Pub Date : 2024-05-08DOI: 10.21203/rs.3.rs-4350949/v1
Namdev S Togre, Naveen Melaka, Priyanka Bhoj, Nikhita Mogadala, Malika Winfield, Jayshil Trivedi, Deborah Grove, Sudhir Kotnala, Slava Rom, Uma Sri, Yuri Persidsky
Abstract Alcohol consumption leads to neuroinflammation and blood‒brain barrier (BBB) damage, resulting in neurological impairment. We previously demonstrated that ethanol-induced disruption of barrier function in human brain endothelial cells was associated with mitochondrial injury, increased ATP and extracellular vesicle (EV) release, and purinergic receptor P2X7R activation. Therefore, we aimed to evaluate the effect of P2X7r blockade on peripheral and neuro-inflammation in EtOH-exposed mice. In a chronic intermittent ethanol (CIE)-exposed mouse model, P2X7R was inhibited by two different methods: Brilliant Blue G (BBG) or gene knockout. We assessed blood ethanol concentration (BEC), plasma P2X7R and P-gp, number of extra-cellular vesicles (EV), serum ATP and EV-ATP levels. Brain microvessel gene expression and EV mtDNA copy numbers were measured by RT2 PCR array and digital PCR, respectively. A RT2 PCR array of brain microvessels revealed significant upregulation of proinflammatory genes involved in apoptosis, vasodilation, and platelet activation in CIE-exposed animals, which were decreased 15–50-fold in BBG-treated CIE-exposed animals. Plasma P-gp levels and serum P2X7R shedding were significantly increased in CIE-exposed animals. Pharmacological or genetic suppression of P2X7R decreased P2X7R shedding to levels equivalent to those in control group. The increase in EV number and EV-ATP content in the CIE-exposed mice was significantly reduced by P2X7R inhibition. CIE mice showed augmented EV-mtDNA copy numbers which were reduced in EVs after P2X7R inhibition or receptor knockout. These observations suggested that P2X7R signaling plays a critical role in ethanol-induced brain injury. Increased eATP, EV-ATP, EV numbers, and EV-mtDNA copy numbers highlight a new mechanism of brain injury during alcohol exposure via P2X7R and biomarkers of such damage. In this study, for the first time, we report the in vivo involvement of P2X7R signaling in CIE-induced brain injury.
{"title":"Neuroinflammatory Responses and Blood–Brain Barrier Injury in Chronic Alcohol Exposure: Role of Purinergic P2X7 Receptor Signaling","authors":"Namdev S Togre, Naveen Melaka, Priyanka Bhoj, Nikhita Mogadala, Malika Winfield, Jayshil Trivedi, Deborah Grove, Sudhir Kotnala, Slava Rom, Uma Sri, Yuri Persidsky","doi":"10.21203/rs.3.rs-4350949/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4350949/v1","url":null,"abstract":"Abstract Alcohol consumption leads to neuroinflammation and blood‒brain barrier (BBB) damage, resulting in neurological impairment. We previously demonstrated that ethanol-induced disruption of barrier function in human brain endothelial cells was associated with mitochondrial injury, increased ATP and extracellular vesicle (EV) release, and purinergic receptor P2X7R activation. Therefore, we aimed to evaluate the effect of P2X7r blockade on peripheral and neuro-inflammation in EtOH-exposed mice. In a chronic intermittent ethanol (CIE)-exposed mouse model, P2X7R was inhibited by two different methods: Brilliant Blue G (BBG) or gene knockout. We assessed blood ethanol concentration (BEC), plasma P2X7R and P-gp, number of extra-cellular vesicles (EV), serum ATP and EV-ATP levels. Brain microvessel gene expression and EV mtDNA copy numbers were measured by RT2 PCR array and digital PCR, respectively. A RT2 PCR array of brain microvessels revealed significant upregulation of proinflammatory genes involved in apoptosis, vasodilation, and platelet activation in CIE-exposed animals, which were decreased 15–50-fold in BBG-treated CIE-exposed animals. Plasma P-gp levels and serum P2X7R shedding were significantly increased in CIE-exposed animals. Pharmacological or genetic suppression of P2X7R decreased P2X7R shedding to levels equivalent to those in control group. The increase in EV number and EV-ATP content in the CIE-exposed mice was significantly reduced by P2X7R inhibition. CIE mice showed augmented EV-mtDNA copy numbers which were reduced in EVs after P2X7R inhibition or receptor knockout. These observations suggested that P2X7R signaling plays a critical role in ethanol-induced brain injury. Increased eATP, EV-ATP, EV numbers, and EV-mtDNA copy numbers highlight a new mechanism of brain injury during alcohol exposure via P2X7R and biomarkers of such damage. In this study, for the first time, we report the in vivo involvement of P2X7R signaling in CIE-induced brain injury.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" 33","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140999133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.21203/rs.3.rs-4214768/v1
Victoria M. Brown, Emily A. Ogutu, Alexandra E. Kauffman, Shanika S. Kennedy, Rebecca A. Tenner, A. Wurcel, Chad J. Zawitz, Anne C Spaulding, Matthew J. Akiyama
Abstract Background Little guidance exists on best practices for implementing and sustaining wastewater-based surveillance (WBS) for SARS-CoV-2 in carceral settings. To ensure alignment with priorities of stakeholders, we aimed to understand the perspectives of persons with lived experience (PLE) of jail who were incarcerated during the height of the COVID-19 pandemic on infection control. Methods We recruited two PLE at each of four jails: Cook County (IL), Fulton County (GA), Middlesex County (MA), and Washington DC. Focus Group Discussion (FGD) guides followed the Consolidated Framework for Implementation Research (CFIR). Two FGDs focusing on lived experience with jail infection control protocol and WBS were conducted, and six Key Informant (KI) interviews followed to gain insights on communicating WBS results. We used a combination of deductive thematic analysis based on CFIR constructs and inductive analysis to capture emergent themes. Results Themes from FGDs included: (1) variable experiences with COVID-19 infection control protocols including intake processes, individual testing, isolation and quarantine, (2) the perceived attitudes of fellow residents and staff surrounding COVID-19 mitigation in a carceral setting; and (3) perceived benefits and challenges involving WBS implementation and messaging. KIs emphasized 1) The importance of straightforward health messaging and trustworthiness in the communication of WBS results, 2) Support for enhanced health education around outbreaks, and 3) Receptiveness to WBS being used as a tool to measure common infectious agents (i.e., influenza) but hesitancy regarding its application to conditions such as HIV and illicit drug use. PLE articulated support of robust infection control programs and receptiveness to expanding WBS if conducted in a non-stigmatizing manner. Conclusion Perspectives from PLE can help shape the infection control programs for future outbreaks and inform the expansion of WBS implementation in carceral facilities. It will be important to consider the voices of current and former residents, as receivers of care, to promote an environment conducive to comprehensive infection control. In addition to having infection control programs consistently execute set protocols and educate all stakeholders, PLE identified collaboration between jail staff and residents, and clear communication around program expectations as priorities. Findings from this qualitative study can be shared with jail decision makers and the perceived engagement of stakeholders can be measured.
{"title":"Guiding the Implementation of Wastewater-based Surveillance for Carceral Infection Control with Perspectives from People with Lived Experience of Incarceration during the COVID-19 Pandemic","authors":"Victoria M. Brown, Emily A. Ogutu, Alexandra E. Kauffman, Shanika S. Kennedy, Rebecca A. Tenner, A. Wurcel, Chad J. Zawitz, Anne C Spaulding, Matthew J. Akiyama","doi":"10.21203/rs.3.rs-4214768/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4214768/v1","url":null,"abstract":"Abstract Background Little guidance exists on best practices for implementing and sustaining wastewater-based surveillance (WBS) for SARS-CoV-2 in carceral settings. To ensure alignment with priorities of stakeholders, we aimed to understand the perspectives of persons with lived experience (PLE) of jail who were incarcerated during the height of the COVID-19 pandemic on infection control. Methods We recruited two PLE at each of four jails: Cook County (IL), Fulton County (GA), Middlesex County (MA), and Washington DC. Focus Group Discussion (FGD) guides followed the Consolidated Framework for Implementation Research (CFIR). Two FGDs focusing on lived experience with jail infection control protocol and WBS were conducted, and six Key Informant (KI) interviews followed to gain insights on communicating WBS results. We used a combination of deductive thematic analysis based on CFIR constructs and inductive analysis to capture emergent themes. Results Themes from FGDs included: (1) variable experiences with COVID-19 infection control protocols including intake processes, individual testing, isolation and quarantine, (2) the perceived attitudes of fellow residents and staff surrounding COVID-19 mitigation in a carceral setting; and (3) perceived benefits and challenges involving WBS implementation and messaging. KIs emphasized 1) The importance of straightforward health messaging and trustworthiness in the communication of WBS results, 2) Support for enhanced health education around outbreaks, and 3) Receptiveness to WBS being used as a tool to measure common infectious agents (i.e., influenza) but hesitancy regarding its application to conditions such as HIV and illicit drug use. PLE articulated support of robust infection control programs and receptiveness to expanding WBS if conducted in a non-stigmatizing manner. Conclusion Perspectives from PLE can help shape the infection control programs for future outbreaks and inform the expansion of WBS implementation in carceral facilities. It will be important to consider the voices of current and former residents, as receivers of care, to promote an environment conducive to comprehensive infection control. In addition to having infection control programs consistently execute set protocols and educate all stakeholders, PLE identified collaboration between jail staff and residents, and clear communication around program expectations as priorities. Findings from this qualitative study can be shared with jail decision makers and the perceived engagement of stakeholders can be measured.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140999531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.21203/rs.3.rs-3243545/v1
John Wilson, Blaise R. Kimmel, Karan Arora, Neil Chada, Vijaya Bharti, Alexander J Kwiatkowski, Jonah Finklestein, Ann Hanna, Emily Arner, Taylor L. Sheehy, L. Pastora, Jinming Yang, Hayden M Pagendarm, P. Stone, Brandie Taylor, Lauren Hubert, Kathern Gibson-Corley, Jody May, John McLean, Jeffrey Rathmell, Ann Richmond, Wendy Rathmell, Justin Balko, Barbara Fingleton, Ebony Hargrove-Wiley
Abstract Stimulator of interferon genes (STING) is a promising target for potentiating antitumor immunity, but multiple pharmacological barriers limit the clinical utility, efficacy, and/or safety of STING agonists. Here we describe a modular platform for systemic administration of STING agonists based on nanobodies engineered for in situ hitchhiking of agonist cargo on serum albumin. Using site-selective bioconjugation chemistries to produce molecularly defined products, we found that covalent conjugation of a STING agonist to anti-albumin nanobodies improved pharmacokinetics and increased cargo accumulation in tumor tissue, stimulating innate immune programs that increased the infiltration of activated natural killer cells and T cells, which potently inhibited tumor growth in multiple mouse tumor models. We also demonstrated the programmability of the platform through the recombinant integration of a second nanobody domain that targeted programmed cell death ligand-1 (PD-L1), which further increased cargo delivery to tumor sites while also blocking immunosuppressive PD-1/PD-L1 interactions. This bivalent nanobody carrier for covalently conjugated STING agonists stimulated robust antigen-specific T cell responses and long-lasting immunological memory, conferred enhanced therapeutic efficacy, and was effective as a neoadjuvant treatment for improving responses to adoptive T cell transfer therapy. Albumin-hitchhiking nanobodies thus offer an enabling, multimodal, and programmable platform for systemic delivery of STING agonists with potential to augment responses to multiple immunotherapeutic modalities.
摘要 干扰素基因刺激器（STING）是增强抗肿瘤免疫力的有望靶点，但多种药理学障碍限制了 STING 激动剂的临床实用性、有效性和/或安全性。在这里，我们介绍了一种用于全身给药 STING 激动剂的模块化平台，该平台以纳米抗体为基础，可使激动剂货物原位搭乘血清白蛋白。我们发现，将 STING 激动剂与抗白蛋白纳米抗体共价结合可改善药代动力学并增加货物在肿瘤组织中的积聚，刺激先天性免疫程序，增加活化的自然杀伤细胞和 T 细胞的浸润，从而有效抑制多种小鼠肿瘤模型中的肿瘤生长。我们还通过重组整合针对程序性细胞死亡配体-1（PD-L1）的第二个纳米抗体结构域，证明了该平台的可编程性，从而进一步增加了向肿瘤部位的货物输送，同时还阻断了免疫抑制性 PD-1/PD-L1 的相互作用。这种用于共价共轭 STING 激动剂的二价纳米抗体载体能激发强大的抗原特异性 T 细胞反应和持久的免疫记忆，增强疗效，并能有效作为新辅助治疗手段，改善对采用 T 细胞转移疗法的反应。因此，白蛋白搭桥纳米抗体为 STING 激动剂的全身给药提供了一个有利的、多模式的和可编程的平台，具有增强多种免疫治疗模式反应的潜力。
{"title":"Programable Albumin-Hitchhiking Nanobodies Enhance the Delivery of STING Agonists to Potentiate Cancer Immunotherapy","authors":"John Wilson, Blaise R. Kimmel, Karan Arora, Neil Chada, Vijaya Bharti, Alexander J Kwiatkowski, Jonah Finklestein, Ann Hanna, Emily Arner, Taylor L. Sheehy, L. Pastora, Jinming Yang, Hayden M Pagendarm, P. Stone, Brandie Taylor, Lauren Hubert, Kathern Gibson-Corley, Jody May, John McLean, Jeffrey Rathmell, Ann Richmond, Wendy Rathmell, Justin Balko, Barbara Fingleton, Ebony Hargrove-Wiley","doi":"10.21203/rs.3.rs-3243545/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3243545/v1","url":null,"abstract":"Abstract Stimulator of interferon genes (STING) is a promising target for potentiating antitumor immunity, but multiple pharmacological barriers limit the clinical utility, efficacy, and/or safety of STING agonists. Here we describe a modular platform for systemic administration of STING agonists based on nanobodies engineered for in situ hitchhiking of agonist cargo on serum albumin. Using site-selective bioconjugation chemistries to produce molecularly defined products, we found that covalent conjugation of a STING agonist to anti-albumin nanobodies improved pharmacokinetics and increased cargo accumulation in tumor tissue, stimulating innate immune programs that increased the infiltration of activated natural killer cells and T cells, which potently inhibited tumor growth in multiple mouse tumor models. We also demonstrated the programmability of the platform through the recombinant integration of a second nanobody domain that targeted programmed cell death ligand-1 (PD-L1), which further increased cargo delivery to tumor sites while also blocking immunosuppressive PD-1/PD-L1 interactions. This bivalent nanobody carrier for covalently conjugated STING agonists stimulated robust antigen-specific T cell responses and long-lasting immunological memory, conferred enhanced therapeutic efficacy, and was effective as a neoadjuvant treatment for improving responses to adoptive T cell transfer therapy. Albumin-hitchhiking nanobodies thus offer an enabling, multimodal, and programmable platform for systemic delivery of STING agonists with potential to augment responses to multiple immunotherapeutic modalities.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141001418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.21203/rs.3.rs-4328156/v1
Viet Nguyen, D. Ha, O. M. Tran, Hoa L. Nguyen, Robert J. Goldberg, J. Allison, Neil S. Fleming, Phuong Khanh Nguyen
Abstract Between 2010 and 2011, stakeholders implemented a multi-faceted community-based intervention in response to the escalating issue of uncontrolled hypertension in Hung Yen province, Vietnam. This initiative integrated expanded community health worker services, home blood pressure self-monitoring, and a unique "storytelling intervention" into routine clinical care. From the limited societal perspective, our study evaluates the cost-effectiveness of this intervention using a Markov model with a one-year cycle over a lifetime horizon. The analysis, based on a cohort of 671 patients, reveals a lifetime incremental cost of approximately VND 90.37 million (USD 3,930) per quality-adjusted life year (QALY) gained. With a willingness to pay at three times GDP (VND 259.2 million per QALY), the intervention proves cost-effective 80% of the time. This research underscores the potential of the community-based approach to effectively control hypertension, offering valuable insights into its broader implications for public health.
{"title":"Cost-utility analysis of community-based interventions for hypertension control in Vietnam","authors":"Viet Nguyen, D. Ha, O. M. Tran, Hoa L. Nguyen, Robert J. Goldberg, J. Allison, Neil S. Fleming, Phuong Khanh Nguyen","doi":"10.21203/rs.3.rs-4328156/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4328156/v1","url":null,"abstract":"Abstract Between 2010 and 2011, stakeholders implemented a multi-faceted community-based intervention in response to the escalating issue of uncontrolled hypertension in Hung Yen province, Vietnam. This initiative integrated expanded community health worker services, home blood pressure self-monitoring, and a unique \"storytelling intervention\" into routine clinical care. From the limited societal perspective, our study evaluates the cost-effectiveness of this intervention using a Markov model with a one-year cycle over a lifetime horizon. The analysis, based on a cohort of 671 patients, reveals a lifetime incremental cost of approximately VND 90.37 million (USD 3,930) per quality-adjusted life year (QALY) gained. With a willingness to pay at three times GDP (VND 259.2 million per QALY), the intervention proves cost-effective 80% of the time. This research underscores the potential of the community-based approach to effectively control hypertension, offering valuable insights into its broader implications for public health.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"112 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141003837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.21203/rs.3.rs-4331290/v1
Michael F. Royer, Michelle E. Hauser, Astrid N Zamora, Maria I. Campero, Dulce M. Garcia, Martha Gabaray, Jylana L. Sheats, Abby C. King
Abstract Background: Food insecurity, an ongoing and accelerating problem in the U.S., is an economic and social condition involving limited or uncertain access to adequate food. Some of the highest rates of food insecurity in 2022 were found among individuals who were Hispanic-Latinx (20.8%), a population that already faces disproportionate health and socioeconomic disadvantages. There remains an urgent health-related need to identify sustainable strategies to prevent food insecurity in the Latinx population. Methods: A first-generation pilot investigation was conducted using data derived from a sub-study connected to the Computerized Physical Activity Support for Seniors (COMPASS) Trial, a 12-month cluster-randomized controlled trial among older Latinx adults. The sub-study focused on two nutrition interventions that included 1) the Food Literacy and Nutrition (FLAN) curriculum, and 2) a nutrition information-only control. Research hypotheses aimed to determine whether the FLAN intervention reduced food insecurity and increased daily fruit and vegetable servings. Results: On average, participants (n = 39) were 61.5 years of age (SD = 6.7), mostly female (69%), and reported Spanish as their primary language (69%). The FLAN intervention was associated with decreased odds of food insecurity at 12 months (AOR = 0.71, 95% CI = 0.54, 0.95; p = 0.03) when compared to the nutrition-information only control intervention. Although no between-group differences in daily fruit and vegetable servings were found, there was a significant correlation between changes in daily fruit and vegetable servings from baseline to six months and changes in food insecurity from baseline to 12 months (r = -0.51, p = 0.01). Conclusions: The FLAN intervention, a bilingual and culturally tailored educational curriculum, yielded 12-month improvements in food security among a small sample of older Latinx adults. Evidence from this investigation suggests the potential utility of implementing the FLAN curriculum among individuals who are at an increased risk of food insecurity. Further investigation in a larger sample is merited to determine whether the 12-month decreases in food insecurity that were produced by the FLAN intervention can be replicated. Trial Registration: ClinicalTrials.gov Identifier: NCT02111213
{"title":"Serving Up FLAN. A Food Literacy and Nutrition Intervention to Fend Off Food Insecurity.","authors":"Michael F. Royer, Michelle E. Hauser, Astrid N Zamora, Maria I. Campero, Dulce M. Garcia, Martha Gabaray, Jylana L. Sheats, Abby C. King","doi":"10.21203/rs.3.rs-4331290/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4331290/v1","url":null,"abstract":"Abstract Background: Food insecurity, an ongoing and accelerating problem in the U.S., is an economic and social condition involving limited or uncertain access to adequate food. Some of the highest rates of food insecurity in 2022 were found among individuals who were Hispanic-Latinx (20.8%), a population that already faces disproportionate health and socioeconomic disadvantages. There remains an urgent health-related need to identify sustainable strategies to prevent food insecurity in the Latinx population. Methods: A first-generation pilot investigation was conducted using data derived from a sub-study connected to the Computerized Physical Activity Support for Seniors (COMPASS) Trial, a 12-month cluster-randomized controlled trial among older Latinx adults. The sub-study focused on two nutrition interventions that included 1) the Food Literacy and Nutrition (FLAN) curriculum, and 2) a nutrition information-only control. Research hypotheses aimed to determine whether the FLAN intervention reduced food insecurity and increased daily fruit and vegetable servings. Results: On average, participants (n = 39) were 61.5 years of age (SD = 6.7), mostly female (69%), and reported Spanish as their primary language (69%). The FLAN intervention was associated with decreased odds of food insecurity at 12 months (AOR = 0.71, 95% CI = 0.54, 0.95; p = 0.03) when compared to the nutrition-information only control intervention. Although no between-group differences in daily fruit and vegetable servings were found, there was a significant correlation between changes in daily fruit and vegetable servings from baseline to six months and changes in food insecurity from baseline to 12 months (r = -0.51, p = 0.01). Conclusions: The FLAN intervention, a bilingual and culturally tailored educational curriculum, yielded 12-month improvements in food security among a small sample of older Latinx adults. Evidence from this investigation suggests the potential utility of implementing the FLAN curriculum among individuals who are at an increased risk of food insecurity. Further investigation in a larger sample is merited to determine whether the 12-month decreases in food insecurity that were produced by the FLAN intervention can be replicated. Trial Registration: ClinicalTrials.gov Identifier: NCT02111213","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"21 22","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141005129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.21203/rs.3.rs-4289663/v1
E. Peyster, David Smith, Therese Bittermann, Paco Bravo, Kenneth Margulies
Abstract Cardiac sarcoidosis is poorly understood, challenging to diagnose, and portends a poor prognosis. A lack of animal models necessitates the use of residual human samples to study sarcoidosis, which in turn necessitates the use of analytical tools compatible with archival, fixed tissue. We employed high-plex spatial protein analysis within a large cohort of archival human cardiac sarcoidosis and control tissue samples, studying the immunologic, fibrotic, and metabolic landscape of sarcoidosis at different stages of disease, in different cardiac tissue compartments, and in tissue regions with and without overt inflammation. Utilizing a small set of differentially expressed protein biomarkers, we also report the development of a predictive model capable of accurately discriminating between control cardiac tissue and sarcoidosis tissue, even when no histologic evidence of sarcoidosis is present. This finding has major translational implications, with the potential to markedly improve the diagnostic yield of clinical biopsies obtained from suspected sarcoidosis patients.
{"title":"Beyond the Granuloma: New Insights into Cardiac Sarcoidosis Using Spatial Proteomics","authors":"E. Peyster, David Smith, Therese Bittermann, Paco Bravo, Kenneth Margulies","doi":"10.21203/rs.3.rs-4289663/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4289663/v1","url":null,"abstract":"Abstract Cardiac sarcoidosis is poorly understood, challenging to diagnose, and portends a poor prognosis. A lack of animal models necessitates the use of residual human samples to study sarcoidosis, which in turn necessitates the use of analytical tools compatible with archival, fixed tissue. We employed high-plex spatial protein analysis within a large cohort of archival human cardiac sarcoidosis and control tissue samples, studying the immunologic, fibrotic, and metabolic landscape of sarcoidosis at different stages of disease, in different cardiac tissue compartments, and in tissue regions with and without overt inflammation. Utilizing a small set of differentially expressed protein biomarkers, we also report the development of a predictive model capable of accurately discriminating between control cardiac tissue and sarcoidosis tissue, even when no histologic evidence of sarcoidosis is present. This finding has major translational implications, with the potential to markedly improve the diagnostic yield of clinical biopsies obtained from suspected sarcoidosis patients.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"27 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141004765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.21203/rs.3.rs-4371952/v1
Benson Musinguzi, Andrew Akampurira, Hope Derick, Alex Mwesigwa, Edson Mwebesa, Vicent Mwesigye, Immaculate Kabajulizi, Tahalu Sekulima, Francis Ocheng, Herbert Itabangi, Gerald Mboowa, O. J. Sande, B. Achan
Abstract Background Oropharyngeal Candida species are part commensal microflora in the the oral cavity of health individuals. Commensal Candida species can become opportunist and transition to pathogenic causes of oropharyngeal candidiasis (OPC) in individuals with impaired immunity through ecological cues and expression of virulence factors. Limited studies have evaluated virulence attributes of oropharyngeal Candida species among people living with human immunodeficiency virus (PLHIV) with OPC on antiretroviral therapy (ART) in Uganda. Objective Evaluation of the Virulence Attributes of Oropharyngeal Candida Species Isolated from People Living with Human Immunodeficiency Virus with Oropharyngeal Candidiasis on Antiretroviral Therapy Methods Thirty-five (35) Candida isolates from PLHIV with OPC on ART were retrieved from sample repository and evaluated for phospholipase activity using the egg yolk agar method, proteinase activity using the bovine serum albumin agar method, hemolysin activity using the blood agar plate method, esterase activity using the Tween 80 opacity test medium method, coagulase activity using the classical tube method and biofilm formation using the microtiter plate assay method in vitro . Results Phospholipase and proteinase activities were detected in 33/35 (94.3%) and 31/35 (88.6%) of the strains, respectively. Up to 25/35 (71.4%) of the strains exhibited biofilm formation while esterase activity was demonstrated in 23/35 (65.7%) of the strains. Fewer isolates 21/35 (60%) of the strains produced hemolysin and coagulase production was the least virulence activity detected in 18/35 (51.4%). Conclusion Phospholipase and proteinase activities were the strongest virulence attributes of oropharyngeal Candida species.
{"title":"In Vitro Evaluation of the Virulence Attributes of Oropharyngeal Candida Species Isolated from People Living with Human Immunodeficiency Virus with Oropharyngeal Candidiasis on Antiretroviral Therapy","authors":"Benson Musinguzi, Andrew Akampurira, Hope Derick, Alex Mwesigwa, Edson Mwebesa, Vicent Mwesigye, Immaculate Kabajulizi, Tahalu Sekulima, Francis Ocheng, Herbert Itabangi, Gerald Mboowa, O. J. Sande, B. Achan","doi":"10.21203/rs.3.rs-4371952/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4371952/v1","url":null,"abstract":"Abstract Background Oropharyngeal Candida species are part commensal microflora in the the oral cavity of health individuals. Commensal Candida species can become opportunist and transition to pathogenic causes of oropharyngeal candidiasis (OPC) in individuals with impaired immunity through ecological cues and expression of virulence factors. Limited studies have evaluated virulence attributes of oropharyngeal Candida species among people living with human immunodeficiency virus (PLHIV) with OPC on antiretroviral therapy (ART) in Uganda. Objective Evaluation of the Virulence Attributes of Oropharyngeal Candida Species Isolated from People Living with Human Immunodeficiency Virus with Oropharyngeal Candidiasis on Antiretroviral Therapy Methods Thirty-five (35) Candida isolates from PLHIV with OPC on ART were retrieved from sample repository and evaluated for phospholipase activity using the egg yolk agar method, proteinase activity using the bovine serum albumin agar method, hemolysin activity using the blood agar plate method, esterase activity using the Tween 80 opacity test medium method, coagulase activity using the classical tube method and biofilm formation using the microtiter plate assay method in vitro . Results Phospholipase and proteinase activities were detected in 33/35 (94.3%) and 31/35 (88.6%) of the strains, respectively. Up to 25/35 (71.4%) of the strains exhibited biofilm formation while esterase activity was demonstrated in 23/35 (65.7%) of the strains. Fewer isolates 21/35 (60%) of the strains produced hemolysin and coagulase production was the least virulence activity detected in 18/35 (51.4%). Conclusion Phospholipase and proteinase activities were the strongest virulence attributes of oropharyngeal Candida species.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141004252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.21203/rs.3.rs-4331769/v1
Hannah R. Thompson, Kristine A. Madsen, Caroline Nguyen, Thomas L. McKenzie, Sally Picciotto
Abstract Background: School physical education is an important population-level health intervention for improving youth fitness. The purpose of this study is to determine the causal impact of New York City’s PE Works program on student cardiorespiratory fitness. Methods: This longitudinal study (2014-2019) includes 581 elementary schools (n=315,999 4 th /5 th -grade students; 84% non-white; 74% who qualify for free or reduced-price meals). We apply the parametric g-formula to address schools’ time-varying exposure to intervention components and time-varying confounding. Results: After four years of staggered PE Works implementation, 49.7% of students per school (95% CI: 42.6%, 54.2%) met age/sex-specific cardiorespiratory fitness standards. Had PE Works not been implemented, we estimate 45.7% (95% CI: 36.9%, 52.1%) would have met fitness standards. Had PE Works been fully implemented in all schools from the program’s inception, we estimate 57.4% (95% CI: 49.1%, 63.3%) would have met fitness standards. Adding a PE teacher, alone, had the largest impact (6.4% (95% CI: 1.0, 12.0) increase). Conclusion: PE Works, which included providing PE teachers, training for classroom teachers, and administrative/teacher support for PE, positively impacted student cardiorespiratory health. Mandating and funding multilevel, multicomponent PE programs is an important public health intervention to increase children’s cardiorespiratory fitness.
{"title":"Impact of a multi-level, multi-component intervention to improve elementary school physical education on student cardiorespiratory fitness: an application of the parametric g-formula","authors":"Hannah R. Thompson, Kristine A. Madsen, Caroline Nguyen, Thomas L. McKenzie, Sally Picciotto","doi":"10.21203/rs.3.rs-4331769/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4331769/v1","url":null,"abstract":"Abstract Background: School physical education is an important population-level health intervention for improving youth fitness. The purpose of this study is to determine the causal impact of New York City’s PE Works program on student cardiorespiratory fitness. Methods: This longitudinal study (2014-2019) includes 581 elementary schools (n=315,999 4 th /5 th -grade students; 84% non-white; 74% who qualify for free or reduced-price meals). We apply the parametric g-formula to address schools’ time-varying exposure to intervention components and time-varying confounding. Results: After four years of staggered PE Works implementation, 49.7% of students per school (95% CI: 42.6%, 54.2%) met age/sex-specific cardiorespiratory fitness standards. Had PE Works not been implemented, we estimate 45.7% (95% CI: 36.9%, 52.1%) would have met fitness standards. Had PE Works been fully implemented in all schools from the program’s inception, we estimate 57.4% (95% CI: 49.1%, 63.3%) would have met fitness standards. Adding a PE teacher, alone, had the largest impact (6.4% (95% CI: 1.0, 12.0) increase). Conclusion: PE Works, which included providing PE teachers, training for classroom teachers, and administrative/teacher support for PE, positively impacted student cardiorespiratory health. Mandating and funding multilevel, multicomponent PE programs is an important public health intervention to increase children’s cardiorespiratory fitness.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"106 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141003734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.21203/rs.3.rs-4314472/v1
Xiaosi Gu, Sarah Banker, Mathew Schafer, Miles Harrington, Soojung Na, Sarah Barkley, Jadyn Trayvick, Arabella Peters, Abigaël Thinakaran, Jennifer Foss-Feig, Daniela Schiller
Abstract While allowing for rapid recruitment of large samples, online psychiatric and neurodevelopmental research relies heavily on participants’ self-report of neuropsychiatric symptoms, foregoing the rigorous clinical characterization of laboratory settings. Autism spectrum disorder (ASD) research is one example where the clinical validity of such an approach remains elusive. Here, we compared participants characterized online via self-reports against in-person participants evaluated by clinicians. Despite having comparable self-reported autism symptoms, the online high-trait group reported significantly more social anxiety and avoidant behavior than in-person ASD subjects. Within the in-person sample, there was no relationship between self-rated and clinician-rated autism symptoms, suggesting these approaches may capture different aspects of ASD. The online high-trait and in-person ASD participants also differed in their behavior in well-validated social decision-making tasks: the in-person group perceived having less social control and acted less affiliative towards virtual characters. Our study aimed to draw comparisons at three levels: methodological platform (online versus in-person), symptom measurement (self- versus clinician-report), and social behavior. We identified a lack of agreement between self- and clinician-rated measures of symptoms and divergent social tendencies in groups ascertained by each method, highlighting the need for differentiation between in-person versus online samples in autism research.
{"title":"Phenotypical divergence between self-reported and clinically ascertained autism","authors":"Xiaosi Gu, Sarah Banker, Mathew Schafer, Miles Harrington, Soojung Na, Sarah Barkley, Jadyn Trayvick, Arabella Peters, Abigaël Thinakaran, Jennifer Foss-Feig, Daniela Schiller","doi":"10.21203/rs.3.rs-4314472/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4314472/v1","url":null,"abstract":"Abstract While allowing for rapid recruitment of large samples, online psychiatric and neurodevelopmental research relies heavily on participants’ self-report of neuropsychiatric symptoms, foregoing the rigorous clinical characterization of laboratory settings. Autism spectrum disorder (ASD) research is one example where the clinical validity of such an approach remains elusive. Here, we compared participants characterized online via self-reports against in-person participants evaluated by clinicians. Despite having comparable self-reported autism symptoms, the online high-trait group reported significantly more social anxiety and avoidant behavior than in-person ASD subjects. Within the in-person sample, there was no relationship between self-rated and clinician-rated autism symptoms, suggesting these approaches may capture different aspects of ASD. The online high-trait and in-person ASD participants also differed in their behavior in well-validated social decision-making tasks: the in-person group perceived having less social control and acted less affiliative towards virtual characters. Our study aimed to draw comparisons at three levels: methodological platform (online versus in-person), symptom measurement (self- versus clinician-report), and social behavior. We identified a lack of agreement between self- and clinician-rated measures of symptoms and divergent social tendencies in groups ascertained by each method, highlighting the need for differentiation between in-person versus online samples in autism research.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"22 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141005121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.21203/rs.3.rs-4332253/v1
Gregory Klazura, P. Kayima, Martin Situma, Edwin Musinguzi, Robert Mugarura, James Nyonyintono, Ava Yap, James Cope, Richard Akello, Emmanuel Kiwanuka, Moses Odonkara, Chelsea Okellowange, Jennifer Adongpiny, Daniels Lakwanyero, Patricia Atim, Aber Patience Cadrine, Joshua Olara, Amulya Boppana, Ruth Laverde, Sergio d'Agostino, Bruno Cigliano, D. Ozgediz, Thomas Sims, P. Kisa
Abstract Background: In 2022 there were only seven pediatric surgeons in Uganda, but approximately 170 are needed. Consequently, Ugandan general surgeons treat most pediatric surgical problems at regional hospitals. Accordingly, stakeholders created the Pediatric Emergency Surgery Course, which teaches rural providers identification, resuscitation, treatment and referral of pediatric surgical conditions. In order to improve course offerings and better understand pediatric surgery needs we collected admission and operative logbook data from four participating sites. One participating site, Lacor Hospital, rarely referred patients and had a much higher operative volume. Therefore, we sought to understand the causes of this difference and the resulting economic impact. Methods: Over a four-year period, data was collected from logbooks at four different regional referral hospitals in Uganda. Patients < 18 years old with a surgical diagnosis were included. Patient LOS, referral volume, age, and case type were compared between sites and DALYs were calculated and converted into monetary benefit. Results: Over four sites, 8,615 admissions, and 5,457 cases were included. Lacor patients were younger, had a longer length of stay, and were referred less. Additionally, Lacor’s long-term partnerships with a high-income country institution, a missionary organization, and visiting Ugandan and international pediatric surgeons were unique. In 2018, the pediatric surgery case volume was: Lacor (967); Fort Portal (477); Kiwoko (393); and Kabale (153), resulting in a substantial difference in long-term monetary health benefit. Conclusion: Long-term international partnerships may advance investments in surgical infrastructure, workforce, and education in low- and middle-income countries. This collaborative model allows stakeholders to make a greater impact than any single institution could make alone.
{"title":"Pediatric Surgery Collaboration in Uganda, the Benefits of Long Term Partnerships at Regional Referral Hospitals","authors":"Gregory Klazura, P. Kayima, Martin Situma, Edwin Musinguzi, Robert Mugarura, James Nyonyintono, Ava Yap, James Cope, Richard Akello, Emmanuel Kiwanuka, Moses Odonkara, Chelsea Okellowange, Jennifer Adongpiny, Daniels Lakwanyero, Patricia Atim, Aber Patience Cadrine, Joshua Olara, Amulya Boppana, Ruth Laverde, Sergio d'Agostino, Bruno Cigliano, D. Ozgediz, Thomas Sims, P. Kisa","doi":"10.21203/rs.3.rs-4332253/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4332253/v1","url":null,"abstract":"Abstract Background: In 2022 there were only seven pediatric surgeons in Uganda, but approximately 170 are needed. Consequently, Ugandan general surgeons treat most pediatric surgical problems at regional hospitals. Accordingly, stakeholders created the Pediatric Emergency Surgery Course, which teaches rural providers identification, resuscitation, treatment and referral of pediatric surgical conditions. In order to improve course offerings and better understand pediatric surgery needs we collected admission and operative logbook data from four participating sites. One participating site, Lacor Hospital, rarely referred patients and had a much higher operative volume. Therefore, we sought to understand the causes of this difference and the resulting economic impact. Methods: Over a four-year period, data was collected from logbooks at four different regional referral hospitals in Uganda. Patients < 18 years old with a surgical diagnosis were included. Patient LOS, referral volume, age, and case type were compared between sites and DALYs were calculated and converted into monetary benefit. Results: Over four sites, 8,615 admissions, and 5,457 cases were included. Lacor patients were younger, had a longer length of stay, and were referred less. Additionally, Lacor’s long-term partnerships with a high-income country institution, a missionary organization, and visiting Ugandan and international pediatric surgeons were unique. In 2018, the pediatric surgery case volume was: Lacor (967); Fort Portal (477); Kiwoko (393); and Kabale (153), resulting in a substantial difference in long-term monetary health benefit. Conclusion: Long-term international partnerships may advance investments in surgical infrastructure, workforce, and education in low- and middle-income countries. This collaborative model allows stakeholders to make a greater impact than any single institution could make alone.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"111 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141002848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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