The Pharmacogenomics Journal

Sub-Saharan African populations carry pharmacogenomic alleles poorly represented in the European-derived reference panels underlying most clinical genotyping tools. We present a curated, machine-readable catalog of nine actionable alleles across six pharmacogenes (CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP3A5, NAT2) with African-specific frequency ranges, functional annotations, and evidence levels derived from reanalysis of 661 high-coverage whole-genome sequences across seven 1000 Genomes Project African populations. Direct comparison against PharmCAT v3.4.0 shows that CYP2D6 produces zero diplotype calls (0/661 samples callable) due to monomorphic reference positions absent from standard variant-only VCF output, a known limitation whose consequences for African allele carriers had not been reported. afripharmagen's reduced-position strategy identifies 243 CYP2D617 and 134 CYP2D629 carriers from the same input. For CYP2B6, CYP2C9, CYP2C19, and NAT2, both tools show concordance of 95-100%. Frequency gradients (CYP2B66: 30-50%; CYP2D617: 15-35% in West Africa; CYP3A5*1: 60-95%) translate directly into prescribing risk for efavirenz, tramadol, tacrolimus, and isoniazid. Pharmacogenomic decision support in African settings must incorporate population-specific allele definitions and input-format-aware strategies.

Objective: Whether a scheduled antiseizure medication (ASM) continues on schedule across the ICU-to-floor transfer has not been characterized. We quantified ASM administration-gap frequency across this transfer and compared it with gap frequency during matched non-transfer intervals in the same patient and drug. Methods: In this retrospective MIMIC-IV (version 3.1) cohort study, we identified epilepsy and status-epilepticus admissions with an ICU stay followed by floor transfer and a scheduled ASM order active at ICU departure. A gap was defined as an interval exceeding 1.5 times the expected dosing interval between the last ICU dose and first floor dose, or no further dose before discharge, and compared with a matched non-transfer control interval in the same patient and drug (paired McNemar test). A multivariable model evaluated six prespecified clinical predictors; sociodemographic variables were summarized descriptively. Results: Among 2,469 ASM transition-by-drug observations (1,583 admissions, 1,335 patients), an administration gap occurred in 251 (10.2%; 95% CI, 8.7%-11.7%). Gap frequency across the transfer exceeded frequency during matched non-transfer control intervals in the same patient and drug: a paired rate difference of 5.8 percentage points (95% CI, 4.4-7.1; 7.5% vs 1.7%; P = 7.3 x 10^-22) before the transfer and 6.4 percentage points (95% CI, 4.9-7.9; 8.9% vs 2.5%; P = 1.9 x 10^-23) after. Gap rates were similar for intravenous-available (9.9%) and oral-only (11.4%) drugs (rate difference, 1.5 percentage points; 95% CI, -1.6 to 4.5; P = .34). None of six prespecified predictors reached significance after correction. Significance: An antiseizure medication administration gap occurred in approximately 1 of every 10 drug-transition observations at the ICU-to-floor transfer, exceeding matched non-transfer gap rates by 5.8 to 6.4 percentage points. This transfer-associated excess, rather than any single medication or patient characteristic, supports a structured medication-continuity check.

BACKGROUND The optimal antiplatelet regimen in patients with acute coronary syndrome (ACS) and multivessel disease undergoing drug-coated balloon (DCB) angioplasty remains unclear. METHODS This was a prespecified subgroup analysis of the REC-CAGEFREE II trial, which was conducted at 41 sites in China and randomized 1948 exclusively DCB-treated participants with ACS to stepwise dual antiplatelet therapy (DAPT) de-escalation or standard DAPT. The primary endpoint was net adverse clinical events (NACE; including all-cause death, stroke, myocardial infarction, revascularization, and BARC type 3 or 5 bleeding) at 12 months. Participants were stratified into multivessel and single-vessel subgroups according to angiographic characteristics. RESULTS Overall, 720/1948 (37.0%) patients had multivessel disease. The multivessel subgroup was associated with a significantly higher risk of NACE compared with the single-vessel subgroup (12.5% versus 6.7%, HR IPTW:1.84, 95%CI:1.35-2.51, P<0.001). No significant interaction was observed between vessel status (multivessel or single-vessel) and treatment allocation with respect to NACE (Pinteraction=0.542). In the multivessel subgroup, NACE occurred in 44/368 (12.1%) and 45/352 (12.9%) in the stepwise de-escalation and standard DAPT groups (HR IPTW:0.95, 95%CI:0.62-1.75, P=0.818), respectively. In the single-vessel subgroup, NACE occurred in 43/607 (7.1%) and 39/621 (6.3%) in the stepwise de-escalation and standard groups (HR IPTW:1.12, 95%CI:0.72-1.70, P=0.611), respectively. For the prespecified hierarchical secondary endpoint, win ratio analyses yielded more wins for stepwise de-escalation in both subgroups. CONCLUSIONS Among patients with ACS undergoing DCB-only angioplasty, those with multivessel disease were associated with a higher risk of NACE than those with single-vessel disease. Stepwise DAPT de-escalation and standard DAPT exhibited similar risk-benefit profiles in both subgroups.

Background: Unruptured intracranial aneurysms (UIAs) are increasingly identified incidentally, and management balances rupture risk against treatment risk. UIA diagnosis has been linked to psychological distress, but psychotropic medication initiation after UIA discovery has not been compared across the full UIA management spectrum. Methods: We conducted a retrospective cohort study using IBM MarketScan claims (CCAE, MDCD, and MDCR; 2009-2023) among adults with a UIA diagnosis, continuous enrollment for 365 days before and after the index date, and no SAH/rupture on or before the index date. We compared the prevalence of 6 mental-health diagnoses before versus after UIA discovery and used adjusted logistic regression to examine psychotropic medication initiation within 365 days by management strategy (untreated observation as the reference). Results: Among 54,945 patients (untreated, 78.5%; endovascular, 11.3%; clipping, 3.0%; other/uncertain, 7.2%), prevalence of every mental-health diagnosis was higher after UIA discovery, most for depression (+4.6 percentage points) and anxiety (+4.5 points). Medication initiation was most common for benzodiazepines (8.7%). Endovascular treatment was associated with higher adjusted odds of benzodiazepine (aOR, 1.21), SSRI (aOR, 1.20), and sedative-hypnotic (aOR, 1.25) initiation.Surgical clipping demonstrated the broadest association, with higher odds across 5 of 6 classes, including benzodiazepines (aOR, 1.71) and sedative-hypnotics (aOR, 1.86). Benzodiazepines had the lowest 1-year persistence (10.5%) despite being the most commonly initiated class. Findings were consistent across sensitivity analyses, with the exception of the increase in panic disorder, which was no longer observed after applying a 30-day post-index lag. Conclusions: Mental-health diagnoses and psychotropic medication initiation increased after UIA discovery, and medication initiation was most pronounced among patients treated with surgical clipping. These findings support psychological assessment as part of aneurysm management regardless of strategy.

Background. The imprecision of current metrics to capture the complex genetic admixture and racial identity among Hispanic/Latino individuals in the United States [US] is a concern. We examined the relationship of self-reported race and genetic ancestry with hypertension [HTN] among Hispanics/Latinos. Methods. Cross-sectional study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), including 10,586 Hispanic/Latino unrelated adults. Genetic ancestry: West African [AA], Amerindian [AI], and European [EA]. Self-reported race: White, Black, Native American, or Multiple/Missing (More than one race or Unknown/Not reported/Refused). HTN: systolic (SBP) [&ge;]130 mmHg, diastolic blood pressure (DBP) [&ge;]80 mmHg, and/or use of HTN medications. Age- and sex adjusted models were used. Results. Self-reported race was White (38{middle dot}6%), Black (3{middle dot}6%), Native American (4{middle dot}1%), and Multiple/Missing (53{middle dot}7%), with Unknown/Not reported/Refused representing 32{middle dot}7%. Black and White Hispanics/Latinos had the greatest AA (55{middle dot}7%) and EA (69{middle dot}3%) ancestries, respectively. Each 10% AA increase was associated with OR 1{middle dot}15, SBP beta +0{middle dot}9 mmHg, and DBP beta +0{middle dot}7 mmHg. Conversely, each 10% AI increase was associated with OR 0{middle dot}83, SBP beta -0{middle dot}4 mmHg, and DBP beta -0{middle dot}6 mmHg. HTN prevalence was highest among those with Black race or in the highest AA quantile (45{middle dot}6% and 48{middle dot}0%, respectively), and lowest among those with Native American race or in the highest AI quantile (37{middle dot}6% and 26{middle dot}7%, respectively). Conclusion. One-third of Hispanics/Latinos did not self-report race. Black or White self-reporting race did somewhat relate to AA or EA ancestry, respectively. HTN profiles were related to self-reported race and genetic ancestry in this admixed population.

Background: Atrial fibrillation detected after stroke (AFDAS) is frequently diagnosed after embolic stroke of undetermined source (ESUS) and has important implications for secondary stroke prevention. Although prediction scores have been proposed to identify patients at increased risk of AFDAS, prospective evidence supporting their implementation to guide rhythm monitoring in routine clinical practice is limited. Methods: In this prospective, population-based implementation cohort study, adults with ESUS were enrolled between January 2022 and December 2024 across all stroke centers in Styria, Austria. The Graz AF Risk Score was prospectively implemented as part of a risk-adapted diagnostic pathway for cardiac rhythm monitoring. Patients with a score [&ge;]4 were recommended for implantable loop recorder monitoring, whereas monitoring in those with scores <4 remained at the treating physician's discretion. The primary outcome was AFDAS detection; recurrent ischemic stroke and recurrent stroke etiology were secondary outcomes. Results: Among 784 patients (median age 73 years [IQR 64-80], 45.7% women), AFDAS was detected in 166 patients (21.2%) during a median follow-up of 26.3 months (IQR 20-34). AFDAS detection was substantially higher in patients with a Graz AF Risk Score [&ge;]4 than <4 (38.1% vs. 3.9%; p<0.001). After adjustment for age, sex and ILR monitoring, a score [&ge;]4 independently predicted AFDAS (HR 6.3, 95% CI 3.5-11.2; p<0.001) and recurrent ischemic stroke (HR 2.2, 95% CI 1.1-4.1; p=0.023). Only one recurrent stroke in patients with a score <4 was attributable to atrial fibrillation (AF) (1/18, 5.6%). Conclusions: Prospective implementation of the Graz AF Risk Score identified patients with ESUS at markedly different risks of AFDAS. A Graz AF Risk Score [&ge;]4 was also independently associated with recurrent ischemic stroke. These findings support a risk-adapted approach to cardiac rhythm monitoring after ESUS.

Background: Adverse drug withdrawal events (ADWEs) are a key safety concern during deprescribing but remain poorly explored in pharmacovigilance systems. Objectives: To identify and compare ADWE signals across drug classes, different drugs within drug classes, and across patient characteristics, countries, and over time. Methods: A case/non-case disproportionality analysis was conducted in FDA-FAERS and EMA-EudraVigilance pharmacovigilance databases, with stratification by age (adults: 18-64, older adults: [&ge;]65), sex (male/female), reporting time (2004-2023 in 5-year intervals), and country (for EMA data). Disproportionality analysis (quantitative signal detection) was used to detect signals between ADWEs and drugs using the proportional reporting rate (PRR[&ge;]2), reporting odds ratio (ROR>1), and information component (IC>0) with case count [&ge;]5. Results: Overall, 158,501 reports (FDA-FAERS 145,514; EMA-EudraVigilance 12,987) included drug-event pairs related to ADWEs. In FDA-FAERS, clobetasone (IC=5.58; PRR=79.18; ROR=176.90) showed the strongest ADWE signals, followed by hydromorphone (4.85; 29.94; 37.37), hydrocodone, and paroxetine. In EMA-EudraVigilance, ethyl loflazepate (IC=6.01; PRR=119.80; ROR=197.53), clobetasone (5.39; 102.73; 155.10), veralipride, and levomethadone had the strongest signals. Most drugs maintained positive ADWE signals in analysis stratified into adults and older adults. However, among the top 10 drugs (based on highest IC values), buprenorphine/naloxone, desvenlafaxine, and baclofen in FDA-FAERS (ICs 4.95-6.05) showed stronger signals in older adults. A sex-based difference was observed, with paroxetine, venlafaxine, and buprenorphine/naloxone showing a stronger positive signal in females in both databases, whereas several opioids had stronger signals in males versus females across both databases. Conclusion: This study suggests ADWE signals for some medications differ by age and sex, potentially indicating different risks for withdrawal effects.

Background: Aneurysmal subarachnoid haemorrhage (aSAH) is frequently complicated by delayed cerebral ischaemia (DCI), for which current therapies incompletely target the underlying multifactorial pathophysiology. Transauricular vagus nerve stimulation (taVNS) modulates inflammatory, vasoactive and autonomic pathways and may attenuate secondary brain injury after aSAH. Methods: We conducted a prospective, single-centre, single-blind, randomised, sham-controlled pilot trial in adults within 5 days of aneurysm securing for non-traumatic aSAH. Participants were allocated 1:1 to active taVNS (left tragus) or sham (left earlobe) using a portable device delivered for 45 minutes twice daily over 5 days. Primary outcomes were safety (taVNS-related serious adverse events), acceptability, and compliance; secondary outcomes included inflammatory biomarkers, DCI, in-hospital complications, and functional outcomes to 1 month. Results: Thirty patients were randomised (16 taVNS, 14 sham), with numerically more severe aSAH at baseline in the taVNS arm. No taVNS-related serious adverse events occurred; side effects were generally mild and transient, and over 80% of planned sessions were completed. TaVNS produced greater reductions in serum tumour necrosis factor- and trends towards reductions in interleukin-1{beta} and interleukin-10, with numerically fewer DCI events (6.6% vs 35.7%) and neurological impairments (16.7% vs 53.8%), although functional outcomes were not statistically different at 1 month. Conclusions: Early taVNS after aSAH is safe, acceptable, and feasible in the neurocritical care setting and shows biologically plausible signals warranting evaluation in larger multi-centre trials.

Background: Evidence regarding delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains sparse. We aimed to identify its predictors and occurrence and evaluate its role in ischemic stroke and functional outcome under treatment with interventional rescue therapy (IRT). Methods: This retrospective single-center study included 628 adults with aSAH from 2014?2023. The primary endpoint was occurrence of refractory DCI (= refractory despite induced hypertension) treated with at least one IRT. Multivariable models evaluated refractory DCI, new ischemic stroke, and poor functional outcome (mRS 3?6) at 6?12 months. Results: Among 628 included patients, 61 who died within 3 days were excluded from DCI analysis; 166/567 (29%) developed refractory DCI. Younger age (OR = 0.98; P<0.001), female sex (OR = 0.57; P=0.007), and higher WFNS grade (OR = 1.18; P=0.011) were independently associated with refractory DCI. Earlier first IRT was associated with longer DCI duration (IRR = 0.88; P<0.001) and more required IRTs (IRR = 0.91; P<0.001). IRT was performed later than day 14 in 29/166 patients (17.5%); none was older than 70 years. Refractory DCI was associated with new ischemic stroke (OR = 4.68; P<0.001) and poor functional outcome (OR = 2.37; P<0.001); earlier first IRT was associated with poor outcome within the refractory DCI subgroup (OR = 0.86; P=0.03). Outcomes after 1?2 IRTs did not differ from those without refractory DCI (P=0.4), whereas ?3 IRTs were associated with poor outcome (P=0.04). Conclusions: Refractory DCI affected 29% of aSAH patients, predominantly younger women and patients with poorer initial neurological status, and extended beyond day 14 in nearly 20% of affected patients, none of whom was older than 70 years. Refractory DCI and earlier onset were associated with poorer radiological and functional outcomes. The absence of a detected outcome difference after 1?2 IRTs suggests that favorable outcomes may remain achievable despite refractory DCI.

Background. In Europe, first-trimester combined screening with the Fetal Medicine Foundation (FMF) algorithm identifies women at increased risk of preeclampsia who may benefit from personalized aspirin prophylaxis. However, a substantial proportion of early-onset preeclampsia (EOPE) remains undetected at clinically acceptable specificity. Objective. To evaluate the first-trimester performance of MaiRa for early-onset preeclampsia (EOPE) risk stratification by benchmarking it against FMF screening in the same women, characterizing discordant patient-level classification profiles and exploring potential implementation strategies. Study Design. This secondary case-control analysis was nested within the prospective, multicentre PREMOM cohort [NCT04990141], which enrolled women with singleton pregnancies across 14 tertiary hospitals in Spain. First-trimester MaiRa and FMF risk estimates were evaluated in the same 126 pregnant women, comprising 99 uncomplicated controls and 27 EOPE cases, defined by disease onset before 34 weeks. Discrimination was compared using a stratified paired bootstrap analysis of the areas under the receiver-operating-characteristic curves. Performance was assessed at prespecified clinical thresholds, and detection rates were evaluated at fixed false-positive rates. Universal and contingent MaiRa implementation strategies were also evaluated. Results. MaiRa showed greater first-trimester discrimination for EOPE than FMF combined screening (AUC, 0.974 vs 0.900; P=.040) and consistently achieved higher detection rates across fixed false-positive rates. At false-positive rates of 5% and 10%, MaiRa detected 85.2% and 92.6% of EOPE cases, compared with 44.4% and 70.4% for FMF, respectively. Patient-level analysis demonstrated that MaiRa identified 12 of 27 EOPE cases (44.4%) classified as low risk by FMF; these pregnancies generally exhibited less abnormal conventional first-trimester profiles, including fewer maternal risk factors, lower mean arterial pressure and lower uterine artery pulsatility index, yet 8 of 12 (66.7%) subsequently developed severe EOPE. Exploratory implementation analyses showed that universal MaiRa screening achieved the highest EOPE detection, whereas a contingent strategy using FMF for triage and reflex MaiRa testing reduced molecular testing to 35.7% of pregnancies while maintaining 77.8% sensitivity and 97.0% specificity. Conclusion. MaiRa provided greater first-trimester discrimination for EOPE than conventional combined screening and detected additional pregnancies that later developed severe disease despite less abnormal conventional screening profiles. The findings suggest that maternal plasma cfRNA profiling captures biological alterations not fully reflected by combined first-trimester screening and support further prospective evaluation in an independent, unselected obstetric population. Key words: early-onset preeclampsia; first-trimester screening; cell-free RNA; liquid biopsy; Fetal Medicine Foundation algorithm; combined screening; risk stratification; aspirin prophylaxis.

Background: A dose finding trial evaluated safety and adherence for pre-cardiac surgery administration of sodium valproate. Integrated multi-omics analyses of myocardium were used to characterise mechanisms underlying the treatment effects. Methods: Adults undergoing cardiac surgery were randomised 1:1:1:1 with concealed allocation to no treatment (Controls), sodium valproate 15mg/kg/day for 1-2 weeks, 15mg/kg/day for 4-6 weeks, or 25mg/kg/day for 4-6 weeks pre-surgery. The primary analysis evaluated adherence and toxicity. Myocardial injury was defined by high sensitivity serum troponin at 24 hours post-surgery. Single-nucleus Assay for Transposase-Accessible Chromatin with sequencing (snATACseq) and single nuclei RNA sequencing (snRNAseq) of myocardial biopsies collected at surgery assessed treatment effects on chromatin accessibility and gene expression. Candidate mechanisms were validated in in vitro. Results: The analysis cohort included 42 participants enrolled between January 2020 and August 2024. Non-compliance (38%) was highest with longer and higher dosing. Sodium valproate 15mg/kg/day for 1-2 weeks had the highest levels of complete treatment adherence (70%), with 20% experiencing moderate/severe drug related adverse effects. An as-treated analyses demonstrated reductions in troponin release in participants receiving Valproate[&le;]14 days. Myocardial biopsies from trial participants demonstrated activation of hormetic p53 and Akt-GSK-3{beta} ferroptosis protection pathways. Treatment effects were not attributable to chromatin accessibility. Treatment >14 days resulted in a heart failure phenotype with suppression of ferroptosis protection pathways, endothelial mesenchymal transition, and increased myocardial injury. Conclusions: Sodium valproate 15mg/kg/day for [&le;]14 days pre-surgery is well tolerated in adults awaiting cardiac surgery. This treatment was associated with upregulation of ferroptosis protection pathways and reductions in myocardial injury.

Importance: Evidence on GLP-1/GIP therapies is largely derived from trials enrolling selected populations or medical records that miss utilization outside healthcare channels. No nationally representative cohort has characterized real-world uptake, indications, and access. Objective: To characterize GLP-1/GIP prevalence, indication, clinical profile, and access. Design: Prospective cohort study with three GLP-1/GIP surveillance waves (March 2024, December 2024, October 2025). Setting: The Understanding America Study, an address-based, nationally representative panel of approximately 15,000 US adults aged 18+ years initiated in 2014. Participants: UAS participants responding to at least one surveillance wave (n=9150). Exposures: GLP-1/GIP use status (never vs any use, comprising current and former use), self-reported primary indication (diabetes, weight loss, or other), and access pathway (traditional vs non-traditional). Main Outcomes and Measures: Survey-weighted prevalence of GLP-1/GIP use, overall and by indication and access pathway; sociodemographic, cardiometabolic, treatment, and access characteristics; and smartwatch-derived resting heart rate, heart rate variability, maximum activity heart rate, step count, and sleep duration and variability. Results: Among n=9150 adults (1274 with any use; 60.9% female; median age 53 years), weighted prevalence increased 46%, from 8.2% (March 2024) to 12.0% (October 2025) representing 32 million. Weight-loss indications grew, reaching nearly half of use (4.1% to 5.6%); diabetes-indicated use was stable (5.3% to 5.4%). Users carried high cardiometabolic burden (obesity, 68.2%; diabetes, 53.6%) but diverged by indication: diabetes-indicated users were older (median, 59 vs 49 years), whereas weight-loss-indicated users were more often female (69.9% vs 51.3%) and healthier. One in three users (~9 million) had non-traditional access, especially in weight-loss-indicated users, of whom 33% had no conventional prescription; 41% used compounding, online, or foreign pharmacies; and, 43% lacked coverage. Non-traditional users were five times as likely to report an unlisted, likely compounded formulation (19.8% vs 4.1%). All p<0.05. Conclusions and Relevance: Real-world GLP-1/GIP use has grown rapidly and diversified substantially in indication, access, and population profile. One in 3 users obtained treatment through nontraditional channels largely invisible to claims data, raising long-term safety, efficacy, and coverage questions. GLIMMER provides a public, nationally representative longitudinal evidence base for future payer and provider decisions.

Background and Objectives: Deep sequencing of brain tissue in the research setting has established that mosaic variants are a major cause of malformations of cortical development (MCDs) and epilepsy. However, genetic testing in the clinical setting primarily detects germline variants using clinically accessible samples. We aimed to determine the diagnostic yield and clinical utility of deep sequencing in the clinical setting to identify pathogenic mosaic variants for this population. Methods: We performed a retrospective cohort analysis of individuals at Boston Children's Hospital with MCDs with or without epilepsy who received clinical deep sequencing between September 2017 and February 2026. Demographic, clinical, and genetic testing data were abstracted from the medical record. For individuals without systemic features, we classified brain tissue as an affected tissue sample. For individuals with systemic features, we classified brain or relevant non-brain tissue as affected. The primary outcome was the diagnostic yield of clinical deep sequencing performed using affected vs unaffected tissue samples. The secondary outcome was the clinical utility of genetic diagnoses. Results: Our cohort included 37 individuals (19/37 (51%) female, 18/37 (49%) male) with MCDs, of whom 35/37 (95%) had epilepsy (25 with brain tissue samples available from epilepsy surgery) and 8/37 (22%) had systemic features. Most (35/37 (95%)) had dysplasia phenotypes on MRI and 12/27 (44%) with pathology available had Focal Cortical Dysplasia Type I or II. The diagnostic yield was 53% (17/32; 16 mosaic and 1 germline variant) when clinical deep sequencing was performed using an affected tissue sample vs 0% (0/6) using an unaffected tissue sample (p=0.016). Of the diagnosed cases, 13/17 (76%) had testing performed on brain tissue (1 with systemic features) and 4/17 (24%) on non-brain tissue (3 buccal and 1 duodenal tissue, all with systemic features). All but one diagnosis involved the mTOR pathway. All diagnoses had clinical utility. Discussion: Clinical deep sequencing, when performed using an affected tissue sample, has high diagnostic yield and clinical utility for individuals with MCDs, especially dysplasia phenotypes, and epilepsy. Our findings support implementation of clinical deep sequencing for this population, especially as the genetic diagnoses have implications for emerging precision therapies.

Introduction: Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is a common endocrine disorder affecting women of reproductive age. Besides reproductive and metabolic disturbances, PMOS negatively impacts psychological well-being and quality of life. Despite available treatment options, there remains a need for safe and effective therapies that improve both clinical symptoms and fertility outcomes. Aim: To compare the efficacy of VAMHA and MYRHA tablet combination therapy with standard non-hormonal therapy in restoring regular menstruation. Secondary objectives included assessment of ovulation, menstrual symptoms, polycystic ovarian morphology, hormonal and metabolic parameters, anthropometric measures, and skin manifestations. Study Design: Open-label, randomized, multicentre, prospective comparative clinical study. Methods: Seventy-one women with PMOS were randomized to Group A (n=37) or Group B (n=34). Group A received VAMHA and MYRHA tablets (2 tablets each), while Group B received Metformin 500 mg plus Myoinositol 600 mg (1 tablet), twice daily for 180 days. Data were recorded in Case Report Forms. Statistical Analysis: Continuous variables were summarized using mean and standard deviation, while categorical variables were expressed as frequencies and percentages. Appropriate statistical tests, including Chi-square, were used. A p-value [&le;]0.05 was considered significant. Results: Significantly more participants in Group A achieved regular menstrual cycles than Group B (31 vs. 22; p<0.05). Ovulation occurred in 16 participants in Group A compared with 6 in Group B (p<0.05). Both groups showed significant improvement in menstrual irregularity and related symptoms. Significant reductions in Anti-Mullerian Hormone (AMH), fasting insulin, and body mass index (BMI) were observed in both groups (p<0.05). Resolution of polycystic ovarian morphology occurred in 13 participants (38.23%) in Group A and 10 (33.33%) in Group B. Both treatments were well tolerated with no major safety concerns. Conclusions: VAMHA and MYRHA combination therapy was superior to standard non-hormonal therapy in improving menstrual regularity and ovulation. It also produced favourable metabolic, hormonal, and ultrasonographic outcomes, suggesting its potential as a safe and effective option for comprehensive PMOS management and fertility enhancement.

Recent large-scale studies have enabled new knowledge about genetic underpinnings of morphological and electrophysiological alterations of the retina. Variation in retinal traits, often of neurodevelopmental origin, have been linked to major psychiatric disorders (MPDs). Here, we investigate the genetic overlap between MPDs and key retinal traits to identify underlying molecular mechanisms. We obtained genome-wide associations studies data for bipolar disorder (BD), major depression (MD), schizophrenia (SCZ), and the retinal traits retinal nerve fibre layer thickness (RNFL), ganglion cell inner plexiform layer thickness (GCIPL), and vertical cup-disc ratio (VCDR). We estimated the number of trait-influencing variants shared between traits with MiXeR and identified shared genetic loci with condFDR. Subsequently, we examined the biological pathways of the genes mapped to shared loci. This revealed that GCIPL shared the most genetic variants with MPDs (~60%), followed by RNFL (~40%), and VCDR (~20%). The genetic variants shared between retinal traits and MPDs showed disorder-specific patterns with more pronounced overlaps of SCZ and BD with RNFL, and MD negatively correlated with GCIPL. Gene-pathway analysis highlighted the importance of GABAergic neurotransmission and a two-stage neurodevelopmental process in SCZ, whereas the role of mitochondria and a weaker developmental component were observed in BD. The results also implicated synaptic functioning and gene-expression processes in MD. Furthermore, polygenic analysis suggested that the genetic architecture of retinal traits can distinguish between MPDs. Our findings indicate shared genetic underpinnings between retinal traits and SCZ, BD, and MD, implicating altered neurodevelopment and neurotransmission underlying the retinal link to major psychiatric disorders.

Background: On-call clinicians frequently report the anecdotal impression of 'theme shifts' during which specific acute neurological diagnoses appear to cluster. Whether such clustering reflects a statistically true and reproducible phenomenon has not been systematically investigated; the present paper examines seasonality and temporal clustering within six different acute neurological conditions. Methods: In this retrospective, single-center cohort study, we identified all patients admitted to a tertiary neurological department between July 2016 and June 2026 with acute unilateral vestibulopathy, cerebral artery dissection, generalized epileptic seizures, primary intracerebral hemorrhage, peripheral facial nerve palsy, or transient global amnesia (TGA) (n = 2,140). Monthly and seasonal distributions were assessed using chi-squared goodness-of-fit and cosinor analysis. Short-term temporal clustering was tested by Monte Carlo permutation across time windows from 24 hours to 90 days, and endogenous cluster dynamics were characterized using Hawkes self-exciting point process modeling. Results: Admissions for generalized epileptic seizures showed a statistically significant deviation from a uniform monthly distribution with a winter distribution (p<0.001 and q = 0.002), and a significant temporal clustering across time windows from 72 hours to 90 days (all q < 0.05). Peripheral facial nerve palsy presented significant clustering at the 90-day window (q = 0.029) and TGA at 60-day time window (q = 0.041) without seasonality; the diagnostic groups of acute unilateral vestibulopathy, cerebral artery dissection and primary intracerebral hemorrhage showed neither seasonality nor clustering after correction for multiple comparison. No diagnostic group showed clustering within a 24-hour window, statistically significant self-excitation in Hawkes process modelling, or a significant linear trend in monthly case counts over the study period. Conclusion: The anecdotal impression of diagnostic 'theme shifts' among on-call neurologists appears to have a measurable basis, although clustering is confined to specific conditions and rather on a time scale of weeks to months. Generalized epileptic seizures were the only diagnostic group that uniquely combined seasonality with temporal clustering, suggesting a shared trigger, while facial palsy and TGA showed episodic, yet non-seasonal clustering.

Background: Many at-risk patients lack access to genetic services due to a genetic counselor (GC) workforce shortage. Little is known about how digital alternatives impact patients with and without cancer who meet criteria for genetic testing. Methods: eREACH2 is a randomized 4-arm non-inferiority trial where pre-test (visit 1) and/or return of results (visit 2) GC counseling was replaced with a patient-centered digital intervention. Arms include: A (GC/GC), B (GC/digital), C (digital/GC) and D (digital/digital). Primary outcomes were non-inferiority in uptake of genetic services and change in genetic knowledge and general anxiety from baseline to post-disclosure of results (T0-T2). Secondary cognitive and affective outcomes were assessed using non-inferiority ANOVAs and equivalency chi-squared tests in intention-to-treat and per-protocol analyses. Findings: 773 participants were recruited nationwide; 46.6% from rural areas. Mean age was 51 years (range 20-87), 13% male, 12% non-white, 29% had less than a college education, and 33% had a personal history of cancer. 584 (76%) patients completed testing (14% had a positive result, 16% had a VUS). In the primary ITT analyses, we met the non-inferiority for uptake of genetic services and anxiety, but results were inconclusive for knowledge. Secondary outcomes were heterogeneous across arms. Arm C demonstrated consistently favorable effects, while Arms B and D showed less favorable outcomes in select domains (e.g. satisfaction and MICRA). Patients who received positive or VUS results via digital disclosure had significantly higher MICRA scores - indicating greater negative response to testing. Interpretation: In this large, randomized trial of patients with and without cancer, the eREACH intervention was effective for pre-test counseling, but inconclusive for digital disclosure of results. Exploratory analyses suggest that digital delivery could be a reasonable alternative for individuals receiving negative results, while those receiving positive or VUS results may derive some short-term psychosocial benefit from GC disclosure.

We propose two new tests to detect drug effects (DE) in trials of one to very few patients followed during two periods (before and after initiation of a treatment). Both methods use longitudinal natural history data to inform the estimation of each patient's DE. The first method uses a non linear mixed effect model (NLMEM) reflecting an expected natural history with a hypothetical drug effect, to estimate the Conditional Distribution of the Drug Effect (CDDE). The second method trains a Pareto Depth Analysis (PDA) algorithm, a machine learning based approach based on outlier detection, that we implement using data simulated under the NLMEM. We evaluated the two tests with a simulation study. We used data from the PROSPAX study in Autosomal Recessive Cerebellar Ataxias (ARCAs, to derive a NLMEM for the Scale for the Assessment and Rating of Ataxia score. The CDDE method provided controlled type I error and, in some scenarios, adequate corrected power, though sensitivity analyses showed vulnerability to misspecification. The PDA method demonstrated lower statistical power except with high score precision. These results highlight different strategies for quantifying treatment effects in ultra rare, patient' specific trials. They can inform methodological design for future ARCA precision therapies.

Importance: Immune checkpoint inhibitors (ICIs) produce diverse immune toxicities, but whether checkpoint blockade also modifies associations between other drugs and adverse events is poorly understood. Objective: To define ICI-associated toxicity organization and determine whether drug-associated adverse events and onset vary with ICI exposure and checkpoint pathway. Design and Setting: Cross-sectional analysis of deduplicated FAERS reports from 2016 through 2025; analyses performed in 2026. Participants: Among 13,701,106 deduplicated reports, 2,365,269 were cancer associated and 256,940 contained an ICI. Median age among cancer reports with observed age was 66 years (IQR, 56-75 years); 1,031,999 (43.6%) were female and 1,003,154 (42.4%) were male. Exposures: ICI exposure in any reported drug role, individual primary-suspect drugs, and checkpoint-pathway exposure. Main Outcomes and Measures: Reporting odds ratios (ORs), cross-organ adverse-event communities, adjusted primary-suspect drug x ICI interaction ORs for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), interstitial nephritis, drug-induced liver injury (DILI), and vomiting (VOM), and accelerated failure-time model time ratios for documented onset. Results: Of 3001 eligible Preferred Terms in cancer-associated reports, 2091 differed at a false discovery rate (FDR) less than .05. Four cross-organ toxicity communities were identified. Of 138 eligible drug-phenotype pairs, 65 had FDR-significant interactions, including moxifloxacin-SJS/TEN amplification (interaction OR, 101.72; 95% CI, 39.11-264.55), enfortumab vedotin-SJS/TEN attenuation (interaction OR, 0.17; 95% CI, 0.13-0.23), and omeprazole-interstitial nephritis amplification (interaction OR, 10.35; 95% CI, 7.62-14.05). Among 60,324 reports contributing to temporal analyses, ICI exposure was associated with longer adjusted documented time to onset for 5 of 6 phenotypes (time ratios, 1.37-1.59) but not AGEP (time ratio, 0.99; 95% CI, 0.67-1.46). Temporal associations also differed across checkpoint pathways. Conclusions and Relevance: ICIs were associated with a structured cross-organ toxicity landscape, phenotype-specific modification of drug-associated adverse events, and distinct temporal patterns across checkpoint pathways. These findings support checkpoint blockade as a modifier of drug-associated toxicity and motivate longitudinal and mechanistic validation.

Purpose: To evaluate whether initiation of GLP-1 receptor agonists (GLP-1RAs) is associated with anti-VEGF treatment burden in type 2 diabetes patients with diabetic macular edema (DME) in the IRIS(R) Registry (Intelligent Research in Sight). Methods: Incident GLP-1RA initiators were matched 1:1 with controls via Mahalanobis distance matching (9,896 pairs; N=19,792) on sociodemographics, DME risk factors, and factors influencing GLP-1RA prescription including hypertension, obesity, chronic kidney disease. A longitudinal mixed-effects event-study model evaluated monthly anti-VEGF injection frequency over a 36-month window (12 months before through 24 months after initiation), adjusting for DME duration. Visual acuity (VA) and central subfield thickness (CST) were secondary outcomes. Results: Following GLP-1RA initiation, anti-VEGF injection trajectories did not significantly differ between the matched GLP-1RA and control cohorts (interaction coefficients -0.18 to 1.59, P>0.05). Likewise, no differences in VA were observed between cohorts (-0.05 to 0.04 logMAR, P>0.05) or CST (-14.12 to 33.58 {micro}m, P>0.05). Conclusion: In these matched cohorts, GLP-1RA initiation was not associated with the trajectory of anti-VEGF use or changes in VA or CST. Precis We used the American Academy of Ophthalmology IRIS(R) Registry (Intelligent Research in Sight) to identify patients with DME. In 19,792 matched patients, there was no significant reduction in injection frequency post GLP1-RA initiation and no significant change in VA or CST.