medRxiv : the preprint server for health sciences最新文献

{"title":"Metal Mixtures Mediate the Socioeconomic Gradient in Blood Pressure: A Four-Way Decomposition in a Prospective Rural Bangladeshi Cohort.","authors":"Juwel Rana, Mohammad Hasan Shahriar, Syed Emdadul Haque, Samar Kumar Hore, Tariqul Islam, Golam Sarwar, Muhammad Yunus, Maria Argos, Habibul Ahsan, Jay S Kaufman","doi":"10.1101/2025.09.22.25336372","DOIUrl":"https://doi.org/10.1101/2025.09.22.25336372","url":null,"abstract":"<p><strong>Background: </strong>The causal mechanisms by which socioeconomic status (SES) affects blood pressure (BP) in low- and middle-income countries (LMICs) remain poorly understood. We examined the effects of SES on BP, and the extent to which disparities in metal mixture exposures mediate these effects among rural Bangladeshi adults.</p><p><strong>Methods: </strong>This study included 5923 participants from the Bangladesh Vitamin E and Selenium Trial (BEST), a prospective cohort followed for six years with repeated BP assessments at baseline and three biennial follow-ups. Baseline exposures included SES indicators: education and agricultural land ownership (socioeconomic position, SEP), and metal mixtures: blood arsenic, lead, selenium, and urinary arsenic. We applied the parametric and mediational g-formula, along with generalized weighted quantile sum regression, to estimate total, direct, and indirect effects of SES on BP outcomes and conduct causal mediation analysis with four-way decomposition.</p><p><strong>Results: </strong>Higher education increased BP, whereas SEP decreased the elevation of BP. Both higher education and SEP lowered metal exposures. Metal mixtures mediated the effects of SES on BP. For example, higher education increased systolic blood pressure (SBP) by 3.53 mmHg (95% CI: 2.23, 4.82), while the pure natural indirect effect showed a protective pathway of -0.44 mmHg (95% CI: -0.62, -0.27) through reduced metals. For SEP, nearly 42% of its protective effect on SBP was mediated by lower metal exposures.</p><p><strong>Conclusions: </strong>Socioeconomic differentials in BP outcomes in rural Bangladesh are partly explained by inequalities in metal mixture exposures. Reducing metal exposures may mitigate SES-related disparities in BP measures in LMICS.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Applications of Transcranial Temporal Interference Stimulation: A Systematic Review.","authors":"Ilya Demchenko, Ishaan Tailor, Sina Chegini, Haochen Yu, Fatemeh Gholamali Nezhad, Alice Rueda, Anne Kever, Sridhar Krishnan, Abhishek Datta, Jed A Meltzer, Simon J Graham, Tom A Schweizer, Sumientra Rampersad, Edward S Boyden, Ines R Violante, Robert Chen, Andres M Lozano, Venkat Bhat","doi":"10.1101/2025.05.16.25327804","DOIUrl":"10.1101/2025.05.16.25327804","url":null,"abstract":"<p><strong>Background: </strong>Many neurological and psychiatric disorders involve dysregulation of subcortical structures. Transcranial temporal interference stimulation (tTIS) is a novel, non-invasive method developed to selectively modulate deep brain regions and associated neural circuits.</p><p><strong>Methods: </strong>A systematic review was conducted to evaluate human applications of tTIS (PROSPERO ID: CRD42024559678). MEDLINE, Embase, APA PsycINFO, CENTRAL, ClinicalTrials.gov , and WHO ICTRP were searched up to December 12, 2024. Studies involving human applications of tTIS were eligible. Methodological quality was appraised using the NIH and modified Oxford Centre for Evidence-Based Medicine tools.</p><p><strong>Results: </strong>Forty-eight records were reviewed (20 published studies, 28 ongoing trials). Of published studies, 16 single-session and 4 multi-session studies assessed safety, mechanistic outcomes, or therapeutic effects of tTIS in 820 participants. Stimulation was most commonly delivered at beta (20 Hz) or gamma (30-130 Hz) envelope frequencies. Neuroimaging studies support target engagement of the motor cortex, basal ganglia, and hippocampus in humans, particularly when stimulation is paired with behavioural tasks. Preliminary clinical findings in small samples demonstrated acute symptom improvements in bradykinesia and tremor within 60 minutes following a single tTIS session in Parkinson's disease and essential tremor. Reported adverse events across studies were mild (e.g., tingling, itching). Emerging trials increasingly utilize multi-session protocols (2-40 sessions) and are extending tTIS to patients with neurological and psychiatric disorders, particularly epilepsy and depression.</p><p><strong>Conclusions: </strong>Phase 1 studies demonstrate that tTIS is safe, well-tolerated, and capable of engaging deep brain targets in humans. Well-controlled Phase 2 trials are needed to assess its therapeutic potential in patient populations.</p><p><strong>Highlights: </strong>tTIS engages the motor cortex, basal ganglia, and hippocampus across human studies20 studies show tTIS is safe and well-tolerated in healthy and clinical cohortsOne tTIS session improves bradykinesia and tremor in Parkinsonism within 1 hourMulti-session trials now test tTIS in epilepsy, depression, and other disordersRobust Phase 2 trials are needed to study the efficacy of tTIS in patient populations.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12132165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144218051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of language in social-emotional, educational, and vocational outcomes in autism and in individuals who have lost the diagnosis.","authors":"Caroline Larson, Elise Taverna, Anusha Mohan, Teresa Girolamo, Deborah Fein, Inge-Marie Eigsti","doi":"10.1101/2025.09.10.25335495","DOIUrl":"https://doi.org/10.1101/2025.09.10.25335495","url":null,"abstract":"<p><strong>Background: </strong>There is striking heterogeneity in long-term outcomes associated with an autism diagnosis, and the role of language in outcomes has not been sufficiently characterized. This study characterized the roles of structural language ability and early language milestones in long-term social-emotional, educational, and vocational outcomes in individuals with autism and individuals who have lost the autism diagnosis (LAD) relative to neurotypical (NT) peers, over and above the potential confounding role of social skills.</p><p><strong>Methods: </strong>Participants were individuals with autism ( <i>n</i> = 39) or LAD ( <i>n</i> = 32) and NT peers ( <i>n</i> = 38) age 12-39 years. Participants completed standardized and survey-based measures of social-emotional functioning and educational and vocational attainment. Language measures were an experimental structural language task (grammaticality judgement) and caregiver-report of early language milestones. Linear and generalized linear models tested how groups differed in the association between language and outcomes.</p><p><strong>Results: </strong>Language was associated with certain outcomes for all groups, though there were group differences in the nature of these associations. In autism relative to LAD and NT peers, structural language was differentially associated with anxiety/depression, and language milestones were differentially associated with social relationships, quality of life, educational attainment, and full-time employment status.</p><p><strong>Conclusions: </strong>Findings suggest unique pathways of influence between language and outcomes in individuals with autism versus LAD and NT peers. This evidence suggests that current language and early language development must be considered in social-emotional functioning and in educational and vocational supports from childhood <i>through</i> adulthood for individuals diagnosed with autism in childhood.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reconstructing pathogen-specific antibody binding epitopes and age-dependent immune signatures from proteomic-scale peptide libraries.","authors":"Everlyn Kamau, Nikolina Walas, Minlu Zhang, Kathy Kamath, Jack Reifert, John Shon, Shahjahan Ali, Md Ziaur Rahman, Abul K Shoab, Syeda L Famida, Salma Akther, Md Saheen Hossen, Palash Mutsuddi, Mahbubur Rahman, Andrew N Mertens, Richelle C Charles, Daniel T Leung, Stephen Luby, Audrie Lin, Benjamin F Arnold","doi":"10.1101/2025.09.21.25336286","DOIUrl":"10.1101/2025.09.21.25336286","url":null,"abstract":"<p><p>Public health interventions involving improved water, sanitation and promotion of hygiene behaviors (WASH) plus nutrition, were implemented in Bangladesh in a large randomized controlled trial to assess impact on childhood enteric infection and diarrheal disease. Here, we evaluated magnitude and breadth of humoral responses to enteric pathogens in a subset of children among those received intervention (n=60) versus a control group (n=60) using an integrated method of bacterial display peptide library screening, next-generation sequencing and computational analysis to characterize individual antibody repertoires in serum collected at median ages of 3, 14 and 28 months. We determined high seroprevalence for enteric infections and show that antibody recognition of the putative epitopes and antigenic regions remained consistent over time. With mathematical models, we inferred waning of maternal immunity, and a subsequent immunity boost due to infection. Random peptide library screening has potential utility for rigorous analysis of antibody responses and identification of epitopes indicative of protective humoral immune responses.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSF proteogenomics implicates novel proteins and humoral immunity in Alzheimer's disease risk.","authors":"Aliza P Wingo, Yue Liu, Zhen Mei, Michael Wang, Selina M Vattathil, Ekaterina S Gerasimov, Anantharaman Shantaraman, Fang Wu, Duc M Duong, Edward J Fox, David A Bennett, Allan I Levey, Nicholas T Seyfried, Thomas S Wingo","doi":"10.1101/2025.09.21.25336297","DOIUrl":"https://doi.org/10.1101/2025.09.21.25336297","url":null,"abstract":"<p><p>We profiled 2,961 cerebrospinal fluid (CSF) proteins in 1,005 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 1,066 proteins not measured in prior studies, using mass spectrometry (MS). We mapped protein quantitative trait loci (pQTLs) in CSF, compared them with brain and plasma pQTLs, and integrated them with Alzheimer's disease (AD) genome-wide association study (GWAS) data. We identified 1,417 index <i>cis</i> pQTLs for 654 unique genes and 130 index <i>trans</i> pQTLs for 94 unique genes. Cross-tissue and cross-proteomic-platform comparisons show broad consistency between MS-based CSF pQTLs and MS-based brain pQTLs as well as affinity-based CSF and plasma pQTLs. Lastly, through integrating CSF pQTLs with the largest AD GWAS, we identified 24 candidate AD causal proteins in CSF, including 10 novel and 14 previously identified in either brain, CSF, or plasma using similar approaches. These CSF AD candidate causal proteins are involved in immune response - notably humoral immunity (3 of 24) - that expands the role of the immune system in AD beyond innate immunity, as well as lysosomal function and neurovascular growth and remodeling. Together, our findings provide novel insights into AD biology and new targets for biomarker and therapeutic development.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, pharmacodynamics, efficacy and drug resistance selection of injectable long-acting lenacapavir pre-exposure prophylaxis (PrEP) against HIV.","authors":"Hee-Yeong Kim, Antonia Liebenberg, Lanxin Zhang, Max von Kleist","doi":"10.1101/2025.08.26.25334527","DOIUrl":"10.1101/2025.08.26.25334527","url":null,"abstract":"<p><p>Oral pre-exposure prophylaxis (PrEP) denotes an effective strategy to reduce the risk of HIV infection. However, many individuals encounter difficulties adhering to the once-daily regimen, which highlights the need for a broader portfolio of PrEP options. The novel HIV capsid inhibitor lenacapavir (LEN), when injected every six month, has shown potential in the recently completed clinical trials. However, clinical trials may not enable to accurately estimate prophylactic efficacy and protective concentration benchmarks. Moreover, since LEN may persist up to two years, there may be a risk for de novo resistance emergence after stopping PrEP. We developed an integrated pharmacokinetic-pharmacodynamic (PK-PD) model of LEN and incorporated observed variability from Phase III clinical data into our analysis. The model was used to quantify prophylactic efficacy against wild type (WT) and resistant virus, as well as to quantify risks of de novo drug resistance emergence when LEN-PrEP is stopped. We estimated a 95% preventive plasma concentration <math> <mrow> <mfenced><mrow><mi>E</mi> <msub><mi>C</mi> <mrow><mn>95</mn></mrow> </msub> </mrow> </mfenced> </mrow> </math> of 5.8ng/mL. LEN fully prevented infection with WT virus at plasma concentrations above 10ng/mL, which in an 'average individual' is achieved within 155hours after the first subcutaneous injection of 927mg and persists for up to 45weeks after the last injection. However, considering PK variability indicates that >5.8 or >10ng/mL are not surpassed at all times in all individuals. Full protection against mutant strains carrying the Q67H and N74D mutations was achieved at plasma concentrations of 35ng/mL and 85ng/mL, whereas LEN concentrations of 3095ng/mL, 218ng/mL, 100ng/mL provided full protection against variants carrying Q67H+N74D, Q67H+T107N and Q67H+N74S. The mutant selection window for N74D and all double mutants overlapped with steady-state concentrations for twice-yearly dosing. De novo resistance emergence is possible once LEN concentrations fall below 10ng/mL after the last injection and this temporal window lasts for ≈ 201, 105, 79, 96 and 86days for the Q67H, N74D, Q67H+N74D, Q67H+T107N and Q67H+N74S mutants, respectively, in an 'average individual'. Our results highlight a substantial risk for de novo drug resistance emergence when LEN SC injection are stopped, calling for strategies to manage LEN discontinuation.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond <i>BRCA</i> deficiency: Clinical and molecular predictors of survival in patients with <i>BRCA</i> -deficient tubo-ovarian high-grade serous carcinoma.","authors":"Tibor A Zwimpfer, Sian Fereday, Ahwan Pandey, Dinuka Ariyaratne, Madawa W Jayawardana, Laura Twomey, Céline M Laumont, Catherine J Kennedy, Adelyn Bolithon, Nicola S Meagher, Katy Milne, Phineas Hamilton, Jennifer Alsop, Antonis C Antoniou, George Au-Yeung, Matthias W Beckmann, Amy Berrington de Gonzalez, Christiani Bisinotto, Freya Blome, Clara Bodelon, Jessica Boros, Alison H Brand, Michael E Carney, Alicia Cazorla-Jiménez, Derek S Chiu, Elizabeth L Christie, Anita Chudecka-Głaz, Penny Coulson, Kara L Cushing-Haugen, Cezary Cybulski, Kathleen M Darcy, Cath David, Trent Davidson, Arif B Ekici, Esther Elishaev, Julius Emons, Tobias Engler, Rhonda Farrell, Anna Fischer, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Prafull Ghatage, Rosalind Glasspool, Philipp Harter, Andreas D Hartkopf, Arndt Hartmann, Sebastian Heikaus, Brenda Y Hernandez, Anusha Hettiaratchi, Sabine Heublein, David G Huntsman, Mercedes Jimenez-Linan, Michael E Jones, Eunyoung Kang, Ewa Kaznowska, Tomasz Kluz, Felix K F Kommoss, Gottfried Konecny, Roy F P M Kruitwagen, Jessica Kwon, Diether Lambrechts, Cheng-Han Lee, Jenny Lester, Samuel C Y Leung, Yee Leung, Anna Linder, Jolanta Lissowska, Liselore Loverix, Jan Lubiński, Constantina Mateoiu, Iain A McNeish, Malak Moubarak, Gregg S Nelson, Nikilyn Nevins, Alexander B Olawaiye, Siel Olbrecht, Sandra Orsulic, Ana Osorio, Carmel M Quinn, Ganendra Raj Mohan, Isabelle Ray-Coquard, Cristina Rodríguez-Antona, Patricia Roxburgh, Matthias Ruebner, Stuart G Salfinger, Spinder Samra, Minouk J Schoemaker, Hans-Peter Sinn, Gabe S Sonke, Linda Steele, Colin J R Stewart, Aline Talhouk, Adeline Tan, Christopher M Tarney, Sarah E Taylor, Koen K Van de Vijver, Maaike A van der Aa, Toon Van Gorp, Els Van Nieuwenhuysen, Lilian van-Wagensveld, Andrea E Wahner-Hendrickson, Christina Walter, Chen Wang, Julia Welz, Nicolas Wentzensen, Lynne R Wilkens, Stacey J Winham, Boris Winterhoff, Michael S Anglesio, Andrew Berchuck, Francisco J Candido Dos Reis, Paul A Cohen, Thomas P Conrads, Philip Crowe, Jennifer A Doherty, Peter A Fasching, Renée T Fortner, María J García, Simon A Gayther, Marc T Goodman, Jacek Gronwald, Holly R Harris, Florian Heitz, Hugo M Horlings, Beth Y Karlan, Linda E Kelemen, G Larry Maxwell, Usha Menon, Francesmary Modugno, Susan L Neuhausen, Joellen M Schildkraut, Annette Staebler, Karin Sundfeldt, Anthony J Swerdlow, Ignace Vergote, Anna H Wu, James D Brenton, Paul D P Pharoah, Celeste Leigh Pearce, Malcolm C Pike, Ellen L Goode, Susan J Ramus, Martin Köbel, Brad H Nelson, Anna DeFazio, Michael L Friedlander, David D L Bowtell, Dale W Garsed","doi":"10.1101/2025.09.17.25335919","DOIUrl":"https://doi.org/10.1101/2025.09.17.25335919","url":null,"abstract":"<p><p><i>BRCA</i> -associated homologous recombination deficiency (HRD) is present in ∼50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with <i>BRCA</i> -deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with <i>BRCA</i> -deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one <i>BRCA</i> -deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with <i>BRCA1</i> -deficient HGSC with a more elevated HRD score survived significantly longer. Patients with <i>BRCA2</i> -deficient HGSC and loss of <i>NF1</i> survived twice as long as those without <i>NF1</i> loss, whereas <i>PIK3CA</i> or <i>RAD21</i> amplification defined <i>BRCA2</i> -deficient HGSC with exceptionally short survival. <i>BRCA1</i> -deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline <i>BRCA</i> variants (g <i>BRCA</i> pv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in g <i>BRCA</i> pv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in <i>BRCA</i> -deficient HGSC.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of mild cognitive impairment progression using time-sensitive multimodal biomarkers.","authors":"Jonathan Gallego-Rudolf, Alex I Wiesman, Yara Yakoub, Henrik Zetterberg, Kaj Blennow, Sylvain Baillet, Sylvia Villeneuve","doi":"10.1101/2025.09.20.25336240","DOIUrl":"10.1101/2025.09.20.25336240","url":null,"abstract":"<p><p>Alzheimer's disease (AD) develops over a prolonged asymptomatic phase marked by silent pathology. Identifying cognitively unimpaired individuals likely to progress to mild cognitive impairment (MCI) is essential for early intervention. We investigated whether multimodal combinations of biomarkers, including frequency-specific neurophysiological activity, enhance prediction beyond demographic and genetic factors in older adults (n = 102; 31 progressors; mean follow-up = 5.9 years). Biomarkers included MEG-derived alpha power, MRI-derived hippocampal volume, plasma Aβ42/40 ratio and p-tau217, and neocortical Aβ and entorhinal tau PET. Cox regression models estimated progression risk and tested time-varying prognostic effects. Neurophysiological and proteinopathy biomarkers improved prediction beyond clinical and genetic factors. Elevated alpha power predicted short-term risk, but its predictive value weakened over time, whereas high neocortical Aβ became increasingly predictive with longer follow-up. Plasma Aβ42/40, p-tau217, and tau PET each conferred higher risk, while hippocampal volume did not. Findings support a multimodal, time-sensitive framework for individualized risk prediction in preclinical AD.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serial Blood Microbiome Profiles in Kidney Transplant Recipients: Evidence of Circulating Gut Bacteria.","authors":"Alex DeVito, Ananda L Kimm-Drapeau, William J Higgins, Mia Montecillo, Carol Li, Isha Bal, Darshana M Dadhania, Friederike Selbach, John R Lee","doi":"10.1101/2025.09.22.25330581","DOIUrl":"10.1101/2025.09.22.25330581","url":null,"abstract":"<p><p>Innovation in sequencing techniques has enabled the identification of microbiome in low biomass sites. In this study, we sought to investigate the utility of 16S rRNA deep sequencing of whole blood in kidney transplant recipients and to assess a link between the gut microbiota and the blood microbiota. We recruited 63 kidney transplant recipients who provided 163 whole blood specimens over the first 140 days after transplantation. We profiled the blood microbiome using 16S rRNA gene sequencing of the V4-V5 hypervariable region and additionally evaluated the gut microbiota in a subset of kidney transplant recipients who had gut bacteria detected in the blood. We generated a median of 19,959 sequences per blood specimen and found that most whole blood microbiome profiles consisted of mitochondrial DNA. While we did not identify classically pathogenic bacteria in the blood such as <i>Escherichia</i>, <i>Klebsiella</i>, and <i>Enterococcus</i>, we identified 25 gut bacterial taxa at very low levels in the blood of 22 kidney transplant recipients. For 9 of these kidney transplant recipients the same bacterial taxa detected in the blood were also identified in the gut microbiota. Our study is one of the first to show the detection of gut bacterial DNA in the blood of kidney transplant patients.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The \"Sensory Paradox\": Exploring the Positive Association Between Hyper- and Hypo-Responsivity to Sensory Stimuli in Autism and Beyond.","authors":"Kyle E Takach, Kacie Dunham-Carr, Gerardo Parra, Linnea Joffe-Nelson, Lauren Jones, Reanna Mankaryous, Savannah Rogers, Catherine Serianni, Meiwen Shao, Bo Zhang, Ellen Hanson, Nicolaas A Puts, Laura Cornelissen, April R Levin","doi":"10.1101/2025.09.21.25336283","DOIUrl":"https://doi.org/10.1101/2025.09.21.25336283","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Differences in sensory processing are a core feature of autism spectrum disorder. Hyper- and hyporesponsivity to sensory stimuli have historically been conceptualized as separate constructs but may co-occur within individuals. Sensory processing may impact both lower and higher-level cognitive processes; thus, it is crucial to understand the relationships between hyper- and hyporesponsivity within and across modalities, as well as the relationship between sensory processing and other aspects of development in both autistic and typically developing (TD) children.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In 3-4-year-old children ( &lt;i&gt;n&lt;/i&gt; =41 autism; &lt;i&gt;n&lt;/i&gt; =37 TD), we assessed relationships between sensory hyper- and hyporesponsivity both within and across visual, auditory, touch, and oral sensory modalities as measured by caregiver report. Secondary analyses evaluated relationships between sensory responsivity, social communication, and cognitive abilities.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;We found a positive correlation between sensory hyper- and hyporesponsivity (ρ = .788, &lt;i&gt;p&lt;/i&gt; &lt; .001). These associations persisted within groups and within and across modalities. There are positive associations between sensory responsivity and social interaction, communication, and nonverbal developmental quotient, with associations between sensory responsivity and social communication driven by associations within the autism group.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;The positive correlations between hyper- and hyporesponsivity both within and across sensory modalities, which we term the \"Sensory Paradox,\" may provide key clues to understanding sensory processing in autism and other neurodevelopmental disorders by pointing towards neural circuit-level mechanisms that may underlie neurodevelopmental conditions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;This study was funded by NIH/NINDS 1R01NS134948-01 (ARL), NIMH T32MH112510 (KDC), the Simons Foundation Autism Research Initiative (Award number 648277, ARL), and the Eagles Autism Foundation (ARL).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Research in context: &lt;/strong&gt;&lt;b&gt;Evidence before this study:&lt;/b&gt; Up to 95% of autistic individuals are impacted by sensory processing differences. Across the full range of the autism spectrum, including individuals with profound ASD and self-advocates who speak publicly on issues of neurodiversity, improving sensory processing challenges is repeatedly noted as a common goal that would improve quality of life. Classical medical evaluation of sensory processing typically focuses on whether the structural pathways for transmission of sensory information are intact. The modulation of sensory information as it traverses these pathways, however, is a field ripe for further understanding. Initial reports have identified both hyper- and hyporesponsivity to sensory stimuli in autism, with some overlap between the two patterns of behavior.&lt;b&gt;Added value of this study:&lt;/b&gt; This study demonstra","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}