Research square最新文献

{"title":"Associations of Perfluoroalkyl substances (PFAS) with terminal ductal lobular unit involution of the normal breast.","authors":"Katherine W Reeves, Youssef Oulhote, Philippe Grandjean, Flemming Nielsen","doi":"10.21203/rs.3.rs-6829962/v1","DOIUrl":"10.21203/rs.3.rs-6829962/v1","url":null,"abstract":"<p><strong>Background: </strong>Per- and polyfluoroalkyl substances (PFAS) may be carcinogenic, and animal studies demonstrate their harmful effects on mammary gland development. Terminal ductal lobular units (TDLUs) are the structures that produce milk following childbirth, and involution of TDLUs normally occurs with aging. Most breast cancers arise from TDLUs, and a greater degree of TDLU involution is associated with lower breast cancer risk. We estimated associations between PFAS concentrations and TDLU involution in normal breast tissue samples.</p><p><strong>Methods: </strong>Concentrations of seven PFAS were measured in serum provided by a subset of 263 healthy volunteer participants from the Susan G. Komen for the Cure Tissue Bank (KTB) who were postmenopausal, not currently using hormone therapy, and had available TDLU measurements. Bayesian kernel machine regression and quantile-G computation were used to estimate covariate-adjusted associations between the PFAS mixture and measures of TDLU involution (presence of TDLUs, number of observed TDLUs, and median TDLU span) within this population and with stratification on parity and breastfeeding history.</p><p><strong>Results: </strong>Distributions of PFAS were similar between participants with (N = 106) and without (N = 157) observed TDLUs. No strong, statistically significant associations were observed between individual PFAS and presence of observed TDLUs. The overall effect of the PFAS mixture suggested an inverted U-shaped association with odds of observed TDLUs, although this was not statistically significant. Among the subgroup of parous women, stratified analyses suggested a positive association between the PFAS mixture and observed TDLUs among those who had ever breastfed, but a slightly negative association among those who had never breastfed.</p><p><strong>Conclusions: </strong>Overall, our analysis does not support meaningful effects of PFAS on TDLU involution, although we note that these findings are not applicable to premenopausal women or to postmenopausal women using hormone therapy.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593669","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":"CEST MRI Affirms HIV-1-Associated Neurometabolic Impairments in a Humanized Mouse Model.","authors":"Gabriel C Gauthier, Micah Summerlin, Balasrinivasa R Sajja, Mariano G Uberti, Emma G Foster, Manjeet Kumar, Matthew Thiele, Santhi Gorantla, Aditya N Bade, Yutong Liu","doi":"10.21203/rs.3.rs-6821484/v1","DOIUrl":"10.21203/rs.3.rs-6821484/v1","url":null,"abstract":"<p><strong>Purpose: </strong>Human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND) persist in people living with HIV-1 (PLWH) despite antiretroviral therapy (ART), driven by unresolved neuroinflammation and metabolic dysfunction. This study evaluates chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) detection of HIV-1-induced neurometabolic impairments and ART-mediated improvements in a humanized mouse model.</p><p><strong>Methods: </strong>HIV-1-infected CD34-NSG mice (n = 14) underwent CEST MRI to quantify metabolic profiles in the cortex, hippocampus, hypothalamus, piriform cortex, and thalamus at three timepoints: pre-infection (Week 0), 6 weeks-post-infection (WPI), and after 6 weeks of ART- or vehicle-treatment (12 WPI). CEST contrasts were analyzed at 2 ppm (creatine), 3 ppm (glutamate), and - 3.5 ppm (nuclear Overhauser effect, NOE). Neuroinflammation and infection were confirmed using immunohistology and qPCR.</p><p><strong>Results: </strong>At 6 WPI, HIV-1-infection reduced creatine in the cortex (p = 0.0006) and hippocampus (p = 0.01), and elevated NOE in the cortex (p = 0.001). At 12 WPI, vehicle-treated HIV-infected mice exhibited significantly decreased glutamate in the cortex (p = 0.004), hippocampus (p < 0.0001), and piriform cortex (p = 0.002); ART-treatment restored these levels in the cortex and hippocampus. Further, vehicle-treated mice exhibited decreased creatine in the cortex (p = 0.0002), hippocampus (p = 0.0003), piriform cortex (p = 0.0009), and thalamus (p = 0.006); ART-treatment restored these levels in the hippocampus, piriform cortex, and thalamus. Finally, vehicle-treated mice exhibited increased NOE in the cortex (p = 0.002) and thalamus (p = 0.003), but this was not restored by ART. CEST findings were supported by reductions in HIV-1 p24 + cells and neuroinflammatory markers in ART-treated brains.</p><p><strong>Discussion: </strong>CEST MRI detects region-specific HIV-1-induced neurometabolic alterations and ART-mediated restorations. This work establishes CEST MRI as a translational potential, non-invasive technique for monitoring HAND pathology and therapeutic efficacy.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593673","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":"hmmibd-rs: An enhanced hmmIBD implementation for parallelizable identity-by-descent detection from large-scale Plasmodium genomic data.","authors":"Bing Guo, Stephen F Schaffner, Aimee R Taylor, Timothy D O'Connor, Shannon Takala-Harrison","doi":"10.21203/rs.3.rs-7004070/v1","DOIUrl":"10.21203/rs.3.rs-7004070/v1","url":null,"abstract":"<p><strong>Background: </strong>Identity-by-descent (IBD), which describes recent genetic co-ancestry between pairs of genomes, is a fundamental concept in population genomics. It has been used to estimate genetic relatedness, detect selection signals, and understand population demography. The IBD detection method <i>hmmIBD</i> demonstrates high accuracy in inferring IBD segments between haploid genomes, including <i>Plasmodium falciparum</i>, and is widely used in malaria genomic surveillance. However, the current single-threaded implementation of <i>hmmIBD</i> does not utilize the full capacity of multi-processor computers, making it difficult to apply to large data sets, and does not accommodate non-uniform recombination rates across the genome.</p><p><strong>Methods: </strong>We developed an enhanced implementation of <i>hmmIBD</i> in the Rust programming language, named <i>hmmibd-rs</i>, which leverages multi-threaded computing to parallelize IBD inference over genome pairs and which supports optional, user-defined recombination rate maps for more accurate IBD detection and filtration from genomes with non-uniform recombination. We further streamlined large-scale IBD detection by incorporating auxiliary built-in functionalities to preprocess input directly from the standard binary variant call format (BCF) and filter IBD output to reduce disk usage.</p><p><strong>Results: </strong>Our new implementation significantly reduces IBD detection computation time nearly linearly with the increased number of CPU threads used; using 128 threads shortens IBD detection time from 5.2 days to 1.3 hours for 220 million pairs of simulated <i>Plasmodium falciparum</i>-like chromosomes, increasing computational speed by approximately 100x over the single-threaded <i>hmmIBD</i> algorithm. Incorporating non-uniform recombination rates in <i>hmmibd-rs</i> enhances the accuracy of IBD inference by mitigating the overestimation of IBD breakpoints in recombination cold spots and their underestimation in hot spots. It also improves IBD segment length filtration, reducing the false positive rate in recombination cold spots and the false negative rate in hot spots. When applied to empirical data sets, <i>hmmibd-rs</i> completes the detection of IBD from MalariaGEN Pf7 (n ≈ 10,000 monoclonal samples) within hours, enabling a single-day IBD analysis pipeline for large genomic data sets.</p><p><strong>Conclusion: </strong><i>hmmibd-rs</i> builds upon, accelerates, and enhances <i>hmmIBD</i> for efficient and accurate IBD detection, serving as a crucial tool for advancing large-scale malaria genomic surveillance.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593686","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":"FOXM1 targeting alters AURKB activity and reshapes antitumor immunity to curb the progression of small cell lung cancer.","authors":"Md Arafat Khan, Parvez Khan, Mahek Fatima, Asad Ur Rehman, Laiba Anwar, Zahraa Wajih Alsafwani, Aatiya Ahmad, Mohammad Ali Abbas Zaidi, Jesse L Cox, Areem Zahid, Sameer Mohiuddin, Sung Hoon Kim, Juan A Santamaria-Barria, Imayavaramban Lakshmanan, Benita S Katzenellenbogen, John A Katzenellenbogen, Apar K Ganti, Surinder K Batra, Mohd Wasim Nasser","doi":"10.21203/rs.3.rs-6960266/v1","DOIUrl":"10.21203/rs.3.rs-6960266/v1","url":null,"abstract":"<p><strong>Background: </strong>Small cell lung cancer (SCLC) is a lethal lung malignancy and patients are often diagnosed with distant metastasis. Nearly all patients suffer from disease relapsing with inherent chemoresistance. Lack of targeted SCLC therapies further worsens disease outcomes, making it highly desirable to identify novel and effective therapeutic targets.</p><p><strong>Methods: </strong>To search for potential therapeutic targets in SCLC, we analyzed publicly available single-cell and bulk RNA-sequencing (RNA-seq) data from normal, lung adenocarcinoma, and SCLC tumor tissues. To assess the targeting potential of FOXM1, we developed various <i>in vitro</i> models, including DOX-On-shFOXM1 (Tet-ON) inducible stable knockdown systems. Cisplatin resistant human and murine SCLC cell lines were generated to assess the role of FOXM1 in chemotherapy resistance. Immunoblotting, immunohistochemistry (IHC), and immuno-fluorescence were used to analyze the expression of FOXM1 and target proteins. ChIP-assay was used to study protein-gene interactions. Further, multicolor flow cytometry was employed to study the effect of FOXM1 inhibition on human T cells activation and differentiation. Subcutaneous xenograft and SCLC spontaneous (RPM: <i>RB</i> ^<i>fl/fl</i> <i>;TP53</i> ^<i>fl/fl</i> <i>;LSL-MYC</i> ^<i>T58A</i> ) mouse models were used to evaluate the efficacy of FOXM1 inhibitors.</p><p><strong>Results: </strong>Single-cell as well as bulk RNA-seq data revealed that FOXM1, an oncogenic transcription factor, is overexpressed in SCLC, and it was recapitulated in human and murine SCLC tissues and cell lines. Interestingly, chemo-resistant (CR) SCLC showed a substantially higher FOXM1 expression than naïve SCLC. Silencing FOXM1 genetically or pharmacologically by FOXM1 inhibitors revealed a marked reduction in cell viability, colony formation, migration and sphere formation in naïve and CR SCLC cells. Moreover, FOXM1 inhibition induced apoptosis and cell cycle arrest in SCLC cells. Furthermore, FOXM1 inhibition in combination with first-line platinum-based chemotherapy showed synergistic anticancer effects in both xenograft and RPM mouse models of SCLC. Our RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway, which is dysregulated in SCLC. Moreover, we found FOXM1 inhibition enhanced T cell activation and supported the differentiation of CD8 + cytotoxic T cells, and T cell-mediated killing of cancer cells.</p><p><strong>Conclusions: </strong>Our study demonstrates that FOXM1 targeting using small molecule inhibitors has the potential to be a novel therapeutic strategy to combat SCLC progression including chemotherapeutic resistance and reshaping the anti-tumor immune response.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593683","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":"Challenging the notion of Aedes aegypti as the primary chikungunya virus vector: insights from Kédougou, Southeastern Senegal.","authors":"Alioune Gaye, Moussa Moïse Diagne, Diawo Diallo, El Hadji Ndiaye, Marie Henriette Dior Ndione, Moussa Gaye, Idrissa Dieng, Madeleine Dieng, Mouhamed Kane, Safietou Sankhe, Babacar Diouf, Faty Amadou Sy, Caroline Weldon, Ibrahima Dia, Scott C Weaver, Mawlouth Diallo","doi":"10.21203/rs.3.rs-6865029/v1","DOIUrl":"10.21203/rs.3.rs-6865029/v1","url":null,"abstract":"<p><strong>Background: </strong>Chikungunya fever (CHIK) caused by the mosquito-borne chikungunya virus (CHIKV) and transmitted by <i>Aedes</i> mosquitoes, remains a public health burden throughout the tropics. During the CHIK outbreak in the southeastern Senegal in August 2023, an entomologic investigation was conducted to identify the vector(s) and characterize the virus strains.</p><p><strong>Methods: </strong>Adult mosquitoes were collected indoors and outdoors from houses of confirmed CHIK cases and their immediate neighborhoods using Prokopack aspirators and double-net traps and all water containers were inspected for aquatic stages. Mosquito pools were tested for CHIKV by RT-qPCR and positive samples were subjected to whole genome sequencing using Illumina iSeq system.</p><p><strong>Results: </strong>Animal watering points; bricks and tree holes were the most common sites for <i>Aedes aegypti</i> larvae and pupae. While immature <i>Ae. Aegypti</i> were found in all affected villages, with Breteau and Container indices exceeded the WHO epidemic thresholds, <i>Ae. furcifer</i> emerged as the most abundant host-seeking species in domestic areas. CHIKV was detected in 31 mosquito pools, primarily in <i>Ae. furcifer</i> (22 pools) and only one pool of <i>Ae. aegypti</i>. Other <i>Aedes</i> species accounted for 8 positive pools and <i>Anopheles gambiae</i>, the primary malaria vector, one pool. Phylogenetic analysis confirmed the close relationship between 2023 CHIKV strains circulating in humans and mosquitoes, and those responsible for the 2015 outbreak.</p><p><strong>Conclusions: </strong>Our study highlights the urgent need to include sylvatic mosquitoes in surveillance and control programs that until now have mainly focused on <i>Ae. aegypti</i>. Moreover, the potential role of <i>Anopheles gambiae</i> in the CHIKV transmission in Senegal warrants further investigation.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593674","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":"Methods for Preserving Cellular and Milk Fat Globules RNA from Human Milk Samples.","authors":"Zhengfei Li, Nicole Fischbein, Flora Jin, Sarah Nyquist, Kimberly O'Brien, Nadav Ahituv, Valerie Flaherman, Yarden Golan","doi":"10.21203/rs.3.rs-6968867/v1","DOIUrl":"10.21203/rs.3.rs-6968867/v1","url":null,"abstract":"<p><p>Human breast milk contains RNA in various fractions, including milk cells and milk fat globules (MFG), making it a valuable resource for studying lactation physiology. However, preserving RNA integrity, especially in low-resource or at-home collection settings, is challenging due to rapid RNA degradation. This study aimed to evaluate and optimize RNA preservation methods for BM cells and MFGs, including a simplified protocol using RNAlater for stabilization prior to freezing. Human milk samples (n = 16) were collected from lactating participants and either frozen directly (standard practice) or mixed with RNAlater (1:1, v/v) before freezing. RNA was extracted from separated milk cell and MFG fractions and assessed for concentration, quality (RNA quality number-RQN and 28S/18S ratio), and gene expression (<i>ACTB, LALBA, PRLR, PTPRC</i>) using qPCR. MFG fractions consistently yielded higher RNA concentrations than milk cells. Samples preserved with RNAlater showed significantly improved RNA quality, particularly in the MFG fraction, compared to those frozen without RNAlater. Gene expression was largely stable across preservation methods, though the immune marker gene <i>PTPRC</i> was reduced in RNAlater-treated samples, suggesting shifts in immune cell RNA content. Delays in RNAlater addition led to declining RQN values in milk cell fractions, underscoring the need for prompt stabilization. These findings demonstrate that RNAlater pre-freezing stabilization enhances RNA quality and yield, especially from MFGs, and supports its use for lactocytes gene expression analysis. This approach provides a practical, scalable solution for RNA preservation in clinical and field research, including remote and low-resource settings.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593712","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":"Dnmt3a2 expression during embryonic development is required for phenotypic stability.","authors":"Peter Jones, Minmin Liu, Guillermo Urrutia, Rachel Shereda, Stacey Thomas, Gangning Liang","doi":"10.21203/rs.3.rs-6908216/v1","DOIUrl":"10.21203/rs.3.rs-6908216/v1","url":null,"abstract":"<p><p>Proper function and switching of regulatory elements are essential for the development of vertebrates and is known to be controlled by DNA methylation. We used isoform-specific knockouts of the <i>de novo</i> methyltransferase Dnmt3a, namely Dnmt3a1 and Dnmt3a2, to probe their roles in regulatory element methylation during embryogenesis and postnatal development. Mouse embryos lacking Dnmt3a1 showed minimal loss of methylation, suggesting limited involvement in embryonic development. However, they were smaller than their littermates and died about 4 weeks after birth with considerable postnatal demethylation as previously reported. In contrast, embryos lacking Dnmt3a2 showed widespread hypomethylation particularly at enhancers, CTCF sites and imprinted genes. These methylation deficits were largely repaired after birth, presumably by Dnmt3a1. The mice lacking Dnmt3a2 were viable; however, they showed an increased prevalence of sporadic abnormalities previously observed at a low frequency in laboratory mice, including anophthalmia, hydrocephalus, hydronephrosis and male infertility. Interestingly, hypomethylation of several imprinted genes was observed in sperm which might explain the infertility phenotype. Therefore, the interaction between the two isoforms is developmentally regulated, with Dnmt3a2 playing a key role in ensuring the methylation states of enhancers, CTCF sites and imprinted genes, thereby reducing the likelihood of stochastic phenotypes emerging after birth.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593688","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":"Antiretroviral Therapy and Risk of Stroke in People with HIV in Zambia.","authors":"Stanley Zimba, Owen Ngalamika, Emmanuel Mukambo, Theresa Shankanga, Taonga Msimuko, Diwell Mwansa, Bwalya Mulenga, Mike Chisha, Mashina Chomba, Melody Asukile, Lorraine Chishimba, Violet Kayamba, Lloyd Mulenga, Omar Siddiqi, Owen A Ross, Masharip Atadzhanov, Deanna Saylor","doi":"10.21203/rs.3.rs-6945551/v1","DOIUrl":"10.21203/rs.3.rs-6945551/v1","url":null,"abstract":"<p><strong>Background: </strong>People with HIV (PWH) are at increased risk of stroke likely due to many factors including antiretroviral therapy (ART). We sought to evaluate the association between ARTand risk of stroke in PWH.</p><p><strong>Methods: </strong>We conducted a prospective case-control study at the University Teaching Hospital in Lusaka, Zambia between March 2022 and October 2024 in PWH comparing those with stroke (cases) and without (controls) matched (1:2) for age, sex and race. Standardized data collection instruments were used to collect demographic, clinical, laboratory and imaging information. Comparisons were made between the cases and controls, and subgroup analysis by ART duration was done for the cases.</p><p><strong>Results: </strong>We analyzed results for 205 cases and 410 controls. Compared to controls, cases were more likely to have hypertension (71% vs. 18%, <i>p</i>=0.001), lower CD4 counts [293(163-592) cells/μl vs. 533 (376-688) cells/μl, <i>p</i>=0.0001] and to be on second line ART (23% vs. 4%, <i>p</i>=0.001). Hypertension (aOR 19.7, 95% CI 3.1-126.4, <i>p</i>=0.002) and Tenofovir Disoproxil Fumarate (TDF) use (aOR 85.3, 95% CI 5.3-1380.7, <i>p</i>=0.002) were associated with increased odds of stroke, whereas Dolutegravir (aOR 0.03, 95% CI 0.001-0.58, <i>p</i>=0.02) and alcohol use (aOR 0.24, 95% CI 0.06-0.95) were associated with reduced odds of stroke. The majority of stroke patients on long-term ART were using Dolutegravir (80% vs. 35%, <i>p</i>=0.001) and TDF (72% vs. 42%, <i>p</i>=0.01).</p><p><strong>Conclusion: </strong>In PWH, TDF associates with higher odds of stroke. Although Dolutegravir associates with reduced odds of stroke, stroke patients on long-term ART are more likely to be on it.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593668","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":"Ultra-Processed Food Intake is Associated with Altered Glucose Homeostasis in Young Adults.","authors":"Yiping Li, Elizabeth Costello, Sarah Rock, William B Patterson, Zhanghua Chen, Frank Gilliland, Michael I Goran, Tanya L Alderete, Jesse A Goodrich, David V Conti, Nikos Stratakis, Leda Chatzi","doi":"10.21203/rs.3.rs-6875960/v1","DOIUrl":"10.21203/rs.3.rs-6875960/v1","url":null,"abstract":"<p><strong>Background: </strong>Ultra-processed foods (UPFs), often high in sodium, sugar, and unhealthy fats, compose more than half of total dietary energy consumption in the United States. A diet composed of a high amount of UPFs can contribute to glucose dysregulation and insulin resistance, which may lead to prediabetes and type 2 diabetes (T2D). The goal of this study is to examine associations between UPF consumption and prediabetes and related biomarkers in youth.</p><p><strong>Methods: </strong>Young adults (n = 85) aged 17-22 years old from the Meta-AIR study, a subset of the Children's Health Study, were enrolled between 2014-2018 and returned for a second visit between 2020-2022. Participants completed two 24-hour dietary recalls and an oral glucose tolerance test at each visit. Food items were categorized as either an UPF or non-UPF according to NOVA classification guidelines. The proportion of the diet composed of UPFs was calculated for each participant. Regression models were used to assess relationships of UPF consumption at baseline and change between visits with markers of glucose homeostasis at follow-up, adjusting for demographics and physical activity.</p><p><strong>Results: </strong>A 10 percentage-point increase in UPF consumption between visits was associated with a 64% (OR: 1.64, 95% Cl: 1.15, 2.50) higher risk for prediabetes and 56% (OR: 1.56, 95% CI: 1.42, 5.86) higher risk for impaired glucose tolerance at follow-up. Higher baseline UPF consumption was significantly positively associated with fasting insulin (<i>β</i> = 2.09, 95% CI: 0.06, 4.12), 2-hour insulin (<i>β</i> = 44.75, 95% CI: 22.26, 67.25) and insulin area under the curve (<i>β</i> = 63.19, 95% CI: 34.84, 91.54) at follow-up.</p><p><strong>Conclusion: </strong>UPF consumption may increase the risk for T2D among young adults. Our findings suggest that limiting UPF consumption could be an important strategy for T2D prevention in this population.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593730","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":"Brain Age Prediction in Generalized Anxiety Disorder using a Convolutional Neural Network.","authors":"Corey Richier, André Zugman, Anita Harrewijn, Elise M Cardinale, Parmis Khosravi, Moji Aghajani, Willem B Bruin, Kevin Hilbert, Narcis Cardoner, Daniel Porta-Casteràs, Marta Cano, Savannah Gosnell, Ramiro Salas, Andrea P Jackowski, Pedro M Pan, Giovanni A Salum, Karina S Blair, James R Blair, Mohammed R Milad, Katie L Burkhouse, K Luan Phan, Heidi K Schroeder, Jeffrey R Strawn, Katja Beesdo-Baum, Neda Jahanshad, Sophia I Thomopoulos, Jared A Nielsen, Jordan W Smoller, Jair C Soares, Benson Mwangi, Mon-Ju Wu, Giovana B Zunta-Soares, Michal Assaf, Gretchen J Diefenbach, Paolo Brambilla, Eleonora Maggioni, David Hofmann, Thomas Straube, Carmen Andreescu, Rebecca B Price, Gisele G Manfro, Federica Agosta, Elisa Canu, Camilla Cividini, Massimo Filippi, Milutin Kostić, Ana Munjiza Jovanovic, Brenda Benson, Gabrielle F Freitag, Ellen Leibenluft, Grace V Ringlein, Kathryn Werwath, Hannah Zwiebel, Hans J Grabe, Sandra Van der Auwera, Katharina Wittfeld, Henry Völzke, Robin Bülow, Nicholas L Balderston, Monique Ernst, Lilianne R Mujica-Parodi, Helena van Nieuwenhuizen, Hugo D Critchley, Elena Makovac, Matteo Mancini, Frances Meeten, Cristina Ottaviani, Gregory A Fonzo, Martin P Paulus, Murray B Stein, Raquel E Gur, Ruben C Gur, Antonia N Kaczkurkin, Bart Larsen, Theodore D Satterthwaite, Jennifer Harper, Michael T Perino, Chad M Sylvester, Qiongru Yu, Patrick McClure, Francisco Pereira, Ulrike Lueken, Dick J Veltman, Paul M Thompson, Nynke A Groenewold, Janna Marie Bas-Hoogendam, Dan J Stein, Nic J A Van der Wee, Anderson M Winkler, Daniel S Pine, Chelsea K Sawyers","doi":"10.21203/rs.3.rs-6866544/v1","DOIUrl":"10.21203/rs.3.rs-6866544/v1","url":null,"abstract":"<p><p>Higher predicted brain age difference has been associated with several psychiatric disorders. Generalized anxiety disorder (GAD) is associated with markers of accelerated aging. In this study, we determined brain predicted age difference (PAD) in individuals with GAD and healthy controls (HC) as well as group differences in PAD variability using voxel-wise structural MRI. The training dataset included 3,511 controls, and the testing dataset included 1,595 individuals with GAD and 4,552 HC from the ENIGMA-Anxiety GAD Working Group. A convolutional neural network model using four input modalities per subject and a model ensemble approach was used to predict brain age. The PAD was then calculated by subtracting chronological age. Model performance was consistent with other image-based brain age prediction models with similar accuracy across the training set (mean absolute error (MAE) = 2.95 years) and HC in the testing set (MAE = 2.94). We found no evidence of accelerated brain aging in individuals with GAD, though we did find evidence for greater variation in PAD for individuals with GAD (Levene's test: W = 442.98, <i>p</i> < .001) and evidence for greater variability in PAD of those with GAD over 25 years of age. No relationships between PAD and clinical or demographic measures were found. To conclude, using large training and testing samples, the study found no significant association between GAD and PAD, although individuals with GAD had greater heterogeneity in brain-predicted age.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593671","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}