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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}
Pub Date : 2024-05-07DOI: 10.21203/rs.3.rs-4342820/v1
Roddy S. O’Connor, Bakir Valentić, Andre Kelly, Alexander Shestov, Zhiyang Gan, Feng Shen, Adam Chatoff, Alison Jaccard, Claudia V Crispim, John Scholler, Simon Heeke, Nathaniel Snyder, S. Ghassemi, Nicholas Jones, Saar Gill
Abstract Activated T cells undergo a metabolic shift to aerobic glycolysis to support the energetic demands of proliferation, differentiation, and cytolytic function. Transmembrane glucose flux is facilitated by glucose transporters (GLUT) that play a vital role in T cell metabolic reprogramming and anti-tumour function. GLUT isoforms are regulated at the level of expression and subcellular distribution. GLUTs also display preferential selectivity for carbohydrate macronutrients including glucose, galactose, and fructose. GLUT5, which selectively transports fructose over glucose, has never been explored as a genetic engineering strategy to enhance CAR-T cells in fructose-rich tumour environments. Fructose levels are significantly elevated in the bone marrow and the plasma of acute myeloid leukaemia (AML) patients. Here, we demonstrate that the expression of wild-type GLUT5 restores T cell metabolic fitness in glucose-free, high fructose conditions. We find that fructose supports maximal glycolytic capacity and ATP replenishment rates in GLUT5-expressing T cells. Using steady state tracer technology, we show that 13C6 fructose supports glycolytic reprogramming and TCA anaplerosis in CAR-T cells undergoing log phase expansion. In cytotoxicity assays, GLUT5 rescues T cell cytolytic function in glucose-free medium. The fructose/GLUT5 metabolic axis also supports maximal migratory velocity, which provides mechanistic insight into why GLUT5-expressing CAR-Ts have superior effector function as they undergo “hit-and-run” serial killing. These findings translate to superior anti-tumour function in a xenograft model of AML. In fact, we found that GLUT5 enhances CAR-T cell anti-tumour function in vivo without any need for fructose intervention. Accordingly, we hypothesize that GLUT5 is sufficient to enhance CAR-T resilience by increasing the cells’ competitiveness for glucose at physiologic metabolite levels. Our findings have immediate translational relevance by providing the first evidence that GLUT5 confers a competitive edge in a fructose-enriched milieu, and is a novel approach to overcome glucose depletion in hostile tumour microenvironments (TMEs).
摘要 活化的 T 细胞在代谢过程中转向有氧糖酵解，以支持增殖、分化和细胞溶解功能的能量需求。跨膜葡萄糖通量由葡萄糖转运体（GLUT）促进，葡萄糖转运体在 T 细胞代谢重编程和抗肿瘤功能中发挥着重要作用。GLUT 同工型在表达和亚细胞分布水平上受到调控。GLUT 还对包括葡萄糖、半乳糖和果糖在内的碳水化合物主要营养素具有优先选择性。GLUT5 可选择性地转运果糖而不是葡萄糖，但它从未被作为一种基因工程策略用于在富含果糖的肿瘤环境中增强 CAR-T 细胞。急性髓性白血病（AML）患者的骨髓和血浆中果糖水平明显升高。在这里，我们证明了野生型 GLUT5 的表达可恢复 T 细胞在无葡萄糖、高果糖条件下的代谢能力。我们发现，果糖支持表达 GLUT5 的 T 细胞的最大糖酵解能力和 ATP 补充率。利用稳态示踪技术，我们发现 13C6 果糖支持对数期扩增的 CAR-T 细胞的糖酵解重编程和 TCA 失活。在细胞毒性试验中，GLUT5 能在无葡萄糖培养基中挽救 T 细胞的细胞溶解功能。果糖/GLUT5代谢轴还支持最大迁移速度，这从机理上揭示了为什么表达GLUT5的CAR-T细胞在进行 "打了就跑 "的连续杀伤时具有卓越的效应功能。这些发现转化为急性髓细胞性白血病异种移植模型中的卓越抗肿瘤功能。事实上，我们发现 GLUT5 无需果糖干预即可增强 CAR-T 细胞的体内抗肿瘤功能。因此，我们推测 GLUT5 足以通过提高细胞在生理代谢物水平上对葡萄糖的竞争性来增强 CAR-T 的恢复能力。我们的研究结果首次证明 GLUT5 在富含果糖的环境中具有竞争优势，是克服恶劣肿瘤微环境（TMEs）中葡萄糖耗竭的一种新方法，因此具有直接的转化意义。
{"title":"The Glucose Transporter 5 Enhances CAR-T Cell Metabolic Function and Anti-tumour Durability","authors":"Roddy S. O’Connor, Bakir Valentić, Andre Kelly, Alexander Shestov, Zhiyang Gan, Feng Shen, Adam Chatoff, Alison Jaccard, Claudia V Crispim, John Scholler, Simon Heeke, Nathaniel Snyder, S. Ghassemi, Nicholas Jones, Saar Gill","doi":"10.21203/rs.3.rs-4342820/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4342820/v1","url":null,"abstract":"Abstract Activated T cells undergo a metabolic shift to aerobic glycolysis to support the energetic demands of proliferation, differentiation, and cytolytic function. Transmembrane glucose flux is facilitated by glucose transporters (GLUT) that play a vital role in T cell metabolic reprogramming and anti-tumour function. GLUT isoforms are regulated at the level of expression and subcellular distribution. GLUTs also display preferential selectivity for carbohydrate macronutrients including glucose, galactose, and fructose. GLUT5, which selectively transports fructose over glucose, has never been explored as a genetic engineering strategy to enhance CAR-T cells in fructose-rich tumour environments. Fructose levels are significantly elevated in the bone marrow and the plasma of acute myeloid leukaemia (AML) patients. Here, we demonstrate that the expression of wild-type GLUT5 restores T cell metabolic fitness in glucose-free, high fructose conditions. We find that fructose supports maximal glycolytic capacity and ATP replenishment rates in GLUT5-expressing T cells. Using steady state tracer technology, we show that 13C6 fructose supports glycolytic reprogramming and TCA anaplerosis in CAR-T cells undergoing log phase expansion. In cytotoxicity assays, GLUT5 rescues T cell cytolytic function in glucose-free medium. The fructose/GLUT5 metabolic axis also supports maximal migratory velocity, which provides mechanistic insight into why GLUT5-expressing CAR-Ts have superior effector function as they undergo “hit-and-run” serial killing. These findings translate to superior anti-tumour function in a xenograft model of AML. In fact, we found that GLUT5 enhances CAR-T cell anti-tumour function in vivo without any need for fructose intervention. Accordingly, we hypothesize that GLUT5 is sufficient to enhance CAR-T resilience by increasing the cells’ competitiveness for glucose at physiologic metabolite levels. Our findings have immediate translational relevance by providing the first evidence that GLUT5 confers a competitive edge in a fructose-enriched milieu, and is a novel approach to overcome glucose depletion in hostile tumour microenvironments (TMEs).","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141005009","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-4307273/v1
Huixian Hong, Yong Wang, Marissa Menard, Jessica A. Buckley, Lianna Zhou, Laura Volpicelli-Daley, David Standaert, Hongwei Qin, Etty N. Benveniste
Abstract Parkinson’s disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of a-synuclein (a-Syn) into insoluble aggregates called Lewy pathology. The Line 61 a-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human a-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human a-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-a-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-a-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4 + T-cells, CD8 + T-cells, CD19 + B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45 + cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1 , H2-Aa , H2-Ab1 , and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf , Il1b , C1qa , and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.
{"title":"Suppression of the JAK/STAT Pathway Inhibits Neuroinflammation in the Line 61-PFF Mouse Model of Parkinson’s Disease","authors":"Huixian Hong, Yong Wang, Marissa Menard, Jessica A. Buckley, Lianna Zhou, Laura Volpicelli-Daley, David Standaert, Hongwei Qin, Etty N. Benveniste","doi":"10.21203/rs.3.rs-4307273/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4307273/v1","url":null,"abstract":"Abstract Parkinson’s disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of a-synuclein (a-Syn) into insoluble aggregates called Lewy pathology. The Line 61 a-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human a-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human a-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-a-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-a-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4 + T-cells, CD8 + T-cells, CD19 + B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45 + cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1 , H2-Aa , H2-Ab1 , and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf , Il1b , C1qa , and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141003147","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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