British Journal of Clinical Pharmacology

Background Plasma gelsolin (pGSN) is a non-immunosuppressive anti-inflammatory immunomodulator with demonstrated efficacy in animal models of acute lung injury. Its potential role in moderate-to-severe acute respiratory distress syndrome (ARDS) is currently under investigation. Methods We conducted a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of recombinant human pGSN (rhu-pGSN) following intravenous (IV) administration to healthy volunteers. Thirty-two participants were assigned to 4 sequentially ascending dose cohorts (6, 12, 18, 24 mg/kg of body weight) to receive five IV infusions of rhu-pGSN or saline placebo. Each cohort includes 8 subjects randomized 3:1 with rhu-pGSN or placebo. Doses were administered at 0 hours, 12 hours, 36 hours, 60 hours, and 84 hours. The primary outcome is the incidence and severity of clinical and laboratory AEs regardless of causality. Secondary outcomes include the pharmacokinetics of IV rhu-pGSN and the presence of anti-rhu-pGSN antibodies at Day 28. Results Overall, 10 subjects (41.7%) who received rhu-pGSN reported a total of 13 adverse events (AEs), and 1 subject (12.5%) who received placebo reported an AE. All AEs were mild or moderate. AEs in system organ classes that were reported by 2 or more subjects in either arm were skin and subcutaneous tissue disorders (12.5% rhu-pGSN; 0% placebo), gastrointestinal disorders (8.3% rhu-pGSN; 0% placebo), and nervous system disorders (12.5% rhu-pGSN; 12.5% placebo). No AEs by preferred term were reported by more than 1 subject in either arm. Three subjects (12.5%) experienced an AE assessed as related to study drug. No serious AEs occurred, and no AEs led to study discontinuation, dose interruption/reduction, or death. There were no apparent between-treatment differences in laboratory abnormalities, vital signs, or electrocardiogram findings. Conclusions Overall, in this study, IV rhu-pGSN (up to 24 mg/kg daily) appeared safe and well tolerated compared to placebo. The median half-life of rhu-pGSN exceeded 14 h across all dosing regimens, supporting once daily IV dosing in healthy subjects. Trial registration This study was registered with ClinicalTrials.gov on 2023-03-29 under the registration identifier NCT05789745.

Objective To describe trends in dispensing of monoclonal antibodies (mAbs) for autoimmune conditions during and around pregnancy. Design Descriptive study. Setting Lombardy, Italy between 2012 and 2024. Population All women of reproductive age (14-49 years) resident in Lombardy. Methods We described trends in mAb dispensations among women of reproductive age and the prevalence of mAb dispensing before, during and after pregnancy. We explored maternal factors associated with discontinuation. Main outcome measures Change in prescribing of mAbs over time in all women of reproductive age, and before, during and after pregnancy in those who became pregnant. Prevalence of discontinuation and switching mAbs around pregnancy. Results We included 3,049,175 women of reproductive age and 859,699 pregnancies. Prevalence of mAb dispensing during pregnancy increased over 60-fold over the study period, from 0.0041% (95%CI:0.00084, 0.012) in 2012 to 0.27% (95%CI:0.23, 0.32) in 2024. Pregnancy affected mAb dispensing, with mean prevalence decreasing from 0.080% (95%CI:0.074, 0.087) before pregnancy to 0.051% (95%CI:0.046, 0.057) by the third trimester. Over half (53.3%) of pre-existing users discontinued before or during pregnancy; discontinuation decreased over time, and varied substantially between mAbs. Switching mAbs during pregnancy was rare (3.3%). We found limited evidence that sociodemographic factors were associated with discontinuation, but that some health factors may be, such as use of assisted reproductive technology (OR=1.92, 95%CI:0.98-3.77). Conclusions Italian population-wide data from 2012-2024 show an increase in mAbs dispensed during pregnancy, and fewer instances of discontinuing these drugs over time. This may reflect recent changes in prescribing guidelines for mAbs in pregnancy.

Background: Cysteamine is the only disease-modifying therapy for nephropathic cystinosis and has shown promise in mitochondrial disorders, but its clinical utility is limited by poor tolerability due to high peak concentrations with existing formulations. TTI-0102 is a novel natural controlled-release cysteamine prodrug designed to provide sustained cysteamine exposure with improved tolerability. Methods: A multi-center, randomized, single-blind, placebo-controlled Phase 2 trial enrolled 9 patients with MELAS syndrome caused by mtDNA m.3243A>G mutation (>50% heteroplasmy) and moderate disease severity (NMDAS score 15-45). Patients received placebo (n=3) or TTI-0102 at 2.75 g/day for one week then 5.5 g/day (n=6, equivalent to 2.5 g/day cysteamine base). Pharmacokinetic parameters, safety, and pharmacodynamic biomarkers including pyruvate, taurine, pantothenic acid, tryptophan, GSH/GSSG, lactate, GDF-15, and FGF-21 were assessed. Clinical efficacy was evaluated using the Modified Fatigue Impact Scale (MFIS) and 12-minute walk test. Results: TTI-0102 demonstrated expected gastrointestinal side effects (nausea, vomiting, diarrhea) consistent with the cysteamine class, with dropout occurring in patients 50 kg receiving fixed 5.5 g/day dosing. Weight-based dosing at 60 {+/-} 5 mg/kg TTI-0102 (~26 mg/kg cysteamine base equivalent) achieved sustained 24-hour cysteamine exposure with half the daily dose and peak concentrations lower than expected by dose proportionality, compared to approved formulations (Procysbi: 56 mg/kg, peak 2.5 mg/L vs. TTI-0102: 26 mg/kg, peak ~2 mg/L). TTI-0102 significantly elevated pantothenic acid (plateauing at 2 weeks) and taurine levels, providing mitochondrial cofactor support and antioxidant effects. Statistically significant pharmacodynamic effects included increased plasma pyruvate (p=0.03) without lactate elevation, suggesting enhanced glycolytic flux, and decreased tryptophan (p<0.01), potentially reducing oxidative stress from neurotoxic kynurenine pathway metabolites. Interestingly, increase in plasma pyruvate and decrease in tryptophan were negligible at doses up to 40 mg/kg/day, optimal at 60 mg/kg/day, and slightly less at 65 mg/kg/day. GSH/GSSG measurements were confounded by sample stability issues. GDF-15, FGF-21, and 12-minute walk distance showed no treatment-related changes. Most notably, MFIS total scores demonstrated significant improvement in TTI-0102-treated patients at 60 mg/kg/day average dose compared to placebo (p=0.04). Polynomial regression revealed therapeutic onset at ~4 weeks, maximal benefit at ~12 weeks, and subsequent plateau. Conclusions: This Phase 2 trial provides proof-of-concept that TTI-0102 is safe and well-tolerated in MELAS patients while treated with less than 65 mg/kg/day, with efficacy signals in fatigue reduction, a cardinal symptom affecting 71-100% of mitochondrial disease patients. The drug tri-faceted mechanism through sustained cysteamine, taurine, and pantothenic acid delivery addresses oxidative stress, mitochondrial energy metabolism, and cofactor deficiency. Significant MFIS improvement coupled with favorable modulation of pyruvate and tryptophan supports advancing TTI-0102 to larger Phase 2b/3 trials in mitochondrial disease employing weight-based dosing (60 {+/-} 5 mg/kg), validated patient-reported outcomes, and minimum 12-week treatment duration. The same mechanism of cysteamine/cystine thiol-disulfide exchange in lysosomes that may benefit mitochondrial diseases also supports cystinosis treatment. An investigator-initiated study in cystinosis will evaluate whether once-daily TTI-0102 at 60 {+/-} 5 mg/kg can maintain therapeutic WBC cystine levels, potentially offering improved adherence and quality of life compared to current twice-daily or four-times-daily regimens, and this weight-adjusted dosing strategy and pharmacodynamic biomarkers identified in the MELAS study are going to be used to inform the design of the planned Phase 2 study in Leigh syndrome, another mitochondrial disorder, in collaboration with the Childrens Hospital of Philadelphia (CHOP), with particular attention to dose optimization and biomarker-based assessment of pharmacological activity. Acknowledgement: We are very thankful to the patients and the clinical teams of Radboud University Nijmegen Medical Centre (Netherlands) and Centre Hospitalier Universitaire d'Angers (France) for their participation in this operationally challenging study.

BackgroundNon-adherence to lipid-lowering therapy (LLT) affects up to half of patients and contributes substantially to preventable cardiovascular morbidity and mortality. Existing measures, such as the proportion of days covered, provide cross-sectional summaries but fail to capture the dynamic patterns of adherence over time. Although group-based trajectory modelling identifies distinct longitudinal adherence patterns, no approach currently predicts trajectory membership prospectively while incorporating patient-reported barriers. We developed BRIDGE, a barrier-informed Bayesian model to predict adherence trajectories and identify their underlying drivers. MethodsBRIDGE incorporates patient-reported barriers as structured prior information within a Bayesian framework for adherence-trajectory prediction. The model was designed not only to estimate which patients are likely to follow different adherence trajectories, but also to generate clinically interpretable probability estimates that help explain why those trajectories may arise and what modifiable factors may be most relevant for intervention. ResultsBRIDGE achieved a macro AUROC of 0.809 (95% CI 0.806 to 0.813), comparable to random forest (0.815 (95% CI 0.812 to 0.819)) and XGBoost (0.821 (95% CI 0.818 to 0.824)), two widely used machine-learning benchmarks for structured clinical prediction. Calibration was superior to random forest (Brier score 0.530 vs 0.545; ), and performance was stable across six independent training runs (AUROC SD = 0.003). Incorporating barrier-informed priors improved accuracy by 3.5% and calibration by 5.5% compared to flat priors, showing that incorporation of patient-reported barriers added value beyond electronic medical record data alone. Four clinically distinct adherence trajectories were identified: gradual decline associated with treatment deprioritisation amid polypharmacy (10.4%), early discontinuation linked to asymptomatic risk dismissal (40.5%), rapid decline associated with intolerance (28.8%), and persistent adherence (20.2%). Counterfactual analysis identified trajectory-specific intervention levers. ConclusionsBRIDGE provides accurate and well-calibrated prediction of adherence trajectories while offering clinically actionable insights into their underlying drivers. By integrating patient-reported barriers with routine clinical data, the model supports targeted, mechanism-informed interventions at the point of prescribing to improve adherence to cardioprotective therapies. FundingMRFF CVD Mission Grant 2017451 Evidence before this studyWe searched PubMed and Scopus from database inception to December 2025 using the terms "medication adherence", "trajectory", "prediction model", "Bayesian", "lipid-lowering therapy", and "barriers", with no language restrictions. Group-based trajectory modelling has consistently identified three to five adherence patterns across cardiovascular cohorts; however, these applications have been descriptive rather than predictive. Machine-learning models for adherence prediction achieve moderate discrimination but treat adherence as a binary or continuous outcome, thereby overlooking the clinically meaningful heterogeneity captured by trajectory approaches. One prior study applied a Bayesian dynamic linear model to examine adherence-outcome associations, but it did not predict adherence trajectories or incorporate patient-reported barriers. To our knowledge, no published model integrates patient-reported barriers into trajectory prediction. Added value of this studyBRIDGE is, to our knowledge, the first model to incorporate patient-reported adherence barriers as hierarchical domain-informed priors within a Bayesian framework for trajectory prediction. Using 108 predictors derived from routine electronic medical records, the model achieves discrimination comparable to state-of-the-art machine-learning approaches while additionally providing uncertainty quantification, barrier-level interpretability, and counterfactual insights to inform intervention strategies. The identified trajectories differed not only in adherence level but also in switching behaviour, drug-class evolution, and medication burden, suggesting distinct underlying mechanisms of non-adherence that may require tailored clinical responses. Implications of all the available evidenceEach adherence trajectory implies a distinct intervention target: asymptomatic risk communication for early discontinuers (40.5% of patients), proactive tolerability management for rapid decliners, medication simplification for patients with gradual decline associated with polypharmacy, and maintenance support for persistent adherers. By integrating routinely collected clinical data with patient-reported barriers, BRIDGE can be deployed within existing primary care EMR infrastructure to generate actionable, trajectory and patient--specific recommendations at the point of prescribing, helping to bridge the gap between adherence measurement and targeted adherence management.

In the management of atrial fibrillation, the most frequently prescribed oral anticoagulant is apixaban, given at a fixed dose of 5mg BID. Apixaban is predominantly metabolized by cytochrome P4503A4 (CYP3A4) and is also a substrate for the drug efflux transporter P-glycoprotein (P-gp). In nearly 300,000 Medicare patients with AF receiving apixaban, we previously showed that concomitant therapy with drugs that inhibit both CYP3A4 and P-gp, specifically amiodarone or diltiazem, significantly increased serious bleeding that caused hospitalization and/or death. We hypothesized that this adverse effect was mediated by an increase in apixaban plasma concentrations caused by concomitant therapy that reduced drug elimination. Utilizing left-over samples obtained from clinically indicated blood draws that would typically be discarded, the Vanderbilt University Medical Center biobank BioVU contains >353,000 samples linked to de-identified electronic medical records (EMRs), with both DNA and plasma harvested. Of 35 samples drawn from patients taking apixaban 5mg BID, 5 were identified to be drawn from patients concomitantly taking drugs inhibiting both CYP3A4 and P-gp. Using a chromogenic anti-Xa assay, we found that plasma concentrations of apixaban were significantly higher (347{+/-}64 ng/mL; mean{+/-}SEM) for patients receiving concomitant CYP3A4/P-gp-inhibiting drugs compared to those not treated with these drugs (166{+/-}67 ng/mL; P=0.025, Mann Whitney). There were no differences between the 2 patient groups with respect to age, weight, or serum creatinine. The results of this pilot study provide preliminary data to support our hypothesis, and they demonstrate the practicality of obtaining pharmacokinetic data from a large cohort of plasma samples linked to deidentified EMRs. This approach could be used to define the role of apixaban levels in high-risk clinical scenarios and to better understand the relationship between drug levels and bleeding risk.

Importance Women have been under-represented in clinical trials of type 2 diabetes mellitus (T2D), and evidence on sex differences in effectiveness of T2D treatments remains limited. Objective To assess sex differences in comparative effectiveness and safety of four second-line antidiabetic agents: glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), and sulfonylureas (SU). Design Retrospective cohort study using an active-comparator new-user design, following each participant till treatment discontinuation or end of data. Setting Multinational study across ten real-world databases from the Observational Health Data Sciences and Informatics (OHDSI) network in the United States, United Kingdom, Germany, and Spain. Participants 5.15 million adults with T2D who initiated one of the four second-line therapies following metformin during 1992-2021. Exposures GLP-1RA, SGLT2i, DPP4i, or SU. Main Outcomes and Measures Cardiovascular effectiveness as measured through 7 outcomes (major adverse cardiovascular events and glycemic control) and safety through 18 outcomes as highlighted by ADA guideline. Hazard ratios (HRs) are estimated separately for women and men using propensity score-stratified Cox models with empirical calibration. Sex differences were tested using Z-tests on log-HR differences. Results Drug initiation rates differed by sex with 9.28% of women initiating on GLP-1RA, 11.91% SGLT2i, 27.81% DPP4i, and 50.99% SU; the rates among the men were 5.41%, 12.84%, 24.64%, and 57.10%. No significant sex differences were observed for cardiovascular effectiveness outcomes. Several safety outcomes showed significant sex differences that are consistent across drug comparisons. Focusing on GLP-1RA compared to SGLT2i for brevity, GLP-1RA users experienced the following comparative benefits and risks: higher risk of acute pancreatitis among women (HR 1.39 [1.13, 1.70]) while non-differential risk among men (HR 0.91 [0.74, 1.12]) with p = 0.005 for the test of difference; non-differential risk of hypotension among women (HR 1.08 [0.98, 1.19]) while lower risk among men (HR 0.87 [0.78, 0.96]) with p = 0.003. Where no sex differences were found, our findings were consistent with existing evidence. Conclusions and Relevance This large-scale multinational study on antidiabetic agents identified clinically relevant sex differences, which are biologically plausible but previously lacked clinical evidence. Our findings reinforce the importance of tailoring T2D management according to sex.

Background Hyperlipidemia is a major risk factor for cardiovascular disease and is increasingly linked to depression, which is associated with adverse cardiovascular prognosis. As proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are increasingly used for lipid lowering, their neuropsychiatric safety profile compared with established therapies remains uncertain. Objectives This study aimed to compare the risk of incident depression associated with initiation of PCSK9 inhibitor therapy vs statin therapy among adults with hyperlipidemia. Methods In this population-based cohort study, we emulated a target trial using a new-user active-comparator design and real-world data from the TriNetX research network from July 1, 2020, to June 30, 2025. Adults with hyperlipidemia who newly initiated PCSK9 inhibitors or statins were included. The exposure was initiation of PCSK9 inhibitor therapy versus statin therapy. Propensity score matching was performed, yielding 17,805 patients in each group. The primary outcome was incident depression. Cumulative incidence was estimated using the Kaplan-Meier method, and hazard ratios (HRs) with 95% confidence intervals (Cis) were estimated using Cox proportional hazards models. Results Among 35 610 propensity score-matched patients, the mean age was 65.4 (10.6) years and 46.7% were female. During a mean follow-up of 35.0 (21.2) months, incident depression occurred in 546 patients (3.1%) initiating PCSK9 inhibitors and 981 patients (5.5%) initiating statins. The 5-year cumulative incidence of depression was 5.84% for PCSK9 inhibitor initiators and 7.91% for statin initiators. PCSK9 inhibitor initiation was associated with a lower risk of incident depression (HR, 0.74; 95% CI, 0.67-0.82), corresponding to a 5-year number needed to treat of 46. The association was observed for major depressive disorder (HR, 0.71; 95% CI, 0.63-0.80) but not for dysthymic disorder or adjustment disorder. Consistent associations were observed across prespecified subgroups and sensitivity analyses, and the lower depression risk associated with PCSK9 inhibitor initiation remained regardless of comparator statin intensity or lipophilicity. Conclusions In this real-world target trial emulation, initiation of PCSK9 inhibitor therapy was associated with a lower risk of incident depression compared with statin therapy among adults with hyperlipidemia. Further prospective studies are warranted to confirm these findings and clarify underlying mechanisms.

Drug overdose deaths in the United States reached record levels during the fentanyl era before recently declining. A plausible hypothesis is that a sudden drop in fentanyl purity beginning in 2023 caused the downturn in overdose mortality. We evaluated this hypothesis by replicating a published analysis with regional overdose data, using models that account for time trends and autocorrelation, and negative control indicators to test for spurious correlation. When fentanyl purity was rising, the national purity series did not track overdose increases in most regions and showed only a modest association in the West. When both purity and mortality later declined, the observed associations were also seen with unrelated macroeconomic indicators that shared the same time pattern. National fentanyl purity alone does not provide a sufficient explanation for recent overdose declines.

ABSTRACT Objective To estimate the benefit and risk of replacing regular salt with potassium-enriched salt. Design Comparative risk assessment modelling. Setting Worldwide Participants Adult populations aged 25 and above. Intervention (1) worldwide replacement of all salt (discretionary salt used for seasoning or cooking in the home, and non-discretionary salt used in processed and restaurant foods); (2) worldwide replacement of just discretionary salt; (3) worldwide replacement of just non-discretionary salt; (4) replacement of discretionary salt just for people with diagnosed hypertension; and (5) replacement of discretionary salt just for people with treated hypertension. Main outcome measures For scenarios 1-3, we estimated benefits including deaths, new cases and disability-adjusted-life-years (DALYs) from cardiovascular disease and chronic kidney disease (CKD), from blood pressure-lowering as well as harms (CVD deaths) caused by hyperkalaemia among people with CKD stages G3-G5. Results Replacement of all salt worldwide could prevent 2.96 (95% uncertainty interval 2.81-3.12) million deaths, 10.17 (9.59-10.70) million new cases of disease and 69.43 (65.61-72.92) million disability-adjusted life years (DALYs) each year. These figures represent 14.6%, 13.1% and 16.5% of the annual global disease burden attributable to CVD and CKD. Replacement of all discretionary salt (1.85, 1.74-1.97 million deaths) would have a greater impact on mortality than replacement of all non-discretionary salt (1.56, 1.46-1.67 million deaths). In people with CKD Stage G3-G5, there would be a net benefit - replacement of all salt would prevent 0.75 (0.71-0.80) million deaths but might cause 0.10 (0.09-0.11) million deaths from hyperkalaemia. Discretionary salt replacement only among diagnosed or treated hypertensives would prevent 0.59 (0.55-0.63) million and 0.48 (0.45-0.52) million deaths, respectively. Conclusion Switching regular salt to potassium-enriched salt appears to offer large potential for health gains under diverse scenarios, including for people with CKD.

BackgroundHypertension is the leading modifiable risk factor for ischemic stroke, yet the adequacy of preventative hypertension care in routine clinical practice remains suboptimal. Whether gaps in hypertension management represent missed opportunities for stroke prevention remains unclear. ObjectiveTo evaluate the association between hypertension care delivery and the risk of incident ischemic stroke. MethodsWe conducted a retrospective, matched, nested case-control study among adults with hypertension using electronic health record data from a large regional health system (2010-2024). Patients with a first-ever ischemic stroke were matched 1:2 to controls on age, sex, race and ethnicity, and calendar time. Three care metrics were assessed during follow-up: (1) outpatient visits with blood pressure (BP) measurement per year; (2) number of antihypertensive medication ingredients; and (3) medication intensification score. Conditional logistic regression estimated adjusted odds ratios (aORs). ResultsThe study included 13,476 cases and 26,952 matched controls (N = 40,428). Mean (SD) age was 64.8 (12.2) years, 54.1% were female, and mean follow-up was 2,497 (1,308) days. Cases had fewer BP visits per year (median, 2.50 vs. 3.01; p < 0.001), similar number of medication ingredients (2.00 vs 2.00), and lower treatment intensification scores (-0.211 vs - 0.125). In adjusted models, >5 BP visits per year was associated with lower stroke odds (aOR, 0.55; 95% CI, 0.51-0.59) compared with [&le;]1 visit. Use of 2-3 medication ingredients (vs 0) was also associated with reduced stroke odds (aOR, 0.80; 95% CI, 0.75-0.86), whereas >3 ingredients was not significant. The highest quartile of treatment intensification showed the strongest association (aOR, 0.47; 95% CI, 0.44-0.51). Findings were consistent across subgroup and sensitivity analyses, including strata defined by baseline SBP and follow-up SBP. ConclusionsGreater engagement in hypertension care was associated with lower odds of ischemic stroke, suggesting that gaps in routine management may represent missed opportunities for prevention.

BackgroundNicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are NAD+ precursor supplements widely marketed for metabolic health benefits. Despite billions of dollars in annual sales, no head-to-head randomized controlled trial (RCT) has compared their effects on metabolic endpoints, and no systematic characterization of why reliable comparison is currently impossible has been published. ObjectiveTo characterize the structural heterogeneity of the NMN and NR trial evidence bases across population, dose, duration, and biomarker dimensions; to formally assess transitivity; and to estimate indirect NMN versus NR effects where methodologically feasible using the Bucher indirect comparison method. MethodsFive databases (PubMed, Embase, Scopus, Web of Science, Cochrane CENTRAL) were searched from January 2018 to May 2025. Eligible studies were RCTs of oral NMN or NR versus placebo in adults reporting metabolic outcomes. A formal transitivity assessment was conducted comparing effect modifier distributions across NMN and NR trial arms. Random-effects pairwise meta-analyses were conducted for each precursor versus placebo, and Bucher indirect comparisons estimated NMN versus NR effects through the common placebo node. Risk of bias was assessed using RoB 2 and certainty of evidence using the GRADE/CINeMA framework. ResultsFifteen studies (5 NMN, 10 NR; 740 participants) were included. The NMN and NR trial evidence bases were systematically asymmetric across every major effect modifier: NR was dosed 1.9 to 9.2 times higher than NMN on a molar basis; NMN trials were conducted predominantly in East Asian populations while NR trials were predominantly Western; and available NAD+ pharmacodynamic measures used incompatible assay matrices precluding indirect comparison. Across 14 metabolically comparable outcomes, no indirect comparison reached statistical significance and all were rated Very Low certainty by GRADE/CINeMA, consistent with the structural limitations of the evidence base. Leave-one-out sensitivity analyses showed zero pairwise significance changes and one indirect significance change (triglycerides upon exclusion of Conze 2019). ConclusionCurrent evidence is structurally insufficient to support reliable indirect comparison of NMN and NR for metabolic outcomes. The barriers are quantifiable and modifiable: future head-to-head trials should use equimolar dosing (approximately 1,150 mg NMN is molar-equivalent to 1,000 mg NR), harmonized whole-blood NAD+ assays reported in mol/L, minimum 24 weeks duration, and enrollment of metabolically at-risk populations to generate interpretable comparative evidence. RegistrationPROSPERO 2026 CRD420261330487; registered prior to data screening.

Background: Gabapentin prescriptions have increased 123% since 2010, reaching 59 million annually and 15.5 million patients. Recent evidence indicates that concomitant use of gabapentin and dihydropyridine calcium channel blockers (DHP-CCBs) amplifies dementia risk through a dual neuronal calcium signaling blockade mechanism. Whether these cognitive effects are reversible upon discontinuation, and whether the combination accelerates decline in patients with established dementia, remains unknown. Methods: We conducted two complementary studies using the Rutgers Clinical Research Data Warehouse (CRDW; 2015-2024). Study 1: A self-controlled case series (SCCS; N=3,058) comparing cognitive event rates during concomitant gabapentin-DHP-CCB use versus after discontinuation, using strictly duration-matched observation windows. Study 2: A cohort study (N=320) of patients with established dementia initiating gabapentin, comparing outcomes between DHP-CCB, non-DHP-CCB, and no-CCB users. Findings were externally replicated in the NIH All of Us Research Program Controlled Tier (N=8,853). Results: In the CRDW self-controlled analysis, event rates were significantly higher during combination use versus after discontinuation: falls (RR 1.34, 95% CI 1.11-1.61), cognitive symptoms (RR 1.67, 95% CI 1.38-2.01), and composite cognitive endpoint (RR 1.32, 95% CI 1.09-1.59). Effects were greatest when both drugs were discontinued (cognitive symptoms RR 2.21; falls RR 1.76). Protopathic bias was ruled out by monotonically increasing RRs across 0-, 30-, and 60-day lag conditions. In the dementia acceleration cohort, DHP-CCB use tripled encephalopathy risk (HR 3.18, 95% CI 1.36-7.46), with zero events among non-DHP CCB users. External replication in All of Us confirmed all primary outcomes (falls RR 1.53, cognitive symptoms RR 1.26, composite RR 1.42; all p<0.001). A non-DHP CCB negative control in All of Us confirmed mechanistic specificity: cognitive symptom and encephalopathy reversal signals were absent with verapamil/diltiazem. CKD amplified effects in both datasets, consistent with gabapentin accumulation through impaired renal clearance. Conclusions: Cognitive effects associated with concomitant gabapentin-DHP-CCB use appear substantially reversible upon discontinuation, replicated across two independent datasets. The DHP-specific pattern, confirmed through a pharmacological negative control, supports a neuronal L-type calcium channel mechanism. Clinicians should review gabapentin-DHP-CCB combinations in patients with cognitive complaints or falls, as deprescribing - particularly of both agents - may produce meaningful improvement.

Background: Despite optimal lipid-lowering and antithrombotic therapy, substantial residual cardiovascular risk persists in established atherosclerotic cardiovascular disease (ASCVD), partly driven by chronic vascular inflammation. Methods: Systematic review and meta-analysis of RCTs comparing colchicine to placebo or no treatment in adults with established ASCVD. Searches on March 21, 2026 (PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP). PROSPERO CRD420261346516. Primary outcome: 4-point MACE (CV death, MI, stroke, urgent revascularization). DerSimonian-Laird random-effects with HKSJ adjustment. Exploratory trial-level meta-regression: time-to-initiation (TTI) and cumulative dose as continuous moderators. Results: DL pooled HR for 4-point MACE: 0.68 (95% CI 0.51-0.89; p=0.0060). HKSJ-adjusted HR: 0.68 (95% CI 0.27-1.70; p=0.3018). Substantial heterogeneity (I2=81.4%; 95% prediction interval 0.29-1.57, crossing 1.0). Exploratory meta-regression: TTI (beta=-0.00187/day, p=0.003) and cumulative dose (beta=-0.00163/mg-day, p=0.0003; k=5, explicitly underpowered). Non-CV mortality: HR 1.07 (0.76-1.50; p=0.694). GI discontinuation: pooled RR 1.95 (1.09-3.48; p=0.024). GRADE certainty: Moderate (4-point MACE). Conclusions: Low-dose colchicine is associated with reduced 4-point MACE in ASCVD (DL HR 0.68; HKSJ HR 0.68). The substantial heterogeneity and wide prediction interval indicate that effect size varies substantially across clinical settings. The divergence between CLEAR SYNERGY (acute; HR 0.99) and sub-acute/chronic trials (HR 0.33-0.77) drives heterogeneity. Meta-regression suggests TTI and cumulative exposure may be key moderators but is underpowered. The non-CV mortality signal is not confirmed. This analysis informs precision anti-inflammatory prescribing in ASCVD.

Background and hypothesis Autosomal dominant polycystic kidney disease (ADPKD) affects over 12 million people worldwide including an estimated 30,000-70,000 in the United Kingdom (UK). Tolvaptan is the only disease-modifying therapy approved for rapidly progressing disease. Despite national guidance, prescribing rates were hypothesised to vary by kidney centre. Treatment may not always align with guidelines: some patients eligible for tolvaptan may not be initiated, while other patients initiated on tolvaptan may not meet eligibility criteria. This may have important consequences for healthcare costs and health-related quality of life. Methods The National Registry of Rare Kidney Diseases (RaDaR) collects longitudinal data from UK NHS kidney centres. This retrospective cohort study used routinely collected data (2016-2023) to examine tolvaptan prescribing across kidney centres. Kidney centre-level initiation patterns were described, assessed using mixed-effects logistic regression and visualised with funnel plots. Cost-effectiveness analyses combined observed prescribing practices under likely negotiated commercial discounts to estimate costs and quality-adjusted life year (QALY) consequences of prescribing at the national level. Results Our study included 3,609 people with ADPKD from 72 kidney centres. Patients eligible for tolvaptan who were not initiated accounted for 34.8% (292/839). Across centres, five (6.9%) initiated tolvaptan significantly more than expected among eligible participants, while one centre (1.4%) initiated significantly less. Nationally, this could result in up to {pound}53.7 million in lost savings (assuming a 60% medication price reduction) and result in up to 1,245 lost QALYs. Patients initiated on tolvaptan who were not eligible accounted for 26.1% (103/395). Only one centre had significantly fewer eligible patients than expected among initiated patients. Nationally, this could cost up to {pound}15.9 million (assuming a 60% medication price reduction). Conclusions There is evidence of variation in tolvaptan prescribing in the UK. A substantial proportion of patients eligible for tolvaptan were not initiated at the cohort-level, with evidence of variation between centres suggesting differences in treatment decision-making. A substantial proportion of patients initiated on tolvaptan were not eligible at the cohort-level, but there was limited evidence of variation between centres. Together, these findings raise questions regarding the potential consistency of clinical decision-making, equitable access to a sole disease-modifying therapy in a rare disease, alignment with national guidance, and effective use of healthcare resources.

Background. Recent meta-analyses of randomized controlled trials (RCTs) claimed efficacy of higher-dose fluvoxamine (2 x 100 mg/day, as opposed to 2 x 50 mg/day) in prevention of disease deterioration in adults with mild - moderate COVID-19 disease. Objectives. Investigate whether such claims are supported by the data. Methods. Systematic review and meta-analysis of RCTs evaluating higher-dose fluvoxamine in this indication. Results. Seven studies declared as RCTs were identified, one of which was severely biased (open-label, non-standardized and unreported standard of care as a control), and eventually ended as non-randomized (huge attrition). Composite endpoints of deterioration in the 6 included placebo-controlled trials contained elements susceptible to error and bias. Three trials were small (<100 patients/arm), three were larger (270 - 750 patients/arm). Deaths and need for mechanical ventilation were sporadic and observed in only one trial. Hospitalizations were also sporadic in 5/6 trials. Frequentist methods generally appropriate for random-effects analysis of low number of trials with rare outcomes (generalized linear mixed models, beta-binomial or binomial-normal) greatly underestimated heterogeneity, but still did not document benefits regarding the composite endpoints or hospitalizations. Bayesian hierarchical models revealed huge heterogeneity and indicated no benefit regarding: (i) composites of deterioration, large trials OR = 0.78 (95% CrI 0.55 - 1.21); multiplicity corrected OR = 0.87 (0.64 - 1.21); (ii) hospitalizations, small trials OR = 0.88 (0.45 - 1.72); large trials OR = 0.94 (0.52 - 1.75); all trials OR = 0.81 (0.47 - 1.43). Heterogeneity was unlikely due to clinical particulars (vaccination status, treatment duration, time horizon), and more likely due to unidentified bias. Conclusions. RCTs do not support efficacy of higher-dose fluvoxamine in prevention of disease deterioration in adults with mild - moderate COVID-19 disease.

Background: Concomitant gabapentinoid and dihydropyridine calcium channel blocker (DHP-CCB) use amplifies dementia risk, an interaction proposed to involve dual neuronal calcium channel blockade. Whether this risk depends on the sequence of drug initiation - and is therefore preventable by prescribing order - remains unknown. Methods: Using the Rutgers Clinical Research Data Warehouse (2015-2024), we conducted three complementary analyses. The primary analysis (Population 4) compared gabapentin versus pregabalin in 4,451 patients on chronic DHP-CCB therapy who newly initiated a gabapentinoid (55 dementia events; IPTW Cox model). The asymmetry confirmatory analysis (Population 3) compared DHP-CCB versus ACE/ARB initiation in 1,740 patients on chronic gabapentinoid therapy (29 dementia events). A sensitivity analysis replicated prior findings in a broader CCB-first cohort (N=9,383). A dementia acceleration analysis examined outcomes in 273 patients with established dementia initiating gabapentinoid. Results: In Population 4, gabapentinoid initiation on a background of chronic CCB therapy was associated with a 2.23-fold elevated dementia risk compared to pregabalin (IPTW HR 2.23, 95% CI 1.43-3.48, p=0.0004). The Population 3 asymmetry test yielded a null result: adding DHP-CCB to chronic gabapentinoid therapy carried no differential dementia risk versus adding ACE/ARB (IPTW HR 0.995, 95% CI 0.595-1.664, p=0.98). This directional asymmetry - elevated risk only when gabapentinoid is added to pre-existing CCB therapy, not the reverse - is the central finding. Lagged analyses showed HRs increasing monotonically from 2.23 to 2.87 across 0- to 180-day lag windows, reducing concern for protopathic bias. In the dementia acceleration cohort, DHP-CCB use at gabapentinoid initiation was associated with encephalopathy (IPTW HR 2.09, 95% CI 1.19-3.67, p=0.010); zero encephalopathy events occurred among non-DHP CCB users (N=16), consistent with DHP subtype specificity. Conclusions: The gabapentinoid-CCB cognitive interaction is directionally asymmetric: risk concentrates in patients adding gabapentinoid to pre-existing CCB therapy, not the reverse. This pattern is mechanistically consistent with impaired homeostatic synaptic plasticity in neurons compensating for chronic L-type calcium channel blockade. For patients already on CCB therapy requiring neuropathic pain management, pregabalin may be preferable to gabapentin, pending external validation. The asymmetry also implies that initiating a CCB in a patient already on gabapentin may not carry equivalent risk.

Background Cardiac MRI (CMR) is often utilized for patients with suspected cardiac amyloidosis (CA). However, data are lacking for use in patients with advanced renal dysfunction (ARD) (GFR<30 mL/min/1.73 m2, dialysis dependent, or renal transplant). This study evaluates the utility of CMR for diagnosis of CA in this population. Methods Patients with ARD who underwent CMR in a 3T field for suspicion of CA between 2010 and 2024 at our institution were included. A diagnosis of CA was made if any of the following were present a)?PYP scintigraphy grade ? 2, b) positive endomyocardial biopsy, or c) positive extracardiac biopsy with clinical features of CA. Two CMR-trained physicians independently assessed T1 relaxation time, ECV, Ti scout, LGE, and overall likelihood of CA. Results Out of the 65 patients included 14 (22%) had a diagnosis of CA. Although T1 time [1352 (1276-1428) ms] and ECV (40.3% +/- 9.1%) were elevated across the cohort, they were significantly higher in patients with CA (p<0.001 for both). Both ECV and T1 time reliably predicted CA (AUC of 0.87 and 0.88 respectively). ECV of ?45% had 75% sensitivity and 80% specificity for CA. A T1 time ? 1390 ms had 75% sensitivity and 85% specificity for CA. LGE was prevalent and was seen in 86% and 84% patients with and without CA respectively. Of the 31 patients deemed to be unlikely CA by a CMR reader, 6% had CA. However, of the 34 patients read as possible/likely CA, only 35% had confirmed CA. Conclusions In this understudied population of ARD, CMR parametric mapping exhibits high negative predictive value (NPV) for CA and improved positive predictive value (PPV) when higher cutoffs are used for T1 time and ECV. CMR reader overall impression exhibits high NPV but low PPV for CA.

Background & Aims: Per- and polyfluoroalkyl substances (PFAS) are persistent endocrine-disrupting chemicals associated with metabolic dysfunction, including metabolic dysfunction-associated steatotic liver disease (MASLD). While PFAS perturb lipid and bile acid (BA) metabolism in a sex-specific manner, the underlying mechanisms remain unclear. We tested whether steroid hormones mediate PFAS-associated metabolic alterations. Methods: In 104 patients with biopsy-characterized MASLD, we performed sex-stratified analyses applied liquid chromatography coupled to mass spectrometry (LC-MS) for chemical analysis, integrating circulating steroids, PFAS exposure, hepatic lipidomics and BA profiles. Results: Steroid hormones were associated with MASLD severity in a sexually-dimorphic manner. Dihydrotestosterone showed consistent inverse associations with steatosis, fibrosis, necroinflammation and insulin resistance, particularly in females. PFAS exposure was associated with altered steroid profiles, predominantly indicating suppressed steroidogenesis in females. These PFAS-associated hormonal changes were linked to downstream alterations in hepatic lipids and BAs. Mediation analysis supported indirect effects of PFAS on metabolic pathways via steroids, including testosterone/epi-testosterone-mediated effects on ether phospholipids and estradiol-mediated effects on lithocholic acid. Females exhibited stronger PFAS-steroid-BA associations, whereas males showed weaker, lipid-centric effects. Conclusions: PFAS exposure is associated with sex-specific disruption of steroid hormone pathways that may link environmental exposure to lipid and BA dysregulation in MASLD. These findings identify steroid hormones as potential key mediators of PFAS-associated metabolic dysfunction and highlight sex as a critical determinant in environmental liver disease.

Background: Chronic conditions such as hypertension can significantly disrupt daily life and emotional wellbeing. The interaction between patients' perceptions, adherence to antihypertensive medication and quality of life (QoL) remains underexplored outside structured clinical settings. Objectives: To capture unprompted patient perspectives and assess whether hypertension affects QoL and to investigate if patient reported experiences are associated with self-reported antihypertensive medication adherence. Methods: Social media listening (SML) study analyzing 86,368 anonymized posts from individuals with hypertension in 12 countries, collected between January 2022 and May 2024. Posts from 11 countries (n=81,368) were analyzed using artificial intelligence-enabled natural language processing. Posts from China (n=5,000) were analyzed separately using a harmonized framework. Quantitative and qualitative methods assessed variations by country, age, and gender, and associations between emotional expression and antihypertensive medication adherence. Results: Across the 11-country core sample, 45% of posts mentioned at least one QoL impact, most commonly worry/anxiety (11%). Impacts varied across countries. Among 8,096 posts with age identified, individuals <40 years reported emotional balance impacts in 28% of posts versus 22% among those aged 40+. Work/Education impacts were mentioned in 17% of posts by those <40 years vs 12% in 40+. Among 7968 posts explicitly referencing adherence, expressed worry was associated with stricter adherence (62% association score), as were structured routines (79% score), home monitoring (77%), dietary changes (77%), and exercise (71%). In contrast, sadness/depression was associated with inconsistent adherence (71%), as were forgetfulness (79%), side effects (73%), and cost/insurance concerns (65%). Conclusions: These results emphasize the importance of the psychological and emotional impact of hypertension, including on adherence to medication regimens, reinforcing the value of a holistic approach to patient care.

BackgroundPaediatric liquid medicines (PLMs) routinely contain sucrose to improve palatability, yet their cariogenic potential is well established. Healthcare professionals awareness and prescribing practices regarding sugar-free PLMs have received limited study in India, particularly in Uttarakhand. MethodsA descriptive cross-sectional study was conducted among 500 healthcare professionals aged [&ge;]25 years, using a pilot-tested structured questionnaire (Cronbachs = 0.85), administered online and in person across Uttarakhand districts (January-March 2024). After excluding 69 incomplete responses, 431 participants were analysed (response rate: 86.2%), comprising general medicine practitioners (49%, n = 211), paediatricians (27%, n = 116), and dental practitioners (24%, n = 104). Descriptive statistics and chi-square tests were applied (p < 0.05). ResultsPrescription decisions were primarily driven by childs age and weight (58%), cost (40%), and pharmaceutical brand (37%). While 88% recognised PLM sweetness and 67% were aware of pH-dental harm links, only 20% associated PLMs with dental caries. Overall awareness of hidden sugars was 73%. Eighty-three percent knew of sugar-free alternatives (50% local availability), yet 80% found them less palatable and 85% costlier. Only 48% routinely provided oral health advice. A statistically significant association was found between specialty and sugar-free PLM awareness (p = 0.03), with dental practitioners recording the highest awareness (90%). ConclusionsHealthcare professionals demonstrated variable levels of knowledge, attitudes, and practices regarding PLMs, with critical gaps in caries recognition (20%) and oral health counselling (48%). Despite high sugar-free PLM awareness, uptake is constrained by perceived cost and palatability barriers. Targeted continuing medical education and policy measures, including sucrose-free labelling promotion, are needed to improve paediatric oral health outcomes in Uttarakhand. KEY MESSAGESO_LIOnly 20% of healthcare professionals in Uttarakhand associated pediatric liquid medicines (PLMs) with dental caries, representing a critical knowledge gap despite 88% recognising their sweetness. C_LIO_LIOverall awareness of hidden sugars in PLMs was 73%, yet only 48% routinely provided post-prescription oral health counsellingsubstantially below international benchmarks. C_LIO_LIEighty-three percent were aware of sugar-free PLM alternatives, but adoption was constrained by perceived inferior palatability (80%) and higher cost ([~]10% premium, cited by 85%). C_LIO_LIDental practitioners demonstrated significantly higher sugar-free PLM awareness than general practitioners and pediatricians (p = 0.03), supporting the case for interprofessional oral health education in medical training. C_LIO_LITargeted continuing medical education (CME) and policy measuresincluding sucrose-free labelling mandates and institutional formulary inclusionare needed to convert awareness into prescribing practice change. C_LI