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Inherited defects of DNA double-stranded break (DSB) repair can result in radiosensitive/radiation-sensitive (RS) SCID (RS-SCID). We applied base editing to reverse NHEJ1 mutations in patient fibroblasts, exemplifying how this technology can help interrogate RS sequence variants.
PURPOSE: This systematic review and meta-analysis evaluated the diagnostic performance of auditory brainstem response (ABR) for identifying age-related cochlear synaptopathies in rodents. METHOD: Following PRISMA guidelines, searches were conducted in PubMed/MEDLINE, Cochrane Library, Scopus, Embase, Web of Science, SciELO, LILACS, and gray literature. Studies evaluating CS in naturally aged rodents using short-latency auditory evoked potentials (AEPs) were included. Study selection, data extraction, risk-of-bias (JBI Critical Appraisal Checklist for Analytical Cross-Sectional Studies), and certainty of the evidence (GRADE® system) assessment were conducted independently by two reviewers. Meta-analyses were performed using a random-effects model, with standardized mean differences and 95% confidence intervals. ABR wave I amplitudes were analyzed for click (80 and 90 dB SPL) and tone-burst stimuli stratified by frequency. RESULTS: Among 3,008 identified records, 12 studies were included in the review and five in the meta-analysis. All included studies used ABR measures to investigate CS, with wave I amplitude being the most frequently evaluated biomarker. Meta-analysis demonstrated a significant reduction in ABR wave I amplitude in aged rodents compared with young controls for both click- and tone-burst-evoked responses. Tone-burst ABR showed no significant differences among the evaluated frequencies. These findings should be interpreted with caution due to the limited number of studies and the methodological heterogeneity, which may have reduced statistical power and comparability. CONCLUSIONS: The evidence supports ABR wave I amplitude as a sensitive electrophysiological marker of age-related CS in rodents. Nevertheless, further studies with standardized protocols are needed to strengthen its diagnostic utility and improve comparability across studies.
Bovine viral diarrhea virus (BVDV) remains a neglected viral disease in water buffalo despite its significant economic impact in production systems. Although limited epidemiological studies have been reported worldwide, the serostatus and active infection in buffalo have not been systematically reviewed. A systematic review and meta-analysis were conducted to estimate BVDV prevalence in water buffalo and identify associated epidemiological factors. Relevant studies published up to January 31, 2026, were retrieved from five electronic databases. A total of 49 studies were identified from 15 different countries were found for inclusion. A random-effects model was used to estimate pooled-prevalence and assess heterogeneity among studies. A meta-analysis of 37 studies (9270 buffalo) estimated a pooled BVDV seroprevalence of 30.5%, while analysis of 16 studies (7189 animals) indicated an antigen prevalence of 16.5%. Continent-wise analysis revealed the highest BVDV seroprevalence in South-America (44.0%), while antigen prevalence was highest in Africa (21.2%) followed by Asia at 12.2%, and no BVDV data reported from North-America. Among the different countries, the highest BVDV seroprevalence was detected in Turkey (61.6%) and Argentina (59.0%), while antigen prevalence was highest in Egypt (21.2%), with lower estimates in Brazil (11.8%) and Iraq (11.3%). Notably, high heterogeneity (I2 > 90%) was observed in the all-pooled estimates, indicating variations in sampling period, age, sex, sample source and types, diagnostic methods, production-system, and study quality. These findings demonstrate the widespread presence of BVDV in water buffalo populations and indicate the need for targeted control strategies to mitigate its impact on health and productivity.
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Maintaining effective blinding is a major methodological challenge in psychedelic research. This study provides a comprehensive evaluation of blinding integrity in 120 healthy volunteers who received either psilocybin, MDMA, or methylphenidate (active placebo) in a double-blind, randomized controlled trial. Using a multi-level assessment incorporating forced-choice substance guesses, certainty ratings, decision factors, and subjective substance effects, the analyses characterize blinding integrity and its relation to the substance experience. Results indicate that overall blinding was insufficient, with psilocybin showing the highest rates of functional unblinding, MDMA moderate levels, and methylphenidate the lowest. As an active placebo, methylphenidate provided more effective blinding for MDMA than for psilocybin. Incorporating certainty levels of substance guesses revealed a more differentiated pattern, with lower functional unblinding rates. Decision factors and subjective substance experiences were associated with phenomenological substance effects. Prior substance experiences did not influence accuracy of forced-choice substance guesses. These findings provide empirical guidance for the design and reporting of blinding procedures in psychedelic trials and underscore the value of systematic, multi-level assessment of blinding integrity.
OBJECTIVES: To compare the effectiveness and dermatological safety of chlorhexidine gluconate (CHG)-impregnated dressings versus conventional transparent dressings in preventing central line-associated bloodstream infection (CLABSI) in paediatric patients admitted to a PICU. METHODS: A single-blind, randomised controlled trial with a 1:1 allocation ratio was conducted in a tertiary PICU. A total of 250 paediatric patients with a central venous catheter were included (125 per group). Patient characteristics, catheter-related variables, catheter dwell time and skin alterations were recorded. The primary outcome was CLABSI, defined according to CDC/NHSN criteria. Bivariate analyses and multivariable logistic regression were performed, including clinically relevant covariates related to catheter exposure, dressing type, and vaccination status. The trial was registered at ClinicalTrials.gov (NCT07175116). RESULTS: CLABSI incidence was significantly lower in the CHG group compared with the conventional dressing group (2.4% vs. 18.4%; p < 0.001). In multivariable analysis, CHG-impregnated dressings were independently associated with reduced CLABSI risk (OR = 0.15; 95% CI: 0.04-0.58). Longer catheter dwell time (OR = 1.13 per day; 95% CI: 1.04-1.22) and absence of complete vaccination (OR = 8.68; 95% CI: 2.48-30.47) were also associated with increased infection risk. Incomplete vaccination showed a similar trend without reaching statistical significance (OR = 6.48; 95% CI: 0.95-44.20). Skin alterations were more frequent in the CHG group (16.8% vs. 11.2%), predominantly in younger infants. CONCLUSIONS: CHG-impregnated dressings were associated with a significant reduction in CLABSI incidence in critically ill paediatric patients, although their use was linked to a modest increase in mild skin reactions. IMPLICATIONS FOR CLINICAL PRACTICE: CHG-impregnated dressings may be considered as part of a multifaceted infection prevention strategy, alongside appropriate catheter management, minimisation of catheter manipulation and proactive skin monitoring, with cautious and individualised use in infants.
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BACKGROUND: Cognitive reserve may influence responsiveness to cognitive interventions, yet it is rarely used to tailor computerized stimulation. OBJECTIVE: To evaluate the effectiveness of a computerized cognitive stimulation program personalized according to cognitive reserve on cognition, reserve-related activities, and digital competence in community-dwelling older adults without cognitive impairment in Primary Care. METHODS: In this randomized clinical trial, 102 adults aged ≥65 years with normal cognitive performance were recruited from three primary care centers in Zaragoza, Spain, and stratified by cognitive reserve level before random allocation to intervention or control. The intervention comprised digital literacy sessions followed by 8 weeks of home-based computerized cognitive stimulation tailored to participants' cognitive reserve profiles and life history. Controls received a single group-based health education session focused on maintaining everyday cognitive activity. Outcomes were assessed at baseline and post-intervention using global cognition (MEC-35), the Cognitive Reserve Questionnaire, the Mobile Device Proficiency Questionnaire-16, and domain-specific neuropsychological tests. A total of 100 participants completed the final evaluation and were included in complete-case analyses. RESULTS: Compared with controls, the intervention group showed greater adjusted post-intervention improvements in global cognition (MEC-35 between-group difference: 1.8 points) and several cognitive measures, including temporal orientation, calculation, attention, praxis, verbal fluency, processing speed, executive functions, and verbal learning. CRQ scores and digital competence also improved, with small-to-large effect sizes. CONCLUSIONS: A computerized cognitive stimulation program adapted according to cognitive reserve appears feasible in Primary Care and may improve cognition, engagement in reserve-related activities, and digital competence in older adults without cognitive impairment.
BACKGROUND: The pharmacokinetics (PK) of immunosuppressive agents in living donor liver transplantation (LDLT) recipients are expected to differ from those in deceased donor liver transplantation (DDLT) recipients because of the smaller initial liver volume transplanted and pathophysiological changes during liver regeneration. Consequently, the hepatic metabolism, CYP enzyme activity, and glucuronidation may be reduced. The PK of tacrolimus (metabolized by CYP3A5) and mycophenolate (metabolized through glucuronidation) are expected to be affected early post-LDLT. However, the initial dosing recommendations for post-LDLT remain unclear. PURPOSE: This study aimed to recommend initial dosing approaches for tacrolimus and mycophenolate in LDLT recipients based on available PK data in humans. METHODS: A PubMed search was conducted in March 2025 to identify studies investigating the PK data of immediate-release tacrolimus and mycophenolate in pediatric or adult LDLT recipients. RESULTS: After screening, 8 and 8 articles on tacrolimus and mycophenolates, respectively, met the review criteria. The current literature suggests that LDLT recipients require lower tacrolimus doses than DDLT recipients, particularly in the early post-transplant period. In addition, CYP3A5 polymorphisms in both donors and recipients contribute to interindividual variability in tacrolimus exposure, further complicating tacrolimus management. Studies on mycophenolate use in LDLT recipients are limited, with insufficient evidence to support dose reduction. CONCLUSIONS: Reducing the initial tacrolimus dose in LDLT recipients by 30%-50% compared with that in DDLT recipients would be reasonable while maintaining the same initial dose of mycophenolate between LDLT and DDLT recipients.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by early-onset macrocephaly, white matter edema, seizures, and motor and cognitive decline. Approximately 25% of MLC patients carry HEPACAM pathogenic variants, many of which are dominant missense variants causing remitting MLC Type 2b. HEPACAM encodes hepatic and glial cell adhesion molecule (hepaCAM), also known as GlialCAM, an astrocyte-enriched transmembrane protein with important roles in astrocyte territory establishment, gap junction coupling, branching organization, synaptic function, and development of the gliovascular unit. The molecular mechanisms through which pathogenic variants in HEPACAM alter hepaCAM protein function in vivo and facilitate MLC pathogenesis during brain development remain largely unknown. Here, we used new viral tools and proximity-based proteomics to examine how three different dominant pathogenic variants alter hepaCAM subcellular localization and protein interactome in astrocytes of the developing mouse cortex. We found dramatic changes in hepaCAM distribution throughout the astrocyte, which were common to all mutants tested. We also observed significant changes in protein interactome between wild type and mutant hepaCAM, including decreased association with previously described hepaCAM-interacting proteins Connexin 43 and CLC-2. Moreover, we identified the epilepsy-associate potassium channel KCNQ2 as a novel hepaCAM interaction partner and found reduced association between KCNQ2 and pathogenic variants. Collectively, our data provide new insights into hepaCAM protein function in astrocytes during brain development, reveal altered protein dynamics of pathogenic variants, and provide a new resource to explore the molecular underpinnings of MLC pathogenesis.
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BackgroundExistential distress, marked by hopelessness, loss of meaning, and spiritual suffering, is prevalent among patients with advanced illness, and is associated with psychological burden and a wish to hasten death (WTHD).PurposeThis systematic review aimed to synthesize current evidence on meaning in life (MIL) in adult palliative care (PC) populations, focusing on its associations with quality of life (QOL), mental health, existential and spiritual well-being (SWB), and WTHD.MethodsMEDLINE, Web of Science, Scopus, and the Cochrane Library were searched for eligible studies (English, 2016-2024) involving adult cancer patients receiving PC. MIL was examined as a central intervention component or outcome. Risk of bias was assessed: findings were synthesized narratively. The review was registered in PROSPERO.ResultsEight studies (n = 1733 participants) were included: four cross-sectional, two randomized controlled trials, one longitudinal observational study, and one qualitative study. Several studies had small samples and substantial attrition. Risk of bias was high (n = 7), and moderate in one cross-sectional study. MIL was inversely associated with depression, anxiety, demoralization, and WTHD; and positively associated with QOL and SWB. MIL may also mediate psychological outcomes (eg, purpose, coherence, and personal values). However, heterogeneity in MIL conceptualization and measurement, combined with low methodological quality, limited comparability and certainty of findings.ConclusionMIL may be relevant to psychosocial/existential outcomes in PC. Conclusions are constrained by a small and methodologically weak evidence base. Further high-quality, longitudinal research is needed before MIL-centered interventions can be recommended for routine clinical practice.
BACKGROUND: The hippocampus influences the outcomes of amnestic mild cognitive impairment (aMCI) and undergoes different changes during the cognitive decline or recovery of aMCI compared to elderly individuals with normal cognition, which may reveal disease-dependent neurodegeneration or plasticity. We first aimed to investigate the hippocampal changes associated with cognitive changes in aMCI using a combined case-control study design. METHODS: In total, 50 aMCI individuals and 50 healthy controls (HCs) were recruited in Shenyang, China, and separately randomized into training and control groups: aMCI training group, aMCI no training group, HC training group, and HC no training group. The aMCI and HC training groups received computerized cognitive training (CCT) thrice weekly for 12 weeks. Cognitive assessments and MRI data were collected at baseline and follow-up. RESULTS: The primary outcome was significant CCT×diagnosis interaction effect on the change in cognitive performance as measured by clock drawing test (CDT) scores (F = 4.322, P = 0.041); this interaction was driven by CCT specifically in aMCI (F = 4.465, P = 0.038). Significant CCT×diagnosis interaction effects of right-hippocampal FC changes were observed in the bilateral precuneus/cuneus (Pvoxel<0.05) driven by CCT in aMCI (F = 5.429, P = 0.023), and in the left superior temporal gyrus/middle temporal gyrus (STG/MTG, Pvoxel<0.05), driven by CCT of only in HCs (F = 6.587, P = 0.013). A significant interaction effect of left-hippocampal FC changes were observed in the right triangular part of the inferior frontal gyrus (IFGtriang, Pvoxel<0.05), driven by CCT in aMCI and HCs (F = 6.550, P = 0.013; F = 7.097, P = 0.010). No significant interaction effect on the change in hippocampal GMV was noted (P > 0.05). CONCLUSION: CCT can improve the visuospatial ability of aMCI, which is reflected by the CDT scores. CCT can alter hippocampal FC in the bilateral precuneus/cuneus, the right IFGtriang, and the left STG/MTG. The hippocampal GMV is difficult to change in both HCs and aMCI during the cognitive decline. REGISTRATION NUMBER: ChiCTR1900026849. DATE OF REGISTRATION: 24 October 2019 NAME OF TRIAL REGISTRY: Chinese Clinical Trial Registry (ChiCTR).
BACKGROUND: Hemipteran insects harbour several symbiotic partners, mainly bacteria, which play pivotal roles for hosts like dietary provision, support overall physiology, xenobiotic degradation and manipulate/regulate behaviour. Most of these symbionts usually reside and operate from the digestive tracts of the animals. Cotton is one of the major cash crops in India and Dysdercus cingulatus (D. cingulatus) though a secondary pest, is causing significant destruction of cotton bolls, poor lint quality and reduce oil content of seeds. Premature opening of cotton bolls often leads to bacterial and fungal infections, thus resulting in extensive economic loss worldwide. D. cingulatus is a hemimetabolous insect that comprises of developmental stages like egg, nymph (5 instar stages), and adult. The present work explored the ontogeny specific diversity in the associated microbiota and predicted their probable functional inputs in D. cingulatus. RESULTS: The data obtained using 16S rRNA gene sequencing (NovaSeq 6000) revealed presence of members of Proteobacteria (65.83%), Firmicutes (24%), Actinobacteria (10%) phyla throughout the ontogeny of D. cingulatus. Highest alpha diversity of these symbiotic bacteria was recorded in the third instar nymphs in contrast to rest of the developmental stages. Among all the observed genera, Stenotrophomonas, Hungatella and Glutamicibacter were predominant from egg to adult stages. MicFunPred, a tool used for predicting the probable functional inputs of these symbionts, hinted at their probable stage specific contribution in crucial biochemical pathways such as polyketide biosynthesis, ascorbate/aldarate metabolism, pentose phosphate and glyoxylate cycles, steroid hormone and peptidoglycan biosynthesis, and glycolysis/pyruvate metabolism. CONCLUSIONS: The primary investigations on the ontogenetic composition and diversity of associated microbiota, suggest dynamic shifts in D. cingulatus, concurrent with their probable functions/roles in the host development and metabolism. To the best of our knowledge, this is the first report on symbiotic microbiota variation across the developmental stages of D. cingulatus that provides preliminary descriptive observations that may guide future functional and experimental investigations into microbiota-based pest management.
Retinoids comprise vitamin A and its structurally related natural and synthetic derivatives. Retinoid dynamics involves multiple retinoid forms, carrier proteins, and enzymes that orchestrate the absorption, transport, storage and biotransformation of dietary vitamin A. Beyond their canonical metabolic functions, metabolites and proteins involved in retinoid metabolism also play distinct roles in signal transduction and transcriptome reprogramming, broadening the mechanisms that influence immune cell fate decisions. Age‑related changes in retinoid bioavailability and signaling intensity alter immune cell polarization and function, thereby contributing to the pathogenesis of chronic inflammation in neurodegenerative diseases, cardiovascular diseases, osteoarthritis, and other age-related diseases. In this review, we focus on age-related alterations in the retinoid metabolic pathway and their impact on inflammation and the progression of age-related diseases. This review highlights the pivotal role of retinoid metabolism in anti-ageing interventions and considers future directions and challenges in this field.
Enterococci from animal-derived foods are key reservoirs for antimicrobial resistance (AMR) in the food chain. However, comparative genomic studies investigating the distribution of the oxazolidinone resistance gene optrA among food- and human-derived Enterococci remain limited. This study assessed linezolid-resistant Enterococci from retail meat and healthy humans in Beijing, China (2023-2024). Among 87 isolates, E. faecalis and E. faecium predominated. Food-derived isolates showed broader resistance profiles than human isolates. Fourteen optrA-positive strains were identified, accounting for 92.9% of food isolates. optrA frequently co-localized with erm(A), ant(9)-Ia, and fexA on Tn554-family transposons, suggesting a potentially transferable multidrug resistance module. Notably, an optrA-positive E. faecalis ST699 clone was identified for the first time in Chinese retail meat. This clone formed a distinct lineage and carried a complete Tn554-optrA island. A representative ST699 isolate exhibited enhanced fitness and virulence potential in the Galleria mellonella model. These findings highlight animal-derived foods as important reservoirs of linezolid-resistant Enterococci and provide genomic evidence consistent with their role as potential sources of optrA-mediated resistance. The emergence of a multidrug-resistant E. faecalis ST699 clone with enhanced fitness characteristics underscores the need for continued surveillance of foodborne antimicrobial resistance within the One Health framework.
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BACKGROUND: Access to novel HIV prevention technologies often raise concerns of risk compensation. This analysis examined changes in the sexual behaviors of MTN 020/ASPIRE participants, a placebo controlled randomized control trial, who subsequently enrolled in MTN-025/HOPE, an open-label extension using the dapivirine vaginal ring. METHODS: Both studies enrolled healthy, sexually active, HIV-negative women from Malawi, South Africa, Uganda and Zimbabwe. Longitudinal data on participants' sexual behaviors, specifically sex with a nonprimary partner (past 3 months), and use of male or female condoms at the last vaginal sex act were compared between ASPIRE and HOPE. Conditional and mixed ordinal logistic regression models evaluated associations between study and sexual behaviors at enrollment, and quarterly over the first 12 months. RESULTS: Of the 2629 individuals enrolled in ASPIRE, 1456 (55%) participated in HOPE. At enrollment, the proportion of participants who reported sex with a nonprimary partner and condom use at last vaginal sex act did not differ by study. Across all quarterly follow-up visits, sex with a nonprimary partner was more common in HOPE (13.9-18.7%) than ASPIRE (10.7-12.6%); adjusted OR 1.47, 95% CI 1.24-1.75, P < 0.001. There was no difference in condom use at the last vaginal act across all quarterly follow-up visits between ASPIRE (36.5-42.7%) and HOPE (43.6-46.7%); adjusted OR 1.05, 95% CI 0.94-1.18. CONCLUSION: More women reported sex with nonprimary partners in HOPE, with little change in condom use over time between the two studies. Understanding behavior changes during PrEP use allows for tailored, holistic reproductive health programming.