Nevin Manimala

Genetics. 2025 Aug 7:iyaf158. doi: 10.1093/genetics/iyaf158. Online ahead of print.

ABSTRACT

Testing inferred haplotype genealogies for association with phenotypes has been a longstanding goal in human genetics given their potential to detect association signals driven by allelic heterogeneity – when multiple causal variants modulate a phenotype – in both coding and noncoding regions. Recent scalable methods for inferring locus-specific genealogical trees along the genome, or representations thereof, have made substantial progress towards this goal; however, the problem of testing these trees for association with phenotypes has remained unsolved due to the growth in the number of clades with increasing sample size. To address this issue, we introduce several practical improvements to the kalis ancestry inference engine, including a general optimal checkpointing algorithm for decoding hidden Markov models, thereby enabling efficient genome-wide analyses. We then propose LOCATER, a powerful new procedure based on the recently proposed Stable Distillation framework, to test local tree representations for trait association. Although LOCATER is demonstrated here in conjunction with kalis, it may be used for testing output from any ancestry inference engine, regardless of whether such engines return discrete tree structures, relatedness matrices, or some combination of the two at each locus. Using simulated quantitative phenotypes, our results indicate that LOCATER achieves substantial power gains over traditional single marker testing, ARG-Needle, and window-based testing in cases of allelic heterogeneity, while also improving causal region localization. These findings suggest that genealogy-based association testing will be a fruitful approach for gene discovery, especially for signals driven by multiple ultra-rare variants.

PMID:40795253 | DOI:10.1093/genetics/iyaf158

J Gerontol B Psychol Sci Soc Sci. 2025 Aug 7:gbaf151. doi: 10.1093/geronb/gbaf151. Online ahead of print.

ABSTRACT

OBJECTIVES: Recent studies suggest that the association between social participation and mental health may change with age, although the direction of this relationship is unclear. While some suggest that the mental health benefits of social participation decline with age, others argue they become more important in later life. In this paper, we suggest a context-dependent divergence in aging trajectories: whereas urban older adults continue to gain mental health benefits from social participation, their rural counterparts gradually stop deriving such benefits over time.

METHODS: We drew on four waves of the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018; N = 16,233; 53,056 person-years) to examine how social participation shapes depressive symptoms among adults aged 45 and older. Growth curve models were employed to assess the age-related trajectories of the effects of social participation on depressive symptoms, and interaction terms were introduced to analyze urban-rural differences.

RESULTS: A significant three-way interaction (Informal Social Participation × Rural × Age) revealed that the mental health benefits of informal social participation increased with age among urban older adults but gradually declined among their rural counterparts. This divergence became statistically significant at around age 60 and continued to widen thereafter, indicating a growing urban advantage in the protective effects of informal engagement over time.

DISCUSSION: These findings suggest that the mental health benefits of social participation change with age in ways shaped by residential context, highlighting the need to consider how urban and rural environments differently influence aging trajectories.

PMID:40795235 | DOI:10.1093/geronb/gbaf151

Blood Adv. 2025 Aug 12:bloodadvances.2025017004. doi: 10.1182/bloodadvances.2025017004. Online ahead of print.

ABSTRACT

Atypical hemolytic uremic syndrome (aHUS), a life-threatening complement-mediated disorder, is now treatable with terminal complement inhibitors like eculizumab. Although effective, these therapies are costly and increase susceptibility to infections, notably meningococcal disease, raising concerns about long-term use. The optimal duration of complement inhibition remains unclear, prompting efforts to explore the possibility of treatment discontinuation. We conducted a systematic review and meta-analysis to evaluate the benefits and risks of stopping terminal complement inhibitor therapy in aHUS. We searched PubMed, Scopus, and CINAHL for studies of continuing vs. stopping anti-complement treatment in aHUS. Of 3303 identified studies, 13 observational studies (3 case-control, 10 cohort) comprising 584 patients were included. Overall, continuing treatment was associated with an approximately 76% reduction in the odds of relapse (odds ratio [OR] 0.24, 95% CI: 0.09 to 0.62; p= 0.01.) Study design influenced results: cohort studies showed a more modest effect (OR=0.40 (95% CI: 0.15 to 1.09), while case-control studies reported inflated estimates (OR=0.04 (95%CI: 0.02 to 0.08); subgroup interaction p=0.03). Patients with various genetic variants [CFH, CFHdel, MCP] had decreased relapse with continued therapy when case-control studies were included in the analysis. When the analysis was restricted to cohort studies, the effects became uncertain [statistically non-significant with large confidence intervals]. While current evidence is insufficient to provide personalized guidance on which patients with aHUS can safely discontinue anti-complement therapy, findings from higher-quality studies-which show no statistical difference between continued and discontinued treatment-suggest that discontinuation may be possible for at least some patients.

PMID:40795230 | DOI:10.1182/bloodadvances.2025017004

J Antimicrob Chemother. 2025 Aug 7:dkaf295. doi: 10.1093/jac/dkaf295. Online ahead of print.

ABSTRACT

OBJECTIVES: The spread of carbapenem-resistant Gram-negative bacteria (CR-GNB) related to nosocomial infections is an important public health challenge, and polymyxins have become the last line of defence against CR-GNB. In this study, we aimed to compare the efficacy and safety of different polymyxins.

METHODS: This retrospective cohort study included neurocritical care patients with CR-GNB pneumonia. The efficacy and safety were compared in original and inverse probability of treatment weighting cohorts. A subgroup analysis was further conducted to explore the impact of augmented renal clearance status at baseline on treatment efficacy.

RESULTS: Of the 331 patients included, 90 received colistin sulphate, 187 received polymyxin B, and 54 received colistin methanesulfonate sodium. Compared with colistin sulphate, colistin methanesulfonate sodium significantly reduced the clinical failure rate on Day 7 (20.8% versus 37.2%, P = 0.034) and 28-day mortality rate (6.2% versus 16.9%, P = 0.013) and improved the microbiological eradication rate on Day 28 (94.8% versus 84.2%, P = 0.013). The colistin methanesulfonate sodium group also had a lower mortality rate (6.2% versus 15.7%, P = 0.005) and clinical failure rate on Day 28 (17.1% versus 27.4%, P = 0.020) than the polymyxin B group. However, colistin methanesulfonate sodium was more nephrotoxic than colistin sulphate and polymyxin B (P = 0.001 and P = 0.004, respectively). Subgroup analysis revealed no statistical difference in clinical failure rate and mortality risk between the three groups.

CONCLUSIONS: For CR-GNB pneumonia in neurocritical care patients, intravenous colistin methanesulfonate sodium may provide a useful treatment option, but vigilance is warranted for nephrotoxicity.

PMID:40795180 | DOI:10.1093/jac/dkaf295

Subst Use Misuse. 2025 Aug 12:1-10. doi: 10.1080/10826084.2025.2546505. Online ahead of print.

ABSTRACT

BACKGROUND: The Centers for Disease Control and Prevention offered a multicomponent intervention called Local Opioid Overdose Prevention and Response (LOOPR). Five sites (Bell, KY, Boone, WV, Manchester, NH, St. Francois, MO, and Ware, GA) were selected to implement academic detailing (AD). AD is a strategy for communicating safer opioid prescribing practices to clinicians. This is the first study to assess changes in county-level opioid prescribing behaviors after implementing a multicomponent prevention program emphasizing AD.

OBJECTIVES: We examined three opioid prescribing behaviors (percentage of opioid prescribers in the top centile nationally, opioid prescribing rate, and average number of opioid prescriptions per prescriber) before and after program implementation in each site and a paired control. We used paired interrupted time series to examine the effect of LOOPR on each outcome for each site and control.

RESULTS: Five jurisdictions incorporated AD as part of LOOPR. In addition, Bell County, KY implemented three other interventions (coalition establishment, communication campaign, and community-based overdose prevention program). Manchester City, NH (community-based overdose prevention program and public health/public safety partnership) and St. Francois, MO (communication campaign and public health/public safety partnership) implemented two additional interventions. Boone County, WV and Ware County, GA only incorporated AD. Though not always statistically significant, all sites showed decreasing or stabilizing trends after implementation of LOOPR for most outcomes.

CONCLUSIONS/IMPORTANCE: This study shows AD is a versatile strategy and customizable activity that can be implemented in many settings as a separate activity or integrated with various prevention programs, making it particularly suitable for community-level interventions.

PMID:40795158 | DOI:10.1080/10826084.2025.2546505

J Public Health (Oxf). 2025 Aug 7:fdaf092. doi: 10.1093/pubmed/fdaf092. Online ahead of print.

ABSTRACT

BACKGROUND: Migration involves a risk of mental health problems, including stress, anxiety, and depression. This study systematically reviewed social determinants of mental health problems among South Asian migrants living in industrialized countries.

METHODS: Four databases (PubMed, CINAHL, EMBASE, and PsycINFO) were searched for observational studies published between 2000 and 2025. The social ecological model was used as a theoretical framework. Studies that included adult South Asian migrants using validated mental health tools were included. Social determinants of mental health were identified through extraction of social factors that demonstrated statistically significant associations with mental health problems. The study protocol was registered in PROSPERO and followed PRISMA guidelines.

RESULTS: Seventeen studies met the inclusion criteria. The prevalence of stress, anxiety, and depression ranged from 23% to 59%, 20% to 50%, and 9% to 47%, respectively. Common social determinants of mental health problems were age, gender, marital status, social support, language, education, and employment. Being older, female, unmarried, or unemployed or having less social support or lower education, or facing language barriers were major factors influencing mental health problems.

CONCLUSIONS: The findings warrant the development and implementation of policies focused on addressing these social determinants of mental health problems and improving access to and utilization of mental health services.

PMID:40795145 | DOI:10.1093/pubmed/fdaf092

Eur Heart J. 2025 Aug 7:ehaf441. doi: 10.1093/eurheartj/ehaf441. Online ahead of print.

NO ABSTRACT

PMID:40795129 | DOI:10.1093/eurheartj/ehaf441

JAMA Netw Open. 2025 Aug 1;8(8):e2526418. doi: 10.1001/jamanetworkopen.2025.26418.

NO ABSTRACT

PMID:40794411 | DOI:10.1001/jamanetworkopen.2025.26418

JAMA Netw Open. 2025 Aug 1;8(8):e2526616. doi: 10.1001/jamanetworkopen.2025.26616.

ABSTRACT

IMPORTANCE: Pulmonary rehabilitation (PR) improves exercise tolerance, symptom burden, and health-related quality of life for people with chronic respiratory conditions. However, demand for PR outstrips supply. Traditionally, PR has been delivered using specialist, gym-based exercise equipment.

OBJECTIVE: To investigate whether PR using minimal equipment (PR-min) is noninferior to PR using specialist gym exercise equipment (PR-gym).

DESIGN, SETTINGS, AND PARTICIPANTS: This parallel, 2-group, assessor- and statistician-blinded, noninferiority randomized clinical trial compared PR-min with PR-gym. Eligible participants were people with chronic respiratory disease referred for PR to the Regional Pulmonary Rehabilitation Unit in northwest London, UK. Recruitment occurred from October 15, 2018, to December 21, 2021, with a final follow-up to December 14, 2022. Randomization was by an independent web-based system using minimization with 1:1 allocation. Data analysis was performed from May 2023 to January 2025.

INTERVENTIONS: Both PR programs comprised 2 in-person, outpatient supervised sessions per week for 8 weeks. PR-min used minimal equipment (eg, walking circuit and body weight exercises), whereas PR-gym used specialist exercise equipment (eg, treadmills and weights machines).

MAIN OUTCOMES AND MEASURES: The primary outcome was change in incremental shuttle walk (ISW) distance after PR (ie, at 8 weeks; with a predefined noninferiority margin of -24 m). Secondary outcomes included dyspnea, health-related quality of life, costs, and adverse events.

RESULTS: A total of 436 participants (median [IQR] age, 71.7 [63.2-77.7] years; 239 [54.8%] male) were enrolled, with 218 randomized to PR-min and 218 to PR-gym. At 8 weeks, PR-min (n = 136) and PR-gym (n = 130) demonstrated significant improvements in ISW distance with no significant between-group difference in ISW distance change (mean, 1.7 m; 1-sided 97.5% CI lower bound, -16.8), which was within the -24-m noninferiority margin. The intention-to-treat analysis and a robust range of sensitivity analyses all demonstrated that PR-min was noninferior to PR-gym. Similar findings were observed for dyspnea and health-related quality of life. No excess adverse events or costs were seen with intervention.

CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that PR-min demonstrated noninferiority to PR-gym for exercise capacity, dyspnea, and health-related quality of life. PR-min can expand the number of settings where PR can be provided, thus improving patient accessibility.

TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN16196765.

PMID:40794408 | DOI:10.1001/jamanetworkopen.2025.26616

J Mol Neurosci. 2025 Aug 12;75(3):105. doi: 10.1007/s12031-025-02399-4.

ABSTRACT

This study aimed to investigate the effects of a histamine-reducing diet on five developmental domains in autism spectrum disorder subjects and the impact of variants in the AOC1 and HNMT genes on the therapeutic outcomes. Four genetic variants (rs2052129, rs10156191, rs1049742, and rs11558538) in AOC1 and HNMT were genotyped in 400 Bulgarian children with ASD. Genotype and allele frequencies were compared to control data from the GnomAD database. Further analysis was conducted on 91 ASD subjects with elevated histamine who followed the histamine-reducing diet. Significant improvements were observed across all developmental domains measured by the DP-3 test, including physical, adaptive behavior, social-emotional, cognitive, and communication skills. Paired samples T-tests indicated statistically significant increases in all categories (p < 0.001), with physical scores increasing from 82.29 to 89.18, adaptive behavior from 72.68 to 81.35, social-emotional from 71.43 to 80.22, cognitive from 69.33 to 78.66, and communication from 67.36 to 77.54. Minor allele carriers exhibited lower mean improvements across each of the five developmental parameters compared to wild-type carriers, with mean reductions of 0.90 for rs2052129, 0.70 for rs10156191, 2.07 for rs1049742, and 1.94 for rs11558538. These findings highlight the potential role of histamine regulation in autism spectrum disorder, the impact of variants in the AOC1 and HNMT genes on the therapeutic outcome and suggest dietary management as a viable intervention to improve developmental outcomes.

PMID:40794387 | DOI:10.1007/s12031-025-02399-4