Research square最新文献

{"title":"Perceptions about dementia clinical trials among underrepresented populations: A nationally representative survey of U.S. dementia caregivers.","authors":"Brandon Leggins, Danielle M Hart, Ashley J Jackson, Robert W Levenson, Charles C Windon, Jennifer Merrilees, Winston Chiong","doi":"10.21203/rs.3.rs-4492550/v1","DOIUrl":"10.21203/rs.3.rs-4492550/v1","url":null,"abstract":"<p><strong>Background: </strong>The research community has historically failed to enroll diverse groups of participants in dementia clinical trials. A unique aspect of dementia care research is the requirement of a study partner, who can attest to the care recipient's clinical and functional capacity. The aim of this study is to assess racial and ethnic differences and the importance of various trial considerations among dementia caregivers, in their decision to participate in clinical research as study partners.</p><p><strong>Method: </strong>We embedded a vignette about a hypothetical dementia clinical trial in a nationally representative survey of U.S. dementia caregivers, oversampling non-Hispanic Black and Hispanic caregivers. Dementia caregivers were asked about their willingness to participate in the trial with their care recipient and rated the importance of nine considerations in hypothetical decisions to participate. Caregiver demographic characteristics were analyzed as predictors of trial participation in a base demographic model. In a second reasons model caregiver demographic characteristics and the rated importance of the nine considerations were separately analyzed as predictors; both models used survey-weighted logistic regression.</p><p><strong>Result: </strong>The sample consisted of 610 dementia caregivers, including 156 non-Hispanic Black and 122 Hispanic caregiver participants. In the base demographic model, hypothetical trial participation was negatively associated with older caregiver age (OR (odds ratio) = 0.72, p = < 0.001). In the reasons model, the rated importance of a social responsibility to help others by participating in research was significantly associated with participation (OR = 1.56, p = 0.049), while the importance of the possibility of the care recipient experiencing serious side effects was negatively associated with participation (OR = 0.51, p = 0.003). In both models there was no significant difference in hypothetical participation between non-Hispanic Black and non-Hispanic White caregivers, or between Hispanic and non-Hispanic White caregivers.</p><p><strong>Conclusion: </strong>Hispanic and non-Hispanic Black dementia caregivers were not less likely than non-Hispanic White dementia caregivers to participate in a hypothetical dementia clinical trial. Our study suggests that failures to recruit diverse populations in dementia clinical research are not attributable to less willingness among members of underrepresented groups but may instead reflect structural barriers and historic exclusion from trial participation.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474372","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":"A simple phylogenetic approach to analyze hypermutated HIV proviruses reveals insights into their dynamics and persistence during antiretroviral therapy.","authors":"Aniqa Shahid, Bradley R Jones, Maggie C Duncan, Signe MacLennan, Michael J Dapp, Mark H Kuniholm, Bradley Aouizerat, Nancie M Archin, Stephen Gange, Igho Ofotokun, Margaret A Fischl, Seble Kassaye, Harris Goldstein, Kathryn Anastos, Jeffrey B Joy, Zabrina L Brumme","doi":"10.21203/rs.3.rs-4549934/v1","DOIUrl":"10.21203/rs.3.rs-4549934/v1","url":null,"abstract":"<p><p>Hypermutated proviruses, which arise in a single HIV replication cycle when host antiviral APOBEC3 proteins introduce extensive G-to-A mutations throughout the viral genome, persist in all people living with HIV receiving antiretroviral therapy (ART). But, the within-host evolutionary origins of hypermutated sequences are incompletely understood because phylogenetic inference algorithms, which assume that mutations gradually accumulate over generations, incorrectly reconstruct their ancestor-descendant relationships. Using > 1400 longitudinal single-genome-amplified HIV <i>env-gp120</i> sequences isolated from six women over a median 18 years of follow-up - including plasma HIV RNA sequences collected over a median 9 years between seroconversion and ART initiation, and > 500 proviruses isolated over a median 9 years on ART - we evaluated three approaches for removing hypermutation from nucleotide alignments. Our goals were to 1) reconstruct accurate phylogenies that can be used for molecular dating and 2) phylogenetically infer the integration dates of hypermutated proviruses persisting during ART. Two of the tested approaches (stripping all positions containing putative APOBEC3 mutations from the alignment, or replacing individual putative APOBEC3 mutations in hypermutated sequences with the ambiguous base R) consistently normalized tree topologies, eliminated erroneous clustering of hypermutated proviruses, and brought <i>env</i>-intact and hypermutated proviruses into comparable ranges with respect to multiple tree-based metrics. Importantly, these corrected trees produced integration date estimates for <i>env</i>-intact proviruses that were highly concordant with those from benchmark trees that excluded hypermutated sequences, indicating that the corrected trees can be used for molecular dating. Use of these trees to infer the integration dates of hypermutated proviruses persisting during ART revealed that these spanned a wide age range, with the oldest ones dating to shortly after infection. This indicates that hypermutated proviruses, like other provirus types, begin to be seeded into the proviral pool immediately following infection, and can persist for decades. In two of the six participants, hypermutated proviruses differed from <i>env-</i>intact ones in terms of their age distributions, suggesting that different provirus types decay at heterogeneous rates in some hosts. These simple approaches to reconstruct hypermutated provirus' evolutionary histories, allow insights into their <i>in vivo</i> origins and longevity, towards a more comprehensive understanding of HIV persistence during ART.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474309","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":"Development and Optimization of Machine Learning Algorithms for Predicting In-hospital Patient Charges for Congestive Heart Failure Exacerbations, Chronic Obstructive Pulmonary Disease Exacerbations and Diabetic Ketoacidosis.","authors":"Monique Arnold, Lathan Liou, Mary Regina Boland","doi":"10.21203/rs.3.rs-4490027/v1","DOIUrl":"10.21203/rs.3.rs-4490027/v1","url":null,"abstract":"<p><strong>Background: </strong>Hospitalizations for exacerbations of congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) and diabetic ketoacidosis (DKA) are costly in the United States. The purpose of this study was to predict in-hospital charges for each condition using machine learning (ML) models.</p><p><strong>Results: </strong>We conducted a retrospective cohort study on national discharge records of hospitalized adult patients from January 1st, 2016, to December 31st, 2019. We used numerous ML techniques to predict in-hospital total cost. We found that linear regression (LM), gradient boosting (GBM) and extreme gradient boosting (XGB) models had good predictive performance and were statistically equivalent, with training R-square values ranging from 0.49-0.95 for CHF, 0.56-0.95 for COPD, and 0.32-0.99 for DKA. We identified important key features driving costs, including patient age, length of stay, number of procedures. and elective/nonelective admission.</p><p><strong>Conclusions: </strong>ML methods may be used to accurately predict costs and identify drivers of high cost for COPD exacerbations, CHF exacerbations and DKA. Overall, our findings may inform future studies that seek to decrease the underlying high patient costs for these conditions.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474320","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":"Structural disadvantage and HIV risk - comparing risk factors between trans women's partnerships with cis men and trans women sexual partners.","authors":"Erin C Wilson, Bow Suprasert, Dillon Trujillo, Sofia Sicro, Christopher J Hernandez, Caitlin M Turner, Willi McFarland, Sean Arayasirikul","doi":"10.21203/rs.3.rs-4492723/v1","DOIUrl":"10.21203/rs.3.rs-4492723/v1","url":null,"abstract":"<p><strong>Introduction: </strong>Little is known about differences in HIV risk for trans women by partner gender, particularly with respect to social determinants and partner-level circumstances that affect behavior. We examined differences in demographic, social determinants, and HIV-related risk behaviors for trans women with cis men and trans women sexual partners.</p><p><strong>Materials and methods: </strong>Data are from a cross-sectional survey of trans women and their sexual partners conducted between April 2020 and January 2021. Interviews were held remotely during shelter-in-place due to Covid-19 via videoconference. Analysis characterizedassociations between HIV risk and protective behaviors comparing trans women with cisgender men partners to trans women with non-cisgender sexual partners.</p><p><strong>Results: </strong>A total of 336 sexual partners were identified from 156 trans women. Trans women with cis men partners had significantly less education and employment and more incarceration and recidivism than trans women with trans women partners. Trans women and their cisgender men partners had shared experiences of unstable housing, incarceration, and HIV. Trans women with cisgender men partners reported significantly more sex exchange partners, receptive condomless sex, receptive or insertive condomless sex while using substances, and HIV infection compared to trans women with trans women partners.</p><p><strong>Conclusions: </strong>Trans women with cisgender men sexual partners faced higher HIV risk than trans women with trans women sexual partners. These risks may be related to the social and economic drivers that both trans women and their cis men partners faced, including barriers to education and employment, along with incarceration and recidivism. Interventions focused on economic stability, workforce development and post incarceration re-entry support for housing and employment for trans women with cis men partners and the cisgender men partners as well may have the most impact on reducing HIV risk and incidence.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474377","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":"From frozen to feeding: storage characteristics of banked donor human milk used in a single level IV academic neonatal intensive care unit.","authors":"Katherine Chetta, Mary Galemmo, Terence Camilon, Wrenn Tiernan, Whitney Savino, Allison Rohrer, John Baatz, Carol Wagner","doi":"10.21203/rs.3.rs-4486977/v1","DOIUrl":"10.21203/rs.3.rs-4486977/v1","url":null,"abstract":"<p><strong>Background: </strong>The storage time of banked donor human milk (DHM) administered in an academic hospital to critically ill preterm neonates was previously unknown.</p><p><strong>Objective: </strong>This study was designed to determine the storage time of banked DHM by measurements obtained at the hospital level (by lot finish date) and individual patient level (by feeding date) over 2-year observation period.</p><p><strong>Results: </strong>Both methods of measuring storage time (hospital-level and patient-level) showed that DHM was stored on average 8 ±1 months before use. Variations in storage time fluctuated across months with a minimum and maximum storage duration of 119 to 317 days. Most infants received a median of 3 [2-5 IQR] unique lots of DHM.</p><p><strong>Conclusion: </strong>The storage time of DHM was successfully measured. Over 95% of DHM received was stored longer than 6 months. Storage times varied widely, uncovering a potential area of future research.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474346","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 UTHealth Houston Adult Cardiovascular Genomics Certificate Program: Efficacy and Impact on Healthcare Professionals.","authors":"Melyssa Garner, Bansari Rajani, Priyanka Vaidya, Samer Abu Dayeh, Alana C Cecchi, Christina C Miyake, Vicki Huff, Matthew Wanat, Elisabeth Wang, Leonie M Kurzlechner, Andrew P Landstrom, Daniel An, Yafen Liang, Mousumi Moulik, Timothy C Wong, Shane R Cunha, Ashley Cannon, R Lynn Holt, Dianna M Milewicz, Siddharth K Prakash","doi":"10.21203/rs.3.rs-4469272/v1","DOIUrl":"10.21203/rs.3.rs-4469272/v1","url":null,"abstract":"<p><strong>Background: </strong>The demand for genetic services has outpaced the availability of resources, challenging clinicians untrained in genetic integration into clinical decision-making. The UTHealth Adult Cardiovascular Genomics Certificate (CGC) program trains non-genetic healthcare professionals to recognize, assess, and refer patients with heritable cardiovascular diseases. This asynchronous online course includes 24 modules in three tiers of increasing complexity, using realistic clinical scenarios, interactive dialogues, quizzes, and tests to reinforce learning. We hypothesized that the CGC will increase genomic competencies in this underserved audience and encourage applying genomic concepts in clinical practice.</p><p><strong>Methods: </strong>Required course evaluations include pre- and post-assessments, knowledge checks in each module, and surveys for module-specific feedback. After 6 months, longitudinal feedback surveys gathered data on the long-term impact of the course on clinical practice and conducted focused interviews with learners.</p><p><strong>Results: </strong>The CGC was accredited in September 2022. Principal learners were nurses (24%), nurse practitioners (21%), physicians (16%), and physician assistants. Scores of 283 learners in paired pre- and post-assessments increased specific skills related to recognizing heritable diseases, understanding inheritance patterns, and interpreting genetic tests. Interviews highlighted the CGC's modular structure and linked resources as key strengths. Learners endorsed confidence to use genetic information in clinical practice, such as discussing genetic concepts and risks with patients and referring patients for genetic testing. Learners were highly likely to recommend the CGC to colleagues, citing its role in enhancing heritable disease awareness.</p><p><strong>Conclusions: </strong>The CGC program effectively empowers non-genetic clinicians to master genomic competencies, fostering collaboration to prevent deaths from heritable cardiovascular diseases, and potentially transforming healthcare education and clinical practice.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474404","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":"Tensor-valued diffusion MRI detects brain microstructure changes in HIV infected individuals with cognitive impairment.","authors":"Md Nasir Uddin, Meera V Singh, Abrar Faiyaz, Filip Szczepankiewicz, Markus Nilsson, Zachary D Boodoo, Karli R Sutton, Madalina E Tivarus, Jianhui Zhong, Lu Wang, Xing Qiu, Miriam T Weber, Giovanni Schifitto","doi":"10.21203/rs.3.rs-4482269/v1","DOIUrl":"10.21203/rs.3.rs-4482269/v1","url":null,"abstract":"<p><p>Despite advancements, the prevalence of HIV-associated neurocognitive impairment remains at approximately 40%, attributed to factors like pre-cART (combination antiretroviral therapy) irreversible brain injury. People with HIV (PWH) treated with cART do not show significant neurocognitive changes over relatively short follow-up periods. However, quantitative neuroimaging may be able to detect ongoing subtle microstructural changes. This study aimed to investigate the sensitivity of tensor-valued diffusion encoding in detecting such changes in brain microstructural integrity in cART-treated PWH. Additionally, it explored relationships between these metrics, neurocognitive scores, and plasma levels of neurofilament light (NFL) chain and glial fibrillary acidic protein (GFAP). Using MRI at 3T, 24 PWH and 31 healthy controls underwent cross-sectional examination. The results revealed significant variations in b-tensor encoding metrics across white matter regions, with associations observed between these metrics, cognitive performance, and blood markers of neuronal and glial injury (NFL and GFAP). Moreover, a significant interaction between HIV status and imaging metrics was observed, particularly impacting total cognitive scores in both gray and white matter. These findings suggest that b-tensor encoding metrics offer heightened sensitivity in detecting subtle changes associated with axonal injury in HIV infection, underscoring their potential clinical relevance in understanding neurocognitive impairment in PWH.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474379","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":"Treatment with lipoxin A 4 improves influenza A infection outcome through macrophage reprogramming, anti-inflammatory and pro-resolutive responses.","authors":"Flavia Rago, Eliza Mathias Melo, Leigh M Miller, Alexis M Duray, Franciel Batista Felix, Juliana Priscila Vago, Ana Paula Faria Gonçalves, Ana Luiza Pessoa Mendonça Angelo, Giovanni D Cassali, Monica Gaetano, Eoin Brennan, Benjamin Owen, Patrick Guiry, Catherine Godson, John F Alcorn, Mauro Martins Teixeira","doi":"10.21203/rs.3.rs-4491036/v1","DOIUrl":"10.21203/rs.3.rs-4491036/v1","url":null,"abstract":"<p><strong>Objective and design: </strong>Here, we evaluated whether a synthetic lipoxin mimetic, designated AT-01-KG, would improve the course of influenza A infection in a murine model.</p><p><strong>Treatment: </strong>Mice were infected with influenza A/H1N1 and treated with AT-01-KG (1.7 mg/kg/day, i.p.) at day 3 post-infection.</p><p><strong>Methods: </strong>Mortality rate was assessed up to day 21 and inflammatory parameters were assessed at days 5 and 7.</p><p><strong>Results: </strong>AT-01-KG attenuated mortality, reducing leukocyte infiltration and lung damage at day 5 and day 7 post-infection. AT-01-KG is a Formyl Peptide Receptor 2 (designated FPR2/3 in mice) agonist, and the protective responses were not observed in FPR2/3 ^-/- animals. In mice treated with LXA₄ (50mg/kg/day, i.p., days 3-6 post-infection), at day 7, macrophage reprogramming was observed, as seen by a decrease in classically activated macrophages and an increase in alternatively activated macrophages in the lungs. Furthermore, the number of apoptotic cells and cells undergoing efferocytosis was increased in the lavage of treated mice. Treatment also modulated the adaptive immune response, increasing the number of anti-inflammatory T cells (Th2) and regulatory T (Tregs) cells in the lungs of the treated mice.</p><p><strong>Conclusions: </strong>Therefore, treatment with a lipoxin A₄ analog was beneficial in a model of influenza A infection in mice. The drug decreased inflammation and promoted resolution and beneficial immune responses, suggesting it may be useful in patients with severe influenza.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474406","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":"Rare pathogenic structural variants show potential to enhance prostate cancer germline testing for African men.","authors":"Vanessa Hayes, Tingting Gong, Jue Jiang, Riana Bornman, Kazzem Gheybi, Phillip Stricker, Joachim Weischenfeldt, Shingai Mutambirwa","doi":"10.21203/rs.3.rs-4531885/v1","DOIUrl":"10.21203/rs.3.rs-4531885/v1","url":null,"abstract":"<p><p>Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline testing guidelines exclude for African men. Established that structural variations (SVs) are major contributors to human disease and prostate tumourigenesis, their role is under-appreciated in familial and therapeutic testing. Utilising a clinico-methodologically matched African (n = 113) <i>versus</i> European (n = 57) deep-sequenced PCa resource, we interrogated 42,966 high-quality germline SVs using a best-fit pathogenicity prediction workflow. We identified 15 potentially pathogenic SVs representing 12.4% African and 7.0% European patients, of which 72% and 86% met germline testing standard-of-care recommendations, respectively. Notable African-specific loss-of-function gene candidates include DNA damage repair <i>MLH1</i> and <i>BARD1</i> and tumour suppressors <i>FOXP1</i>, <i>WASF1</i> and <i>RB1</i>. Representing only a fraction of the vast African diaspora, this study raises considerations with respect to the contribution of kilo-to-mega-base rare variants to PCa pathogenicity and African associated disparity.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474329","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":"Evaluation of Aav Capsids and Delivery Approaches for Hereditary Hemorrhagic Telangiectasia Gene Therapy.","authors":"Alka Yadav, Rich Liang, Kelly Press, Annika Schmidt, Zahra Shabani, Kun Leng, Calvin Wang, Abinav Sekhar, Joshua Shi, Garth W Devlin, Trevor J Gonzalez, Aravind Asokan, Hua Su","doi":"10.21203/rs.3.rs-4469011/v1","DOIUrl":"10.21203/rs.3.rs-4469011/v1","url":null,"abstract":"<p><p>Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous delivery of soluble FMS-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of <i>endoglin</i> deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84 and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered intravenously (i.v.) or intranasally (i.n.) to wild-type mice. A CMV promoter driven <i>Alk1</i> transgene was packaged into AAV.cc84 and delivered to PdgfbiCre;<i>Alk1</i> ^f/f mice through i.v. injection followed by brain AVM induction. Transduced cells in different organs, vessel density and abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain ECs and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and skeletal muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. Delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre;<i>Alk1</i> ^f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474327","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}