PURPOSE:To describe nationwide dispensing patterns of methylphenidate in Australia before and during recent prolonged supply shortages, and to assess the extent to which Section 19A (S19A) overseas substitutes contributed to population-level utilisation during the shortage period. Secondary aims were to compare methylphenidate dispensing with other ADHD medicines, examine changes in dispensing across individual strengths and formulations and quantify delays between S19A approval and Pharmaceutical Benefits Scheme (PBS) listing. METHODS:An interrupted time series (ITS) and descriptive analysis of population-level dispensing patterns was conducted using publicly available monthly dispensing data from the Pharmaceutical Benefits Scheme (PBS) and Repatriation PBS (January 2020-March 2026). Data were standardised to dispensings and defined daily doses (DDD) per 100 000 population. Methylphenidate shortages were identified using the Therapeutic Goods Administration Medicines Shortages database and shortage months were designated where there was at least 1 day of shortage in a month. S19A approvals, PBS listing and lapse dates were obtained from the S19A approvals database to determine delays to subsidised access. RESULTS:Dispensing of ADHD medicines increased substantially from 2020 to 2025. Methylphenidate dispensing increased overall but plateaued from late 2024 onward, coinciding with widespread supply disruptions affecting multiple strengths and formulations. DDD ITS analysis demonstrated abrupt reductions in methylphenidate strengths (particularly 36 and 54 mg) during shortages, with partial compensatory increases for some other strengths. Fifteen overseas-registered methylphenidate products received S19A approval; however, of the 14 listed on the PBS, time to PBS listing ranged from 83 to 166 days (median 162 days). After PBS listing, S19A products contributed to 1.3% of all methylphenidate dispensings between July 2025 and March 2026. CONCLUSION:Methylphenidate dispensing in Australia became unstable during extensive supply shortages from late 2024. Although numerous S19A products were approved, there was minimal uptake of S19A PBS-listed products at the population level. As ADHD medicine utilisation continues to rise, strengthened national strategies to improve supply chain resilience, transparency and responsiveness are required.
PURPOSE:Doxorubicin (DOX), an effective anticancer agent, is associated with dose-dependent cardiovascular toxicity. Understanding its mechanisms and risk factors will facilitate novel interventions to minimize DOX-induced cardiovascular toxicity. Thus, this study performed data mining of the FDA Adverse Event Reporting System (FAERS) to detect and analyze DOX-induced cardiac-related adverse events (AEs). METHODS:Data from 2004 to 2025, where DOX was the primary suspect, were extracted from FAERS via OpenVigil. Using the Medical Dictionary for Regulatory Activities, AEs were categorized into preferred terms (PTs) and system organ classes (SOCs). This study used descriptive analysis and signal detection algorithms including Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN). RESULTS:A total of 2421 reports of DOX-associated AEs were extracted in FAERS. Reports primarily involved female cancer patients (55.02%) between 18and 65 years (48.12%) from the United States. Most signals were of moderate to strong signal intensity, with cardiotoxicity, cardiac failure, and cardiomyopathy being the most reported. Interestingly, while cardiac disorders were mainly found to be strongly linked to DOX, novel vascular AEs like endothelial dysfunction were also among the top signals strongly associated with DOX. Out of the six serious AEs associated with DOX-induced cardiotoxicities, "Death" and "Initial/prolonged hospitalization" were the most commonly reported. CONCLUSION:This study provides valuable insights into DOX-induced cardiovascular toxicity using real-world data from FAERS. Vascular events like endothelial dysfunction were shown to be significant novel AEs experienced by cancer patients undergoing treatment with DOX. Thus, careful monitoring of potential DOX-AEs associations will help improve the risk-benefit ratio of DOX-treated patients.
BACKGROUND:Proton pump inhibitors (PPIs) are the global gold standard for acid-related disorders; however, their proliferation into long-term, often non-indicated use raises significant concerns regarding qualitative nutrient depletion. OBJECTIVE:This study primarily aimed to evaluate the independent association between PPI use and malnutrition risk according to the Global Leadership Initiative on Malnutrition (GLIM) criteria in a nationally representative US population. METHODS:We conducted a cross-sectional analysis of 23 363 adults from the NHANES 1999-2020 database. Malnutrition was operationalized via the GLIM approach, integrating phenotypic criteria (weight loss, low BMI, or DXA-derived reduced muscle mass) with etiologic criteria (inflammation or reduced calorie intake). Robust Poisson regression models estimated relative risks (RRs) for general malnutrition, while logistic regression estimated odds ratios (ORs) for severe malnutrition. Models were adjusted for sociodemographics, food security, comorbidities, and appetite-affecting medications. RESULTS:The prevalence of malnutrition was 18.9% (95% CI: 18.4%-19.4%) and PPI use was associated with a 10% increased risk of malnutrition (RR 1.10; 95% CI: 1.01-1.19; p = 0.031) in the adjusted model. For severe malnutrition, PPI exposure was a robust independent predictor (OR 1.36; 95% CI: 1.13-1.63; p = 0.001). Notably, sex-stratified analysis revealed a RR associated with PPIs was significantly more pronounced in females (RR 1.37; 95% CI: 1.06-1.79; p = 0.018) than in males (RR 1.07; p = 0.11). In the geriatric population (≥ 65 years), chronic PPI use increased the odds of severe malnutrition by 57% (OR 1.57; 95% CI: 1.15-2.14; p = 0.004). CONCLUSION:Prolonged iatrogenic hypochlorhydria may represent an important contributor to malnutrition, particularly to its more severe forms and among older adults. These findings support the need for regular medication reviews to identify and discontinue unnecessary long-term PPI therapy. Preserving metabolic and nutritional health may therefore require the implementation of non-pharmacological approaches as first-line management options for acid-related disorders whenever clinically appropriate. Such strategies may help reduce unnecessary long-term PPI exposure and its potential adverse effects on nutritional status.
INTRODUCTION:Postpartum psychotropic medication use is heterogeneous, comprising continuation of prenatal treatment, initiation, transient use and complex polypharmacy. Prior studies have reported the prevalence of potential infant exposure to psychotropics via breast milk, but characterisations better capturing the heterogeneity of this exposure are lacking. We aimed to identify distinct postpartum psychotropic treatment patterns using hierarchical clustering accounting for medication type, timing and polypharmacy, and to describe breastfeeding characteristics across these patterns. METHODS:Population-based cohort study of mothers using psychotropics during the first postpartum year using linked Danish national registers 2012-2023. From a source population of 659 866 mother-child pairs with live-born singleton births, 38 528 mothers redeemed at least one psychotropic prescription during the first postpartum year and comprised the study cohort. Weekly psychotropic use was defined by redeemed prescriptions using prescribed daily dose assumptions. Hierarchical agglomerative clustering (tame R package) identified distinct treatment patterns based on medication type, timing and polypharmacy. The number of patterns was determined from interpretability, size and examination of the hierarchical dendrogram. Exclusive breastfeeding prevalence and duration were described across patterns among pairs with recorded breastfeeding habits (64%). RESULTS:Eight distinct treatment patterns were identified, differing in psychotropic type, timing and polypharmacy. Three SSRI-dominated patterns (24 225 pairs, 63%) ranged from increasing SSRI use (Pattern I; n = 11 731), through continued SSRI use with high persistence (Pattern II; n = 7167), to mixed use involving SSRIs and other psychotropics (Pattern III; n = 5327; 48% using three or more medications). The remaining five patterns (14 303 pairs, 37%) were dominated by benzodiazepine-related drugs, other antidepressants, centrally acting sympathomimetics, antipsychotics or complex mixed use, ranging from late-initiated benzodiazepine-related use (Pattern IV; median initiation Week 27; persistence 13%) to early-initiated, highly persistent mixed use (Pattern VIII; median initiation Week 4; persistence 94%). Exclusive breastfeeding duration varied across patterns, with long-duration exclusive breastfeeding (181 days or more) highest in the SSRI-continued pattern (Pattern II, 10.6%) and lowest in the mixed-use-increasing and antipsychotics-sporadic patterns (Patterns III and VII, 5.1% and 5.2%). CONCLUSION:Postpartum psychotropic treatment patterns are clinically heterogeneous and exclusive breastfeeding practices differ across treatment patterns.
PURPOSE:Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are increasingly used to treat renal anemia in patients with chronic kidney disease (CKD). We evaluated the risk of heart failure associated with HIF-PHIs compared with erythropoiesis-stimulating agents (ESAs) in routine clinical practice. METHODS:We conducted a nationwide, retrospective, active-comparator cohort study using a Japanese claims database. We included adults with non-dialysis CKD and heart failure initiating HIF-PHIs or ESAs alongside diuretic therapy between August 2020 and March 2025. The primary outcome was heart failure hospitalization. Secondary outcomes included emergency heart failure hospitalization and hospitalization requiring intravenous diuretics. Baseline characteristics were balanced using inverse probability of treatment weighting (IPTW) based on propensity scores. Hazard ratios (HRs), 95% confidence intervals (CIs), and sensitivity analyses were evaluated in predefined subgroups using Cox proportional hazards models. RESULTS:The cohorts comprised 14 995 HIF-PHI and 22 889 ESA users with baseline characteristics well balanced after IPTW adjustment. Heart failure hospitalization incidence rates per 1000 person-years (PY) were 157.8 for HIF-PHIs and 177.0 for ESAs. HRs were 0.93 [95% CI 0.87-1.01] for heart failure hospitalization, 0.94 [95% CI 0.84-1.03] for emergency heart failure, and 0.87 [95% CI 0.81-0.94] for intravenous diuretic administration. Results were generally consistent across subgroup and sensitivity analyses. CONCLUSIONS:Although residual confounding cannot be excluded because of the observational study design, HIF-PHIs were not associated with evidence of an increased risk of heart failure hospitalization in patients with heart failure.
BACKGROUND:Anthracycline plus taxane (ATAX) regimens are associated with improved survival in HER2-negative breast cancer (HBC) compared to taxane-based (TAX) regimens. However, anthracyclines are known for their cardiotoxicity, which could increase the risk of neurocognitive deficits, raising concerns about neurocognitive safety, particularly in older adults. Limited evidence exists comparing neurocognitive outcomes between these two regimens. OBJECTIVE:To compare the incidence of Alzheimer's disease and related dementias (ADRD) between ATAX and TAX regimens in neoadjuvant (Trial #1) and adjuvant (Trial #2) settings among older women with early-stage HBC. METHODS:Using SEER-Medicare data (2010-2021), we identified women aged ≥ 66 years with newly diagnosed HBC and no prior neurocognitive conditions between 2011 and 2021. Patients were longitudinally tracked, and their eligibility for each regimen was evaluated. We applied the clone-censor-weight method and used weighted pooled logistic regression to estimate the 10-year risks of ADRD, Alzheimer's disease (AD), and vascular dementia (VD). RESULTS:We identified 14 079 and 9321 eligible individuals in Trial #1 and Trial #2, respectively. For ADRD outcome, the 10-year risk difference (RD) was -6.91% (95% CI: -15.60% to 0.91%) for HR+/HER2- cohort and -2.14% (95% CI: -9.57% to 5.46%) for TNBC cohort in Trial #1. The 10-year RD was -1.42% (95% CI: -9.33% to 6.98%) for HR+/HER2- cohort and -2.91% (95% CI: -9.54% to 7.86%) for TNBC cohort in Trial #2. CONCLUSION:Our findings suggest that ATAX regimens were not associated with increased risks of ADRD, AD, and VD compared to TAX regimens in older women with HBC. However, the risks of AD and VD should be interpreted with caution due to sparse events. These findings may support the continued use of ATAX regimens in this population, while also informing more personalized, risk-adapted treatment strategies.
PURPOSE:Traditional drug-induced liver injury (DILI) surveillance relying on static laboratory thresholds frequently misses early kinetic evolution. To address this, a fundamentally drug-agnostic unsupervised ensemble framework, integrating pharmacokinetic (WCEDR) and polypharmacy (HAMPIS) features, was developed for early DILI detection. Antiepileptic drugs (AEDs) were utilised as a proof-of-concept validation cohort. METHODS:Using Thailand's national electronic health record database (2021-2024), a multi-view ensemble (Isolation Forest, Local Outlier Factor, One-Class Support Vector Machine) evaluated longitudinal physiological deviations. Feature engineering prioritised acute kinetic volatility to mitigate irregular sampling intervals. Diagnostic performance was benchmarked against standard criteria (ALT > 3 × ULN) and validated through blinded expert adjudication of 140 clinical episodes. RESULTS:From 616 425 treatment episodes, the framework isolated 86 high-probability anomalies. Benchmarking revealed the model captured 80.2% of rule-based positives while proactively identifying 17 AI-only sub-threshold episodes (19.8%) exhibiting distinct enzymatic velocity; over half (52.9%) were clinically confirmed as DILI. Blinded adjudication yielded a clinical plausibility rate of 69.8% and a negative predictive value of 92.6%. Operationally, the framework achieved a number needed to review (NNR) of 1.43, substantially optimising triage efficiency. Digital phenotyping stratified alerts into three distinct archetypes: complex polypharmacy, atypical pharmacokinetic burden, and active idiosyncratic injury. CONCLUSION:By prioritising kinetic volatility and multidimensional pharmacological context, the unsupervised ensemble functions as a high-precision, complementary surveillance tool. It successfully detects early-onset idiosyncratic reactions frequently overlooked by rigid static thresholds, offering a scalable blueprint for proactive pharmacovigilance.
Key Points The FDA's accelerated approval pathway was designed to get promising drugs to patients faster, approving them based on surrogate endpoints before confirmatory evidence of clinical benefit is available. Sponsors are required to complete confirmatory trials after approval; however, Medicare pays for these therapies immediately, regardless of where those trials are met. Public dollars, in other words, are already moving while the fundamental question of whether these drugs actually work remains unanswered. Financial incentives for manufacturers further complicate this issue; revenue is generated regardless of the trial's progress, reducing the urgency to complete them. We propose extending Coverage with Evidence Development (CED), an existing CMS policy tool, to drugs approved through the accelerated approval pathway. Under this framework, Medicare coverage would continue following FDA approval but would be contingent on participation in evidence‐development activities, including disease registries, real‐world data collection, and confirmatory trials. This approach operates within existing CMS authority and requires no new legislation. Linking reimbursement to evidence generation would better align financial incentives with the public interest and strengthen accountability during the confirmatory trial phase without restricting patient access.
PURPOSE:The prescribing of 5-hydroxytryptamine 3 receptor and type 3 serotonin receptor (5-HT3) antagonists, particularly ondansetron, for nausea and vomiting in pregnancy (NVP) has increased globally. However, evidence on the safety of these medications in pregnancy remains unclear. This review aims to examine the available literature surrounding the safety of 5-HT3 antagonist medication use for NVP. METHODS:Embase, Ovid Medline, Global Health, and CINAHL were searched from inception to 20 March 2024, updated on 7 May 2025. Full-text, original articles available in English, examining the use of 5-HT3 antagonist medications (ondansetron, granisetron, tropisetron, dolasetron, palonosetron, ramosetron) for NVP were included. Any maternal, neonatal, or child health outcomes were of interest. RESULTS:Results were screened and extracted using Covidence and synthesized in Excel. The search strategy returned 1942 articles of which 39 unique, full-text studies were included. Most papers examined ondansetron (34/39 papers, 87%) with limited evidence for granisetron (5/39 papers, 13%). Ondansetron use for NVP yielded minimal complications for maternal health and late pregnancy outcomes. No elevated risk of any congenital anomalies overall was observed. Although the risks of cardiac and orofacial anomalies were conflicting, the absolute changes in risk are minimal for either anomaly, especially considering potential confounding from study methodology and limited sample sizes. CONCLUSION:Ondansetron likely poses low risk of harm to maternal and neonatal health, especially considering the excess risks of untreated NVP; however additional research is required for certain congenital anomalies. Further investigation is also warranted into granisetron safety before its widespread use during pregnancy.
PURPOSE:Studying patients with bacteremia in real-world data often requires using microbiologic data to confirm bacterial growth and species. When microbiologic data are unavailable, pathogen-specific diagnostic codes may be used to classify the bacteremia type. We developed and validated ICD-10-CM-based algorithms for identifying any bacteremia, Gram-negative bacteremia, and Enterobacteriaceae bacteremia. METHODS:We identified patients ≥ 18 years with a hospitalization ≥ 2 days to any Duke Antimicrobial Stewardship Outreach Network hospital from January 1, 2021 to May 31, 2024. Blood culture results were the reference standard for classifying true cases of bacteremia. We evaluated 15 candidate algorithms developed based on previously published algorithms, in addition to the bacteremia ICD-10-CM code (R78.81) and pathogen-specific ICD-10-CM codes. We estimated sensitivity, specificity, positive predictive value (PPV), and negative predictive value with 95% confidence intervals using generalized estimating equations to account for correlated hospitalizations. RESULTS:Among 907 958 hospital admissions (623 556 patients), algorithms with bacteremia and pathogen-specific codes had high specificity (range: 97.3%-100.0%) and low sensitivity (range: 4.9%-58.1%). Algorithms with bacteremia codes and no pathogen codes were more sensitive (range: 67.4%-68.6%) and less specific (range: 91.1%-91.2%). In subgroup analyses, PPV for any bacteremia was highest among patients alive at discharge, age ≥ 65, and discharged on antibiotics with Gram-negative coverage (68.9% [65.1%-72.7%]). CONCLUSIONS:We developed and internally validated algorithms to identify bacteremia, Gram-negative bacteremia, and Enterobacteriaceae bacteremia in adult patients. Studies seeking to maximize specificity could consider algorithms that include bacteremia and pathogen-specific codes, whereas studies seeking to maximize sensitivity could consider algorithms only requiring a bacteremia code.
BACKGROUND:Overuse of antibiotics contributes to antibiotic resistance, and may result in gut microbiome dysbiosis, potentially increasing the risk of chronic childhood conditions. OBJECTIVES:To examine patterns of antibiotic dispensing in utero and during the first 5 years of life. METHODS:We conducted a retrospective cohort study of all children (n = 315 786) born in New Zealand from 2005 to 2010 using linked pharmaceutical dispensing data to ascertain antibiotic use during the mother's pregnancy and for the first 5 years of life. Descriptive analyses were conducted as well as negative binomial regression controlled for potential confounders. RESULTS:In total, 96% of children had been dispensed ≥ 1 course of antibiotics by age five; for pregnant women this was 30%. Penicillin, particularly Amoxicillin, was most frequently dispensed during both periods. Postnatal antibiotic dispensing was higher for males (adjusted IRR 1.09, 95% CI 1.08-1.10); Māori (1.16, 1.15-1.17), Pacific peoples (1.32, 1.30-1.33), and Middle East Latin American and African (MELAA) ethnicities (1.07, 1.04-1.10); children in the highest deprivation quintile (1.16, 1.15-1.17) and those born pre-term (1.05, 1.04-1.05); and urban children (1.21, 1.20-1.22). Low and high birthweight and caesarean deliveries were also associated with higher antibiotic dispensing. Similar patterns were observed for antibiotic dispensing for mothers during pregnancy. Dispensing rates were highest during winter months. CONCLUSION:Antibiotic dispensing is high in New Zealand children and pregnant women, with significant ethnic and socioeconomic differences, suggesting that current antibiotic stewardship programmes are not fully effective.
ABSTRACT Purpose This study quantified temporal trends in antidepressant dispensing among children and adolescents and described patterns by antidepressant class, drug, and demographic subgroups. Methods This population‐based cohort study used administrative health data from Manitoba, Canada and included individuals aged 6–18 years between 2000 and 2024. Antidepressant dispensing was identified in prescription dispensing records using the Anatomical Therapeutic Chemical code N06A. Annual prevalence was defined as the proportion of individuals dispensed antidepressants in a given year; annual incidence rate was defined as the rate of new antidepressant dispensing following a 2‐year washout period. Analyses were stratified by antidepressant class, drug, age group (6‐12, 13‐18), sex and neighborhood income quintiles. Results The cohort included 699 526 individuals; 66 895 (9.6%) had an antidepressant dispensing, of which most were dispensed selective serotonin reuptake inhibitors ( n = 49 219, 73.6%). The prevalence of antidepressant dispensing increased from 14.9 (95% confidence interval [CI] 14.5–15.5) to 48.7 (95% CI 47.9–49.6) per 1000 individuals in 2000 and 2024, respectively. The incidence increased from 9.2 (95% CI 8.8–9.6) to 17.4 (95% CI 16.8–17.9) per 1000 person‐years. A decline in dispensing between 2003 and 2005, and a sharp rise beginning in 2020, were observed. Subgroup analyses showed a temporal increase in antidepressant dispensing across all subgroups, particularly among females and adolescents aged 13–18 years. Conclusions This study found a marked increase in antidepressant dispensing in children and adolescents over time, particularly in females and adolescents. Future studies are needed to evaluate appropriateness, clinical outcomes and long‐term safety of antidepressant use in this population.
PURPOSE:Although antidepressant use during pregnancy has been linked to adverse birth outcomes such as stillbirth and preterm delivery, existing evidence is conflicting and rarely presents absolute risk estimates. We aimed to assess the association between antidepressant use during pregnancy and birth outcomes, alongside estimates of absolute risk to aid clinical interpretation. METHODS:We conducted a multi-country cohort study using data from the UK Clinical Practice Research Datalink (1996-2018), Norwegian Medical Birth Registry (2009-2020), and Swedish Medical Birth Register (2006-2020). Discordant sibling analyses and paternal negative controls were used to investigate associations with stillbirth, neonatal death, gestational age, size for gestational age, and Apgar score < 7 at 5-min among pregnancies delivered at ≥ 22 weeks' gestation. RESULTS:Among 120 209 (4.8%) pregnancies exposed to antidepressants, maternal use was associated with stillbirth (adjusted pooled odds ratio [aOR] 1.16, 95% CI 1.05-1.28), preterm delivery (aOR 1.26, 95% CI 1.23-1.30), and low Apgar score (aOR 1.83, 95% CI 1.75-1.91). Associations persisted in sibling analyses with greater uncertainty. The predicted absolute risk of stillbirth was 0.34% among unexposed pregnancies and 0.40% among exposed. When restricting to mothers with depression or anxiety, the association with stillbirth attenuated (aOR 1.07, 95% CI 0.94-1.21). Paternal antidepressant use was modestly associated with preterm delivery and low Apgar score. CONCLUSIONS:Maternal antidepressant use during pregnancy may be associated with increased risks of preterm delivery and low Apgar score, though absolute risks remain low. Residual confounding related to parental mental health is likely to explain part of these associations.
PURPOSE:This study quantified temporal trends in antidepressant dispensing among children and adolescents and described patterns by antidepressant class, drug, and demographic subgroups. METHODS:This population-based cohort study used administrative health data from Manitoba, Canada and included individuals aged 6-18 years between 2000 and 2024. Antidepressant dispensing was identified in prescription dispensing records using the Anatomical Therapeutic Chemical code N06A. Annual prevalence was defined as the proportion of individuals dispensed antidepressants in a given year; annual incidence rate was defined as the rate of new antidepressant dispensing following a 2-year washout period. Analyses were stratified by antidepressant class, drug, age group (6-12, 13-18), sex and neighborhood income quintiles. RESULTS:The cohort included 699 526 individuals; 66 895 (9.6%) had an antidepressant dispensing, of which most were dispensed selective serotonin reuptake inhibitors (n = 49 219, 73.6%). The prevalence of antidepressant dispensing increased from 14.9 (95% confidence interval [CI] 14.5-15.5) to 48.7 (95% CI 47.9-49.6) per 1000 individuals in 2000 and 2024, respectively. The incidence increased from 9.2 (95% CI 8.8-9.6) to 17.4 (95% CI 16.8-17.9) per 1000 person-years. A decline in dispensing between 2003 and 2005, and a sharp rise beginning in 2020, were observed. Subgroup analyses showed a temporal increase in antidepressant dispensing across all subgroups, particularly among females and adolescents aged 13-18 years. CONCLUSIONS:This study found a marked increase in antidepressant dispensing in children and adolescents over time, particularly in females and adolescents. Future studies are needed to evaluate appropriateness, clinical outcomes and long-term safety of antidepressant use in this population.
OBJECTIVE:To assess the risk of major congenital anomalies (MCAs) and other adverse outcomes following prenatal exposure to modafinil. METHODS:This retrospective cohort study used the French national healthcare database (SNDS) to include singleton children born between January 2009 and September 2024 of women aged 15-55 years. Prenatal exposure to psychostimulants was defined as maternal dispensation during pregnancy. Children prenatally exposed to modafinil were compared with two control groups: children prenatally exposed to methylphenidate and children prenatally unexposed to any psychostimulant matched to the exposed group using propensity-score matching (PSM). Outcomes included MCAs, neurodevelopmental disorders (NDs), and specialized consultations. Analyses included descriptive statistics, survival analysis, regression models, and dose-response analyses. RESULTS:Of 10 955 766 included children, 865 were prenatally exposed to modafinil and 950 to methylphenidate. Exposure to modafinil during the first trimester of pregnancy was statistically associated with increased risk of MCA compared to methylphenidate, although the confidence interval was wide and close to the null (aRR = 1.77 [1.01-3.07]). Comparison with PS-matched unexposed population indicated a possible modest increase in risk, albeit with a wide confidence interval crossing the null (aRR = 1.23 [0.76-1.99]), showing no clear association. Occurrence of NDs (aHR = 0.96 [0.56-1.65]), and specialized consultations (aHR = 1.08 [0.91-1.28]) were similar in the modafinil and PSM unexposed groups but were higher in the methylphenidate group (NDs: aHR = 0.48 [0.29-0.80]; specialized consultations: aHR = 0.71 [0.59-0.85]). CONCLUSION:This study shows no increase in neurodevelopmental risk, while a moderate MCA risk cannot be excluded.
Key Points The climate‐medication relationship is bidirectional: climate‐amplified exposures such as extreme heat affect medication access, stability, and safety/effectiveness (downstream), while the use and disposal of medications add to healthcare's carbon footprint, thereby contributing to the very warming that intensifies those exposures (upstream). Downstream: Extreme heat, extreme weather, and supply chain disruption are concrete threats to drug stability and access, from mail‐order degradation of insulin and epinephrine to the Hurricane Helene IV‐fluid shortage, and environmental exposures may alter the effects of common medications. Upstream: Therapeutically equivalent options can differ substantially in carbon intensity; eliminating unnecessary prescribing and selecting lower‐carbon therapeutic equivalents are the levers most directly available to prescribers and pharmacists. The evidence base is still immature: current drug‐heat warnings rest largely on mechanistic evidence and case reports, and advancing the field requires linking environmental exposure data to medication outcomes through case‐crossover and time‐series designs, where confounding by indication and polypharmacy represent central challenges. Where lower‐carbon options are already guideline‐concordant, clinicians and pharmacists can act now through prescribing choices, patient education on heat precautions and proper medication storage and disposal, along with healthcare system preparedness. Broader change requires guideline revision, formulary reform, transparent industy data, and collective action through professional societies, including the International Society for Pharmacoepidemiology.
ABSTRACT Objective To assess, by a systematic review and network meta‐analysis, the comparative efficacy and safety of second‐generation antipsychotics in managing aggressive behavior associated with autism spectrum disorder in children and adults. Methods Searches were conducted in MEDLINE, Embase, CENTRAL, PsycINFO, LILACS, CINAHL, trial registries, and grey literature from database inception to July 2025. Randomized controlled trials comparing second‐generation antipsychotics with placebo or other antipsychotics in individuals with autism were included. Outcomes were irritability (Aberrant Behavior Checklist–Irritability subscale—ABC‐I), global clinical impression (CGI), treatment discontinuation, and central nervous system–related adverse events. Data extraction and risk‐of‐bias assessment (RoB 2.0) were performed independently. Certainty of evidence was evaluated using CINeMA. Frequentist random‐effects network meta‐analyses reported mean differences (MD) or relative risks (RR) with 95% confidence intervals (CI). Incoherence and small‐study effects were assessed. Results Fourteen trials including 1195 children with autism were analyzed; no studies involved adults. Aripiprazole at low (MD: −5.83; 95% CI: −8.63, −3.02), recommended (MD: −5.69; 95% CI: −7.34, −4.04), and high doses (MD: −6.91; 95% CI: −10.04, −3.77), and recommended‐dose risperidone (MD: −6.91; 95% CI: −9.52, −4.31) reduced irritability versus placebo; lurasidone showed no benefit. No significant differences were observed for CGI. Recommended‐dose aripiprazole (RR: 0.57; 95% CI: 0.36, 0.90) and risperidone (RR: 0.29; 95% CI: 0.10, 0.83) lowered discontinuation risk. Both drugs increased sedation, drowsiness, and tremor. Evidence certainty ranged from very low to moderate. Head‐to‐head comparisons were inconclusive, and evidence was limited by the absence of adult studies and the small number of trials for some comparisons. Conclusions Risperidone and aripiprazole reduce irritability in pediatric autism but increase sedation, drowsiness, and tremor. No robust differences between active treatments were identified. PROSPERO Registration: 42022353795
ABSTRACT The Problem Transportability considerations are increasingly important to answer research questions in comparative effectiveness research (CER) to support the transfer of evidence on medicinal products across countries or settings. As drug development costs rise and healthcare systems and professionals face economic and resource pressures, leveraging existing data and evidence generated across borders or settings can improve efficiency and inform decisions in product development and decision‐making (regulatory, health technology assessment [HTA] and clinical care). Differences in population characteristics, healthcare systems, and data availability, including coding discrepancies, may present significant challenges to the transportability of CER evidence. Without rigorous methodological approaches, the utility of transportability analyses is limited. What we Did This article provides a structured framework for considering transportability exercises in CER analyses. We outlined key methodological principles, when and why to use transportability exercises in CER, feasibility assessments including effect modifier identification and causal inference techniques such as weighting, outcome regression, and combined methods to guide transportability analytical approaches in CER. By synthesizing existing literature and expert insights, we identified opportunities and trade‐offs in applying transportability methods to support decisions across the product lifecycle. Strategies to Disseminate and Facilitate Use To enhance the adoption of transportability analyses, we proposed best practices for researchers, regulators, HTA bodies, and industry stakeholders. These include early engagement with regulatory agencies and HTA bodies, transparent documentation of data assumptions, quality, fitness, and comparability assessments while ensuring robust analytical approaches. We also emphasized the need for standardized reporting guidelines and cross‐country collaborations to validate transportability methods in real‐world settings and communicate uncertainty in transported evidence. Conclusions Transportability analyses offer a powerful tool for extending the applicability of CER findings across healthcare systems, improving evidence generation efficiency, and supporting global drug development and evaluation. By implementing best practices that promote a rigorous and transparent approach to the design and conduct of such analyses, stakeholders can maximize the value of transported treatment effects while ensuring scientific rigor and decision‐making relevance. Future research should focus on empirical testing and validation of transportability methods targeting different questions across the product lifecycle and the development of harmonized regulatory and HTA methodological standards. “This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE).” Official Endorsement was received on 5/13/26.
PURPOSE:Nursing home (NH) residents are at high risk for major bleeding and are frequently exposed to complex medication regimens that may increase the likelihood of clinically important drug-drug interactions (DDIs). However, DDI evidence from community-dwelling populations may not generalize to NH residents, and real-world signals involving clopidogrel and oral anticoagulants remain incompletely characterized in this setting. We aimed to identify and interpret candidate DDI signals for major bleeding involving clopidogrel and oral anticoagulants among NH residents. METHODS:Using linked Minimum Data Set assessments and Medicare fee-for-service claims (2013-2020), we conducted high-throughput, self-controlled case series (SCCS) screening analyses for four object drugs (clopidogrel, apixaban, rivaroxaban, and warfarin) paired with candidate precipitant medications. We estimated rate ratios (RRs) and 95% confidence intervals (CIs) comparing periods of concomitant use versus object drug use alone, applying semi-Bayes shrinkage to reduce false-positive signals. To aid interpretation, we incorporated two negative controls: a negative-control object drug (pravastatin) and a negative-control outcome (fall-related injury). A panel of experts evaluated signals for biological plausibility and potential bias. RESULTS:After semi-Bayes adjustment, 5/40 clopidogrel, 1/29 apixaban, 2/15 rivaroxaban, and 6/22 warfarin signals remained significant, and none did for pravastatin. Signals were also observed for fall-related injury. Experts identified only clopidogrel/sertraline and warfarin with cephalexin, sulfamethoxazole-trimethoprim, and furosemide as biologically plausible signals. CONCLUSION:SCCS screening for DDIs in NH residents identified bleeding signals for clopidogrel and oral anticoagulants, but few were mechanistically coherent and fall-related injury signals suggested residual bias.
ABSTRACT Background Multiple myeloma (MM) is the second most common hematologic malignancy worldwide. Despite therapeutic advances that have improved survival, MM treatment remains complex and costly, particularly across multiple lines of therapy. Real‐world data (RWD) from Latin America on MM care patterns and associated costs are limited. This study applied process mining techniques to analyze RWD from a Brazilian private insurer, aiming to describe treatment patterns and healthcare resource utilization. Methods This retrospective, observational study analyzed de‐identified administrative claims data from Unimed Paraná, Brazil, from 2014 to 2024. Eligible patients had ≥ 9 claims associated with the ICD‐10 code for multiple myeloma (C90.0) or recurrent use of MM‐specific therapies, including proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, bispecific antibodies, or CAR‐T cell therapy. This study describes a selected administrative‐claims cohort from a Brazilian private payer; therefore, findings should not be interpreted as representative of an incident MM population. Process mining was performed using UpFlux AI to identify care pathways and cost dynamics across treatment lines. Statistical analyses were conducted using R and GraphPad Prism, adopting a 5% significance level. Results A total of 68 patients were included (62% male; mean age 65.8 ± 11.1 years). Autologous stem cell transplantation (ASCT) was performed in 42.7% of cases. Twenty‐one therapeutic regimens were identified, most commonly those containing bortezomib, daratumumab, and lenalidomide. The mean total treatment cost per patient was USD 186350.83 (SD = 164645.73), with a mean annual cost of USD 78425.81. Descriptive differences in annual expenditures were observed between patients who initiated therapy in 2014–2019 and those in 2020–2024 (USD 57083.10 vs. USD 97397.11; p = 0.011). First‐line therapy accounted for 50% of total costs, followed by first‐line maintenance (25%). Mean monthly costs increased significantly with treatment complexity (single‐exposed: USD 3491.26; double‐exposed: USD 9504.87; triple‐exposed: USD 12796.55; p < 0.001). Conclusions RWD derived from process mining enabled a structured description of MM treatment pathways and associated costs within a Brazilian managed‐care context. Costs increased with treatment complexity, and variation in cost patterns was observed across treatment phases. Findings should be interpreted considering limitations inherent to claims‐based analyses, including lack of clinical detail and potential selection and immortal time bias.
