionality analyses were performed using reporting OR (ROR), proportional reporting ratio (PRR), informational component (IC) and empirical Bayesian geometric mean (EBGM) to identify potential safety signals.

4005 TEE from FAERS and 569 from JADER were analysed. Venous TEE showed higher prevalence and signal intensity (FAERS: n=1489, ROR 4.19, PRR 4.14, EBGM05 3.94, IC025 0.37; JADER: n=269, ROR 15.95, PRR 14.27, EBGM05 12.56, IC025 2.14). Lusutrombopag had the strongest TEE signal (FAERS: n=7, ROR 8.80, PRR 7.77, EBGM05 4.00, IC025 1.25; JADER: n=41, ROR 38.02, PRR 16.94, EBGM05 11.45, IC025 2.38). FAERS identified 49 positive signals, while JADER identified 30, with 20 signals overlapping. Subgroup analysis indicated males had higher arterial TEE risk with TPO-RAs, while females had higher venous TEE risk in both FAERS and JADER. In FAERS, elderly (≥60 years) showed elevated arterial TEE risk with TPO-RAs and romiplostim, while non-elderly had higher venous TEE risk with avatrombopag and eltrombopag.

The study provided real-world evidence of TEE associated with TPO-RAs, highlighting a strong link despite variations in signal values and regional reporting practices. Findings underscore ongoing clinical safety surveillance for TPO-RAs.

Opioid use disorder (OUD) is a debilitating condition characterised by the overuse of opioid medications and the development of physical and/or psychological dependence. Consequences of this condition include chronic impairment, distress and later life-altering health conditions such as overdose, all of which have been highlighted by the prominence of OUD in the USA in recent years. Buprenorphine is a standard OUD treatment and commonly used for pain management. Understanding changes in distribution patterns across the USA is vital for continuing to improve outcomes for OUD patients.

This study used the Drug Enforcement Administration’s Automated Reports and Consolidated Ordering System (ARCOS) and the US Census Bureau Population Estimates databases to analyse changes in buprenorphine distribution among pharmacies and hospitals from 2019 to 2023, to determine temporal patterns and to identify state-level disparities using the data. The data were corrected for population to identify patterns of buprenorphine distribution in the USA from 2021 to 2022 and 2022 to 2023 through examining percent changes in milligrams per 100 population at the national and state levels.

The year-to-year percent change of national buprenorphine distribution from pharmacies has remained positive but changed from a 12.2% increase from 2019 to 2020 (figure 4) to a four per cent increase every year from 2020 to 2023. From 2021 to 2022, there was a +4.9% increase in total grams of buprenorphine distributed to pharmacies and a 95% CI [–5.1, 14.9], with the District of Columbia, South Dakota and Nebraska outside of the 95% CI. Distribution to hospitals increased by 10.2% [-32.3, 52.7] during 2021–2022, with Hawaii, New Hampshire and Delaware being outside of 95% CI. From 2022 to 2023, there was an increase of +5.7% and 95% CI [–3.5, 14.9] in pharmacy distribution, with states including Washington, Rhode Island and Kansas remain outside of the 95% CI. Hospital distribution has decreased from twenty per cent between 2019 and 2020 (figure 4) to eighteen per cent between 2022 and 2023.

Following increases in buprenorphine distribution during the COVID pandemic, a consistent increase has continued year-over-year in most states and the country overall by both pharmacies and hospitals. Some states (eg, Rhode Island, Georgia, District of Columbia) have not followed this pattern. Notably, Hawaii went from the most negative percent change in hospital distribution to the most positive change in the timeframe analysed. This may offer opportunities to analyse more specific impacts of the increased buprenorphine distribution on populations and their outcomes associated with OUD.

To evaluate whether remdesivir is associated with cardiac adverse events (CAEs), addressing concerns raised by basic experiments, clinical case reports and observational studies.

Systematic review and meta-analysis.

MEDLINE and Embase, searched from January 2020 to December 2023.

Randomised controlled trials (RCTs) comparing remdesivir with placebo or standard care in patients with COVID-19, with a primary focus on cardiac safety.

We included RCTs that evaluated the safety of remdesivir in patients with COVID-19 . Eligible studies were those that compared remdesivir with placebo or standard care in adult patientsCOVID-19 . Inclusion criteria emphasised safety outcomes, particularly CAEs, as primary endpoints.

Two reviewers independently extracted data. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-Harms guidelines. Risk of bias (RoB) was assessed using the Cochrane Collaboration tool. A random-effects model was used for data synthesis. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was applied to assess the certainty of evidence. The primary outcome was the incidence of any CAEs, defined as a composite of all reported cardiac-related harms. Secondary outcomes included specific CAEs such as arrhythmias, heart failure and myocardial disorders.

We identified 1698 studies, of which seven RCTs met the inclusion criteria, comprising a total of 4566 participants. The RoB was assessed across multiple domains, with four RCTs showing low risk and three showing moderate risk in specific areas. Pooled analysis revealed no significant association between remdesivir use and CAEs (RR=0.84, 95% CI: 0.68 to 1.04, p=0.118). Subgroup analyses showed consistent findings across different patient demographics and comorbidities. GRADE assessment indicated moderate certainty for overall CAEs, low certainty for arrhythmias and heart failure (due to imprecision and study-level bias), and very low certainty for myocardial disorders (due to small sample size and indirectness).

Contrary to preliminary concerns and case reports, our meta-analysis found no evidence of a statistically significant association between remdesivir and CAEs among patients with COVID-19 . These findings provide reassurance to clinicians regarding the safety profile of remdesivir in this patient population, supporting its use as an antiviral therapy in the treatment of COVID-19. Further research is warranted to validate these findings and to clarify whether remdesivir may have a neutral or potentially protective effect on cardiac outcomes.

CRD42022383647.