Nevin Manimala

CNS Drugs. 2026 Jul 28. doi: 10.1007/s40263-026-01319-3. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder that often requires sustained symptom control throughout the day. Although bimodal extended-release dexmethylphenidate (d-MPH XR) formulations provide initial and intermediate drug release, they may not consistently maintain therapeutic exposure into the late afternoon and evening. Trimodal formulations with an additional delayed release component may extend drug exposure later in the day, although this remains to be established. To explore differences in pharmacokinetic (PK) profiles between trimodal (CTx-1301) and bimodal delivery of d-MPH XR, a comparative bioavailability study was conducted at the highest and lowest doses for both formulations.

METHODS: In this randomized, 4-period, crossover study, adults with ADHD received single doses of CTx-1301 (50 mg and 6.25 mg) and d-MPH XR (40 mg and 5 mg). Comparative bioavailability was assessed through adjusted geometric mean ratios for exposure parameters (maximum observed plasma concentration [C_max], area under plasma concentration-time curve to last measurable concentration [AUC_last] and extrapolated to infinity [AUC_0-inf]), with a prespecified bioequivalence range of 0.80 to 1.25. Secondary endpoints included partial AUCs and safety assessments.

RESULTS: The study population (N = 45) was predominantly male (88.9%) and White (55.6%), with mean age of 29.6 ± 8.01 years. Adjusted geometric mean ratios comparing the primary exposure parameters (C_max, AUC_last, and AUC_0-inf) for CTx-1301 versus d-MPH XR were within the bioequivalence range (0.80-1.25) at both the high and low doses. The CTx-1301-to-d-MPH XR partial AUC ratios were within the bioequivalence range from 0 to 9 hours post-dose. At later intervals (AUC_9-12 and AUC_12-16), adjusted geometric mean ratios exceeded the upper bioequivalence threshold, consistent with the expected contribution of the third medication release component. Dose proportionality was observed between the two CTx-1301 doses and two d-MPH XR formulations. CTx-1301 was generally well tolerated. The most commonly reported adverse events included tachycardia, insomnia, headache, nausea, and euphoric mood. The incidence of treatment-emergent adverse events was numerically lower with CTx-1301 than with d-MPH XR; however, no statistical analysis was performed.

CONCLUSIONS: Key exposure parameters including C_max, AUC_last, and AUC_0-inf for trimodal CTx-1301 were statistically bioequivalent to bimodal d-MPH XR. Interval‑specific PK analyses demonstrated higher exposure with CTx‑1301 during later post-dose intervals (9-16 h), consistent with the formulation’s third release component. However, the clinical relevance of these PK differences requires further evaluation. CTx-1301 demonstrated dose proportionality and was well tolerated at high and low doses.

REGISTRATION: ClinicalTrials.gov, NCT04138498; 19 September 2019.

PMID:42518155 | DOI:10.1007/s40263-026-01319-3

Eur Geriatr Med. 2026 Jul 28. doi: 10.1007/s41999-026-01562-3. Online ahead of print.

ABSTRACT

PURPOSE: Cortisol dysregulation has been implicated in Alzheimer’s disease (AD), but its associations with amyloid and tau-related outcomes remain unclear. This study examined whether baseline CSF cortisol was associated with cross-sectional and baseline-adjusted 24-month multimodal AD biomarkers and cognitive outcomes.

METHODS: A total of 764 participants were included, comprising cognitively normal (CN; n = 284), individuals with mild cognitive impairment (MCI; n = 356), and patients with AD dementia (n = 124). Associations between baseline CSF cortisol, multimodal AD biomarkers, and cognitive outcomes were assessed with FDR correction.

RESULTS: CSF cortisol increased modestly from CN to MCI and AD dementia, with a small but statistically significant overall group difference after FDR correction. Cross-sectionally, in the MCI group, higher CSF cortisol was associated with higher CSF total tau and p-tau181 and a lower Aβ42/total tau ratio. In baseline-adjusted 24-month analyses, in MCI groups, higher CSF was associated with higher CSF total tau and p-tau181, greater temporal tau-PET burden, lower hippocampal volume, greater ventricular volume, and poorer cognitive outcomes. In the full cohort and MCI group, CSF-defined amyloid positivity strengthened associations of higher baseline CSF cortisol with adverse 24-month tau-related outcomes. Exploratory analyses suggested that 24-month CSF total tau and hippocampal volume partly accounted for the association between higher baseline CSF cortisol and poorer 24-month cognition in MCI; however, these findings do not establish causal mediation.

CONCLUSION: Higher CSF cortisol may be linked to tau-related pathology and poorer cognition, supporting further evaluation of its prognostic value across the AD continuum.

PMID:42518151 | DOI:10.1007/s41999-026-01562-3

Adv Ther. 2026 Jul 28. doi: 10.1007/s12325-026-03707-z. Online ahead of print.

ABSTRACT

INTRODUCTION: To date, no head-to-head comparisons of apalutamide versus darolutamide have been reported for metastatic castration-sensitive prostate cancer (mCSPC). This study compared prostate-specific antigen decline ≥ 90% (PSA90) and overall survival (OS) between apalutamide and darolutamide, both without docetaxel, among patients with mCSPC in real-world clinical practice in the USA.

METHODS: Men diagnosed with mCSPC who initiated apalutamide or darolutamide between 2022 and 2025 were identified from linked electronic medical records and insurance claims. The apalutamide and darolutamide cohorts were balanced using inverse probability of treatment weighting. PSA90 response was assessed on-treatment. The proportions of patients achieving a PSA90 response and OS through a maximum of 6 months and 24 months post-treatment initiation, respectively, were compared between the two cohorts using weighted Kaplan-Meier and weighted Cox proportional hazards models.

RESULTS: For PSA90 analyses, weighted characteristics were well balanced between the apalutamide (n = 714; mean age 73.9 years, 59.6% White, 21.2% Black, 13.7% other, 5.5% unknown race) and darolutamide cohorts (n = 145; mean age 74.3 years, 58.8% White, 21.6% Black, 15.0% other, 4.7% unknown race). PSA90 response rates through 6 months were 49% higher for apalutamide than for darolutamide (weighted hazard ratio [HR]: 1.49 [95% confidence interval (CI) 1.07, 2.07]; p = 0.017). For OS analyses, weighted characteristics were also well balanced between apalutamide (n = 1460; mean age 73.5 years, 59.6% White, 21.5% Black, 13.5% other, 5.4% unknown race) and darolutamide (n = 287; mean age 73.7 years, 60.0% White, 22.4% Black, 12.4% other, 5.2% unknown race). Apalutamide was associated with a 51% lower rate of mortality relative to darolutamide through 24 months (weighted HR: 0.49 [95% CI 0.30, 0.83]; p = 0.007).

CONCLUSION: Among patients with mCSPC treated without docetaxel, apalutamide was associated with higher PSA90 response rates and lower mortality than darolutamide. These findings indicate a potential difference in disease control and survival between the two androgen receptor-targeted agents in routine clinical practice.

PMID:42518140 | DOI:10.1007/s12325-026-03707-z

Adv Ther. 2026 Jul 28. doi: 10.1007/s12325-026-03719-9. Online ahead of print.

ABSTRACT

INTRODUCTION: This study aimed to evaluate the effectiveness and safety of vosoritide in Chinese children with achondroplasia (ACH) in a real-world setting.

METHODS: A total of 26 children diagnosed with ACH and treated with vosoritide were enrolled in the study. Clinical indicators such as height, sitting height, and body mass index (BMI), as well as laboratory indicators including bone age and insulin-like growth factor level, were collected and analyzed before and after treatment. Improvements in height standard deviation score (SDS), sitting height/height ratio, and BMI were evaluated. Statistical differences were analyzed across different age and sex groups. Adverse reactions during the treatment were also monitored.

RESULTS: Among the 17 patients assessed at 12 months, height SDS (based on general population growth charts) improved from – 4.7 ± 0.1 at baseline to – 4.3 ± 0.2 at 12 months (P < 0.001). With continued treatment, annual growth velocity (AGV) significantly increased, reaching 8.7 ± 1.4 cm/year in 12 patients who remained under follow-up after 18 months of treatment. Furthermore, BMI SDS exhibited a continuous decline. The sitting height/height ratio decreased during the treatment, indicating an optimization of body proportions. Additionally, growth improvement was found in both age (below five years old and above five years old) and sex (male and female) groups. Except for the total procollagen I intact N-terminal (TP1NP), which significantly increased at 12 months of treatment compared to baseline, other biochemical indicators (including insulin-like growth factor, alkaline phosphatase, and osteocalcin) showed no significant differences after the treatment.

CONCLUSION: Vosoritide exerts significant growth-promoting effects and favorable safety in Chinese children with ACH. It improves height SDS and body proportions, demonstrating consistent effectiveness across various age groups and sex groups. Early diagnosis and timely initiation of vosoritide treatment can significantly alter the growth trajectory of these children.

PMID:42518139 | DOI:10.1007/s12325-026-03719-9

Prev Sci. 2026 Jul 28. doi: 10.1007/s11121-026-01959-3. Online ahead of print.

ABSTRACT

Suicide remains a significant public health issue in corrections settings in the United States, requiring systems-focused strategies for prevention and policy. We aggregated across 37 suicide rates, structural, social, and corrections-related variables from publicly available data sources. We used Latent Profile Analysis to identify clusters by profiles of correction systems across 50 states. We analyzed descriptive statistics of state characteristics by cluster to better understand their profiles. Lastly, we conducted ANOVAs to examine differences in suicide rates between clusters. We identified four clusters of states based on their profiles of corrections variables: number of facilities, populations in prisons, jails, and private prisons, prison overcrowding, prisoner-to-staff ratios, and disparities by race/ethnicity and gender. Thirteen states showed the highest racial and gender disparities in prison populations. Twenty-eight states showed average scores across all variables. Four states showed the highest proportion of people incarcerated in privately owned facilities. Five states showed the highest incarceration rates in both prisons and jails. Significant differences in suicide rates were observed across clusters, especially within jails. Findings from this study enhance our understanding of how structural and social factors may be associated with suicide in corrections settings. The discussion includes specific, tailored prevention strategies and policy solutions aimed at systems-level intervention.

PMID:42518125 | DOI:10.1007/s11121-026-01959-3

Addiction. 2026 Jul 28. doi: 10.1111/add.70558. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Amid ongoing debate on whether low-to-moderate alcohol consumption reduces cardiovascular risk, studies examining the association between alcohol consumption and cognitive function have reported inconsistent results. To quantitatively assess this association, we conducted a dose-response meta-analysis of cohort studies, including stratified analyses by potential modifiers and study-level characteristics.

METHODS: Eligible studies were identified by searching PubMed, Embase and Web of Science for articles published through 13 June 2025. Studies investigating major cognitive impairment were excluded. Pooled standardized mean differences (SMDs) were calculated using a random-effects model.

RESULTS: We identified 20 studies including 78 657 participants. A weak inverted J-shaped association between alcohol consumption and cognitive function was observed, but the test for nonlinearity did not reach statistical significance (P for nonlinearity = 0.06). Compared with no alcohol consumption, heavy alcohol consumption (≥67 g/day) was inversely associated with cognitive function [SMD at 67 g/day = -0.18, 95% confidence interval (CI) = -0.36 to -0.00; 20 studies, 78 657 participants], while the evidence for a protective effect of low-to-moderate alcohol intake remained uncertain. In studies that accounted for baseline cognition, alcohol consumption of ≥28 g/day was associated with lower cognitive function (SMD at 28 g/day = -0.08, 95% CI = -0.15 to -0.01; 9 studies, 23 385 participants), whereas the association remained uncertain in studies that did not account for baseline cognition (SMD at 28 g/day = 0.13, 95% CI = -0.05 to 0.32; 11 studies, 55 272 participants) (P for interaction < 0.01). By region, alcohol consumption of ≥33 g/day was associated with lower cognitive function in studies conducted in the United States (SMD at 33 g/day = -0.11, 95% CI = -0.22 to -0.01; 7 studies, 25 538 participants), whereas the association remained uncertain in studies conducted in Europe (SMD at 33 g/day = 0.07, 95% CI = -0.08 to 0.22; 10 studies, 44 235 participants) (P for interaction = 0.02).

CONCLUSIONS: A review of current evidence shows that heavy alcohol consumption (≥67 g/day) is inversely associated with cognitive function, while the evidence for a protective effect of low-to-moderate alcohol intake remains uncertain. The inverse association is stronger in studies that accounted for baseline cognition, with the alcohol intake threshold (~28 g/day) for lower cognitive function close to the drinking guideline limits, although these findings should be interpreted cautiously because of the limited number of studies.

PMID:42517285 | DOI:10.1111/add.70558

J Sleep Res. 2026 Jul 28:e70411. doi: 10.1111/jsr.70411. Online ahead of print.

ABSTRACT

Sleep-related and chronotype traits have been shown to impact health in observational studies. To identify whether these associations are potentially causal, we conducted phenome-wide Mendelian randomisation analyses of short sleep, insomnia symptoms, total sleep duration, long sleep, snoring, daytime sleepiness and morning chronotype with a broad range of health-related phenotypes. We assessed the association between the genetic predisposition to these traits and the occurrence of 702 health-related phenotypes, using summary statistics of the largest genome-wide association studies in European individuals. Results that were significant (multiple comparisons: False Discovery Rate) and valid (robust genetic instruments, unaffected by horizontal pleiotropy) were validated using data from the second largest European genome-wide association study. Genetically determined short sleep was associated with increased risks of attention-deficit/hyperactivity disorder and neuroticism, musculoskeletal conditions, asthma and gastroesophageal reflux and lower educational attainment. Genetically determined insomnia symptoms showed associations with increased risk of coronary artery disease, major depression and osteoarticular disease. Genetically determined long sleep was linked to higher risk of iron deficiency anaemia and lower bone mineral density. Genetic predisposition to snoring was associated with more falls, greater body mass and higher low-grade inflammation. Genetically determined morning chronotype was related to higher vitamin D levels and lower risk of irritable bowel syndrome. No associations were found for daytime sleepiness. Overall, these findings indicate that genetically determined short sleep duration and insomnia symptoms are associated with mental and neurological problems, cardiovascular disease and musculoskeletal disorders, suggesting a potentially preventive, causal role of healthy sleeping patterns on chronic disease.

PMID:42517234 | DOI:10.1111/jsr.70411

Circ Arrhythm Electrophysiol. 2026 Jul 28:e014755. doi: 10.1161/CIRCEP.125.014755. Online ahead of print.

ABSTRACT

BACKGROUND: Large left atrial volume (LAV) is a strong predictor of advanced left atrial substrate and is associated with less successful outcomes following pulmonary vein isolation (PVI) alone. Prespecified variables of the aMAZE trial were evaluated to access for the impact of LAV and left atrial appendage ligation on atrial fibrillation (AF) outcomes.

METHODS: The aMAZE trial (REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02513797) was a multicenter, randomized-controlled study evaluating the effects of LAV on freedom from atrial arrhythmias (AA) following PVI-only compared with LARIAT and PVI (LARIAT+PVI). In total, 610 drug-refractory patients with nonparoxysmal AF were randomized 2:1 to LARIAT versus PVI alone. Freedom from AA was assessed 12 months postprocedure. LAV was independently assessed by a core laboratory from cardiac computed tomography performed before ablation.

RESULTS: There were 404 patients in the LARIAT+PVI group and 206 in the PVI-only group. Logistic regression performed within each subgroup for primary effectiveness with LAV demonstrated that the recurrence of AA after PVI was directly related to increasing LAV. Freedom from recurrence of AA in the LARIAT+PVI arm was independent and preserved irrespective of LAV. Similar results were seen with LAV index. A tercile analysis of early persistent AF (perAF) patients (AF >7 days and <6 months) and LARIAT+PVI in the highest (>148 cm³) LAV tercile showed statistically significant freedom from AA compared with PVI-only (69% versus 49%; P=0.02). Significant differences (P<0.04) between groups in the early perAF cohort began at an LAV of 130 cm³ and an LAV index of 65 cm³/m².

CONCLUSIONS: The correlation of LAV with PVI effectiveness in this study demonstrates that AA recurrence after PVI alone is directly related to increasing LAV. Freedom from AA after left atrial appendage ligation in addition to PVI is independent of increasing LAV, and left atrial appendage ligation may therefore provide an adjunctive benefit in patients with nonparoxysmal AF and enlarged LAV.

PMID:42517227 | DOI:10.1161/CIRCEP.125.014755

Circ Arrhythm Electrophysiol. 2026 Jul 28:e014785. doi: 10.1161/CIRCEP.125.014785. Online ahead of print.

ABSTRACT

BACKGROUND: Recent meta-analyses of randomized controlled trials have raised concerns that treatment with omega-3 fatty acids may increase the risk of atrial fibrillation (AF). However, these meta-analyses included at most 8 trials. The aim of this current meta-analysis was to expand the search by including other eligible omega-3 randomized controlled trials with AF incidence data, incorporating both published and unpublished data.

METHODS: Eligible studies were randomized controlled trials investigating daily doses of ≥500 mg/d of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Additional inclusion criteria included ≥12 months of treatment with EPA/DHA, participants ≥50 years of age, and, where possible, the absence of known AF/atrial flutter at baseline. The primary outcome was the occurrence of new-onset AF. Our primary hypothesis was that risk for AF would simultaneously depend on both omega-3 dose (above or below 1500 mg/d) and background cardiovascular disease risk status, and that their combined impact on AF risk would be synergistic.

RESULTS: A total of 35 randomized controlled trials (37 data sets; n=114 592) were included in this meta-analysis. Only studies including patients at high-risk for cardiovascular disease who were treated with high-doses of EPA/DHA (>1500 mg/d) showed a statistically significant increase in AF risk with a pooled odds ratio (OR) of 1.43 (95% CI, 1.14-1.79) and an absolute risk difference of 0.8% (0.40%-1.1%). None of the other 3 groups showed statistically significant levels of AF risk (odds ratios, 1.07 [high risk-low dose], 1.06 [low risk-low dose], and 1.03 [low risk-high dose]).

CONCLUSIONS: This meta-analysis suggests that high-dose EPA/DHA treatment is associated with an increased risk of AF in patients at high cardiovascular disease risk, whereas low-dose EPA/DHA does not appear to increase AF risk, even in high-risk populations. Further prospective studies are needed to evaluate any potential increased risk of higher doses balanced against potential benefits.

PMID:42517224 | DOI:10.1161/CIRCEP.125.014785

AIDS. 2026 Jul 28. doi: 10.1097/QAD.0000000000004588. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare maternal safety and pregnancy outcomes among women who did and did not use daily oral emtricitabine-tenofovir disoproxil fumarate (FTC/TDF) for preexposure prophylaxis (PrEP) during pregnancy and postpartum.

DESIGN: Parallel cohort design, with follow-up from pregnancy to 6 months postpartum.

SETTING: Seven research clinics in Malawi, South Africa, Uganda, and Zimbabwe.

PARTICIPANTS: Three hundred fifty pregnant women aged 16-24 years at 32 weeks or less gestation, meeting local criteria for PrEP. At entry, PrEP initiators and decliners were enrolled 2 : 1. Participants could start or stop PrEP at any time.

MAIN OUTCOME MEASURES: Maternal adverse events were defined as grade ≥3 signs, symptoms, and diagnoses, and grade ≥2 chemistry abnormalities according to Division of AIDS toxicity tables. Adverse pregnancy outcomes included fetal loss, preterm birth, and small-for-gestational-age.

RESULTS: From March to December 2022, 350 eligible participants enrolled: 229 initiating and 121 declining PrEP at entry. Median duration of PrEP use was 34 weeks (interquartile range [IQR]: 16-40). Sixty maternal adverse events were reported over 230.3 person-years (incidence rate: 25.6, 95% confidence interval [95% CI]: 20.0-32.8). Although those on PrEP had higher rates of adverse events, this was not statistically significant (adjusted incidence rate ratio: 1.84, 95% CI: 0.53-6.30). Most frequent grade ≥3 adverse events were complications of pregnancy or delivery. Five (8%) were considered related to PrEP use. Among those with delivery information, 79 (24%) participants reported adverse pregnancy outcomes, with no differences between PrEP groups. No participants acquired HIV infections during follow-up.

CONCLUSION: Daily oral FTC-TDF remains a well tolerated and essential component of HIV prevention in pregnancy.

PMID:42517223 | DOI:10.1097/QAD.0000000000004588