Pub Date : 2024-05-06DOI: 10.21203/rs.3.rs-4308293/v1
Alexander P. Glaser, Abigail R. Smith, Dacey Maglaque, Brian T. Helfand, Rowida Mohamed, Hosanna An, Melissa Marquez, P. Talaty, Padraig Carolan, Aaron M. Geller, Francesca R. Farina, Sally E. Jensen, James W Griffith
Abstract Background Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) significantly impact quality of life among older men. Despite the prevalent use of the American Urological Association Symptom Index (AUA-SI) for BPH, this measure overlooks key symptoms such as pain and incontinence, underscoring the need for more comprehensive patient-reported outcome (PRO) tools. This study aims to integrate enhanced PROs into routine clinical practice to better capture the spectrum of LUTS, thereby improving clinical outcomes and patient care. Methods This prospective observational study will recruit men with LUTS secondary to BPH aged ≥ 50 years from urology clinics. Participants will be stratified into medical and surgical management groups, with PRO assessments scheduled at regular intervals to monitor LUTS and other health outcomes. The study will employ the LURN Symptom Index (SI)-29 alongside the traditional AUA-SI and other non-urologic PROs to evaluate a broad range of symptoms. Data on comorbidities, symptom severity, and treatment efficacy will be collected through a combination of electronic health records and PROs. Analyses will focus on the predictive power of these tools in relation to symptom trajectories and treatment responses. Aims are to: (1) integrate routine clinical tests with PRO assessment to enhance screening, diagnosis, and management of patients with BPH; (2) examine psychometric properties of the LURN SIs, including test-retest reliability and establishment of clinically meaningful differences; and (3) create care-coordination recommendations to facilitate management of persistent symptoms and common comorbidities measured by PROs. Discussion By employing comprehensive PRO measures, this study expects to refine symptom assessment and enhance treatment monitoring, potentially leading to improved personalized care strategies. The integration of these tools into clinical settings could revolutionize the management of LUTS/BPH by providing more nuanced insights into patient experiences and outcomes. The findings could have significant implications for clinical practices, potentially leading to updates in clinical guidelines and better health management strategies for men with LUTS/BPH. Trial registration: This study is registered in ClinicalTrials.gov (NCT05898932).
{"title":"Enhanced Clinical Decisions for Management of Benign Prostatic Hyperplasia using Patient-Reported Outcomes: Protocol for a Prospective Observational Study","authors":"Alexander P. Glaser, Abigail R. Smith, Dacey Maglaque, Brian T. Helfand, Rowida Mohamed, Hosanna An, Melissa Marquez, P. Talaty, Padraig Carolan, Aaron M. Geller, Francesca R. Farina, Sally E. Jensen, James W Griffith","doi":"10.21203/rs.3.rs-4308293/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4308293/v1","url":null,"abstract":"Abstract Background Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) significantly impact quality of life among older men. Despite the prevalent use of the American Urological Association Symptom Index (AUA-SI) for BPH, this measure overlooks key symptoms such as pain and incontinence, underscoring the need for more comprehensive patient-reported outcome (PRO) tools. This study aims to integrate enhanced PROs into routine clinical practice to better capture the spectrum of LUTS, thereby improving clinical outcomes and patient care. Methods This prospective observational study will recruit men with LUTS secondary to BPH aged ≥ 50 years from urology clinics. Participants will be stratified into medical and surgical management groups, with PRO assessments scheduled at regular intervals to monitor LUTS and other health outcomes. The study will employ the LURN Symptom Index (SI)-29 alongside the traditional AUA-SI and other non-urologic PROs to evaluate a broad range of symptoms. Data on comorbidities, symptom severity, and treatment efficacy will be collected through a combination of electronic health records and PROs. Analyses will focus on the predictive power of these tools in relation to symptom trajectories and treatment responses. Aims are to: (1) integrate routine clinical tests with PRO assessment to enhance screening, diagnosis, and management of patients with BPH; (2) examine psychometric properties of the LURN SIs, including test-retest reliability and establishment of clinically meaningful differences; and (3) create care-coordination recommendations to facilitate management of persistent symptoms and common comorbidities measured by PROs. Discussion By employing comprehensive PRO measures, this study expects to refine symptom assessment and enhance treatment monitoring, potentially leading to improved personalized care strategies. The integration of these tools into clinical settings could revolutionize the management of LUTS/BPH by providing more nuanced insights into patient experiences and outcomes. The findings could have significant implications for clinical practices, potentially leading to updates in clinical guidelines and better health management strategies for men with LUTS/BPH. Trial registration: This study is registered in ClinicalTrials.gov (NCT05898932).","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141010444","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 : 2024-05-06DOI: 10.21203/rs.3.rs-4294058/v1
Jason S Wasserman, Holly A. Fowle, Rumesa Hashmi, Diba Atar, Kishan Patel, Amir Yarmahmoodi, Alexander W. Macfarlane, Yinfei Tan, Edna Cukierman, Bojana Gligorijevic, Adam Karami, Kelly A. Whelan, Kerry S. Campbell, Xavier Graña
Abstract Prostate cancer (PCa) is the most common cancer diagnosed in men worldwide and the second leading cause of cancer-related deaths in US males in 2022. Prostate cancer also represents the second highest cancer mortality disparity between non-Hispanic blacks and whites. However, there is a relatively small number of prostate normal and cancer cell lines compared to other cancers. To identify the molecular basis of PCa progression, it is important to have prostate epithelial cell (PrEC) lines as karyotypically normal as possible. Our lab recently developed a novel methodology for the rapid and efficient immortalization of normal human PrEC that combines simultaneous CRISPR-directed inactivation of CDKN2A exon 2 (which directs expression of p16INK4A and p14ARF) and ectopic expression of an hTERT transgene. To optimize this methodology to generate immortalized lines with minimal genetic alterations, we sought to target exon 1α of the CDKN2A locus so that p16INK4A expression is ablated while p14ARF expression remains unaltered. Here we describe the establishment of two cell lines: one with the above-mentioned p16INK4A only loss, and a second line targeting both products in the CDKN2A locus. We characterize the potential lineage origin of these new cell lines along with our previously obtained clones, revealing distinct gene expression signatures. Based on the analyses of protein markers and RNA expression signatures, these cell lines are most closely related to a subpopulation of basal prostatic cells. Given the simplicity of this one-step methodology and the fact that it uses only the minimal genetic alterations necessary for immortalization, it should also be suitable for the establishment of cell lines from primary prostate tumor samples, an urgent need given the limited number of available prostate cancer cell lines.
{"title":"Derivation of human primary prostate epithelial cell lines by differentially targeting the CDKN2A locus along with expression of hTERT","authors":"Jason S Wasserman, Holly A. Fowle, Rumesa Hashmi, Diba Atar, Kishan Patel, Amir Yarmahmoodi, Alexander W. Macfarlane, Yinfei Tan, Edna Cukierman, Bojana Gligorijevic, Adam Karami, Kelly A. Whelan, Kerry S. Campbell, Xavier Graña","doi":"10.21203/rs.3.rs-4294058/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4294058/v1","url":null,"abstract":"Abstract Prostate cancer (PCa) is the most common cancer diagnosed in men worldwide and the second leading cause of cancer-related deaths in US males in 2022. Prostate cancer also represents the second highest cancer mortality disparity between non-Hispanic blacks and whites. However, there is a relatively small number of prostate normal and cancer cell lines compared to other cancers. To identify the molecular basis of PCa progression, it is important to have prostate epithelial cell (PrEC) lines as karyotypically normal as possible. Our lab recently developed a novel methodology for the rapid and efficient immortalization of normal human PrEC that combines simultaneous CRISPR-directed inactivation of CDKN2A exon 2 (which directs expression of p16INK4A and p14ARF) and ectopic expression of an hTERT transgene. To optimize this methodology to generate immortalized lines with minimal genetic alterations, we sought to target exon 1α of the CDKN2A locus so that p16INK4A expression is ablated while p14ARF expression remains unaltered. Here we describe the establishment of two cell lines: one with the above-mentioned p16INK4A only loss, and a second line targeting both products in the CDKN2A locus. We characterize the potential lineage origin of these new cell lines along with our previously obtained clones, revealing distinct gene expression signatures. Based on the analyses of protein markers and RNA expression signatures, these cell lines are most closely related to a subpopulation of basal prostatic cells. Given the simplicity of this one-step methodology and the fact that it uses only the minimal genetic alterations necessary for immortalization, it should also be suitable for the establishment of cell lines from primary prostate tumor samples, an urgent need given the limited number of available prostate cancer cell lines.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141009864","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 : 2024-04-24DOI: 10.21203/rs.3.rs-3342413/v2
Reji Babygirija, Michelle M Sonsalla, Jericha Mill, Isabella James, Jessica H Han, Cara L Green, Mariah F Calubag, Gina Wade, Anna Tobon, John Michael, Michaela M Trautman, Ryan Matoska, Chung-Yang Yeh, Isaac Grunow, Heidi H Pak, Michael J Rigby, Dominique A Baldwin, Natalie M Niemi, John M Denu, Luigi Puglielli, Judith Simcox, Dudley W Lamming
Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and many independent groups of researchers have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice and rescuing the glucose intolerance of 3xTg females. We found that PR induces sex-specific alterations in circulating metabolites and in the brain metabolome and lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.
{"title":"Protein restriction slows the development and progression of Alzheimer's disease in mice.","authors":"Reji Babygirija, Michelle M Sonsalla, Jericha Mill, Isabella James, Jessica H Han, Cara L Green, Mariah F Calubag, Gina Wade, Anna Tobon, John Michael, Michaela M Trautman, Ryan Matoska, Chung-Yang Yeh, Isaac Grunow, Heidi H Pak, Michael J Rigby, Dominique A Baldwin, Natalie M Niemi, John M Denu, Luigi Puglielli, Judith Simcox, Dudley W Lamming","doi":"10.21203/rs.3.rs-3342413/v2","DOIUrl":"10.21203/rs.3.rs-3342413/v2","url":null,"abstract":"<p><p>Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and many independent groups of researchers have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice and rescuing the glucose intolerance of 3xTg females. We found that PR induces sex-specific alterations in circulating metabolites and in the brain metabolome and lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41133091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.21203/rs.3.rs-3272974/v2
Azam Yazdani
The full text of this preprint has been withdrawn, as it was submitted in error. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.
{"title":"WITHDRAWN: Broadcasters, receivers, functional groups of metabolites and the link to heart failure using polygenic factors.","authors":"Azam Yazdani","doi":"10.21203/rs.3.rs-3272974/v2","DOIUrl":"10.21203/rs.3.rs-3272974/v2","url":null,"abstract":"<p><p>The full text of this preprint has been withdrawn, as it was submitted in error. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10479558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10208057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-09DOI: 10.21203/rs.3.rs-3922129/v1
Vijjayalakshmi Santhakumar, Deepak Subramanian, C. Eisenberg, Andrew Huang, Jiyeon Baek, Haniya Naveed, Samiksha Komatireddy, Michael Shiflett, Tracy Tran
Abstract Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and epilepsy has not been tested. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.
{"title":"Dysregulation of Neuropilin-2 Expression in Inhibitory Neurons Impairs Hippocampal Circuit Development Leading to Autism-Epilepsy Phenotype","authors":"Vijjayalakshmi Santhakumar, Deepak Subramanian, C. Eisenberg, Andrew Huang, Jiyeon Baek, Haniya Naveed, Samiksha Komatireddy, Michael Shiflett, Tracy Tran","doi":"10.21203/rs.3.rs-3922129/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3922129/v1","url":null,"abstract":"Abstract Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and epilepsy has not been tested. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139964983","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 : 2024-02-09DOI: 10.21203/rs.3.rs-3640878/v1
Guo-Wei Wei, Dong Chen, Jian Liu
Abstract Pre-trained deep Transformers have had tremendous success in a wide variety of disciplines. However, in computational biology, essentially all Transformers are built upon the biological sequences, which ignores vital stereochemical information and may result in crucial errors in downstream predictions. On the other hand, three-dimensional (3D) molecular structures are incompatible with the sequential architecture of Transformer and natural language processing (NLP) models in general. This work addresses this foundational challenge by a topological Transformer (TopoFormer). TopoFormer is built by integrating NLP and a multiscale topology techniques, the persistent topological hyperdigraph Laplacian (PTHL), which systematically converts intricate 3D protein-ligand complexes at various spatial scales into a NLP-admissible sequence of topological invariants and homotopic shapes. Element-specific PTHLs are further developed to embed crucial physical, chemical, and biological interactions into topological sequences. TopoFormer surges ahead of conventional algorithms and recent deep learning variants and gives rise to exemplary scoring accuracy and superior performance in ranking, docking, and screening tasks in a number of benchmark datasets. The proposed topological sequences can be extracted from all kinds of structural data in data science to facilitate various NLP models, heralding a new era in AI-driven discovery.
{"title":"TopoFormer: Multiscale Topology-enabled Structure-to-Sequence Transformer for Protein-Ligand Interaction Predictions","authors":"Guo-Wei Wei, Dong Chen, Jian Liu","doi":"10.21203/rs.3.rs-3640878/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3640878/v1","url":null,"abstract":"Abstract Pre-trained deep Transformers have had tremendous success in a wide variety of disciplines. However, in computational biology, essentially all Transformers are built upon the biological sequences, which ignores vital stereochemical information and may result in crucial errors in downstream predictions. On the other hand, three-dimensional (3D) molecular structures are incompatible with the sequential architecture of Transformer and natural language processing (NLP) models in general. This work addresses this foundational challenge by a topological Transformer (TopoFormer). TopoFormer is built by integrating NLP and a multiscale topology techniques, the persistent topological hyperdigraph Laplacian (PTHL), which systematically converts intricate 3D protein-ligand complexes at various spatial scales into a NLP-admissible sequence of topological invariants and homotopic shapes. Element-specific PTHLs are further developed to embed crucial physical, chemical, and biological interactions into topological sequences. TopoFormer surges ahead of conventional algorithms and recent deep learning variants and gives rise to exemplary scoring accuracy and superior performance in ranking, docking, and screening tasks in a number of benchmark datasets. The proposed topological sequences can be extracted from all kinds of structural data in data science to facilitate various NLP models, heralding a new era in AI-driven discovery.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139964808","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 : 2024-02-09DOI: 10.21203/rs.3.rs-3914483/v1
Samuel Kawuma, Rogers Katwesigye, H. Walusaga, Praise Akatukunda, J. Nangendo, Charles Kabugo, Moses R. Kamya, Fred C. Semitala
Abstract Background Female sex workers (FSWs) have the highest HIV prevalence in Uganda. Pre exposure prophylaxis (PrEP) has been recommended as part of the HIV combination prevention strategy, with improved patient initiation, but continuation on the service is low. We evaluated PrEP continuation among FSWs and explored potential determinants of PrEP continuation within a public referral hospital in Urban Uganda. Methods An explanatory sequential mixed method study was conducted at Kiruddu National referral hospital in Uganda. Secondary data on social demographic characteristics and follow up outcomes of at least one year was collected for all FSWs who were initiated PrEP between May 2020 and April 2021.We used Kaplan–Meier survival analysis to evaluate continuation on PrEP from time of initiation and follow-up period. The capability, opportunity, and motivation to change behaviour model was used to explore perspectives and practices of FSWs (n = 24) and health care providers (n = 8) on continuation on PrEP among FSWs, using semi structured interviews. The qualitative data was deductively coded and analyzed thematically, categorizing the themes related to PrEP continuation as facilitators and barriers. Results Of the 292 FSWs initiated on PrEP during this period, 101 (34.6) % were active on PrEP, 137 (46.9%) were lost to follow-up, 45 (15.4%) were no longer eligible to continue PrEP, eight (2.7%) were transferred out and one (0.3%) had died. Median survival time on PrEP was 15 months (Interquartile range IQR, 3–21). The continuation rates on PrEP at six (6) and 12 months were, 61.1% and 53.1%, respectively. Facilitators of PrEP continuation included awareness of risk associated with sex work, integration of PrEP with other HIV prevention services, presence of PrEP Peer support and use of Drop-in centers. The barriers included low community awareness about PrEP, high mobility of sex workers, substance abuse, and the unfavorable daytime clinic schedules. Conclusion Continuation on PrEP remains low among FSWs. Interventions for PrEP continuation should address barriers such as low community awareness on PrEP, substance abuse and restrictive health facility policies for scale of the PrEP program among FSWs in Uganda. Integration of PrEP with other services and scale up of community PrEP delivery structures may improve its continuation.
{"title":"Determinants to Continuation on Hiv Pre-exposure Propylaxis Among Female Sex Workers at a Referral Hospital in Uganda: a Mixed Methods Study Using Com-b Model","authors":"Samuel Kawuma, Rogers Katwesigye, H. Walusaga, Praise Akatukunda, J. Nangendo, Charles Kabugo, Moses R. Kamya, Fred C. Semitala","doi":"10.21203/rs.3.rs-3914483/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3914483/v1","url":null,"abstract":"Abstract Background Female sex workers (FSWs) have the highest HIV prevalence in Uganda. Pre exposure prophylaxis (PrEP) has been recommended as part of the HIV combination prevention strategy, with improved patient initiation, but continuation on the service is low. We evaluated PrEP continuation among FSWs and explored potential determinants of PrEP continuation within a public referral hospital in Urban Uganda. Methods An explanatory sequential mixed method study was conducted at Kiruddu National referral hospital in Uganda. Secondary data on social demographic characteristics and follow up outcomes of at least one year was collected for all FSWs who were initiated PrEP between May 2020 and April 2021.We used Kaplan–Meier survival analysis to evaluate continuation on PrEP from time of initiation and follow-up period. The capability, opportunity, and motivation to change behaviour model was used to explore perspectives and practices of FSWs (n = 24) and health care providers (n = 8) on continuation on PrEP among FSWs, using semi structured interviews. The qualitative data was deductively coded and analyzed thematically, categorizing the themes related to PrEP continuation as facilitators and barriers. Results Of the 292 FSWs initiated on PrEP during this period, 101 (34.6) % were active on PrEP, 137 (46.9%) were lost to follow-up, 45 (15.4%) were no longer eligible to continue PrEP, eight (2.7%) were transferred out and one (0.3%) had died. Median survival time on PrEP was 15 months (Interquartile range IQR, 3–21). The continuation rates on PrEP at six (6) and 12 months were, 61.1% and 53.1%, respectively. Facilitators of PrEP continuation included awareness of risk associated with sex work, integration of PrEP with other HIV prevention services, presence of PrEP Peer support and use of Drop-in centers. The barriers included low community awareness about PrEP, high mobility of sex workers, substance abuse, and the unfavorable daytime clinic schedules. Conclusion Continuation on PrEP remains low among FSWs. Interventions for PrEP continuation should address barriers such as low community awareness on PrEP, substance abuse and restrictive health facility policies for scale of the PrEP program among FSWs in Uganda. Integration of PrEP with other services and scale up of community PrEP delivery structures may improve its continuation.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139964809","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 : 2024-02-09DOI: 10.21203/rs.3.rs-3748581/v1
Tibor Harkany, Evgenii Tretiakov, Luis Varela, Jasna Jarc, Patrick Rebernik, Sylvia Newbold, Erik Keimpema, Alexei Verkhratsky, Tamas Horvath, Roman Romanov
Abstract Astrocytes safeguard the homeostasis of the central nervous system 1,2 . Despite their prominent morphological plasticity under conditions that challenge the brain’s adaptive capacity 3–5 , the classification of astrocytes, and relating their molecular make-up to spatially devolved neuronal operations that specify behavior or metabolism, remained mostly futile 6,7 . Although it seems unexpected in the era of single-cell biology, the lack of a major advance in stratifying astrocytes under physiological conditions rests on the incompatibility of ‘neurocentric’ algorithms that rely on stable developmental endpoints, lifelong transcriptional, neurotransmitter, and neuropeptide signatures for classification 6–8 with the dynamic functional states, anatomic allocation, and allostatic plasticity of astrocytes 1 . Simplistically, therefore, astrocytes are still grouped as ‘resting’ vs. ‘reactive’, the latter referring to pathological states marked by various inducible genes 3,9,10 . Here, we introduced a machine learning-based feature recognition algorithm that benefits from the cumulative power of published single-cell RNA-seq data on astrocytes as a reference map to stepwise eliminate pleiotropic and inducible cellular features. For the healthy hypothalamus, this walk-back approach revealed gene regulatory networks (GRNs) that specified subsets of astrocytes, and could be used as landmarking tools for their anatomical assignment. The core molecular censuses retained by astrocyte subsets were sufficient to stratify them by allostatic competence, chiefly their signaling and metabolic interplay with neurons. Particularly, we found differentially expressed mitochondrial genes in insulin-sensing astrocytes and demonstrated their reciprocal signaling with neurons that work antagonistically within the food intake circuitry. As a proof-of-concept, we showed that disrupting Mfn2 expression in astrocytes reduced their ability to support dynamic circuit reorganization, a time-locked feature of satiety in the hypothalamus, thus leading to obesity in mice. Overall, our results suggest that astrocytes in the healthy brain are fundamentally more heterogeneous than previously thought and topologically mirror the specificity of local neurocircuits.
{"title":"Molecularly stratified hypothalamic astrocytes are cellular foci for obesity","authors":"Tibor Harkany, Evgenii Tretiakov, Luis Varela, Jasna Jarc, Patrick Rebernik, Sylvia Newbold, Erik Keimpema, Alexei Verkhratsky, Tamas Horvath, Roman Romanov","doi":"10.21203/rs.3.rs-3748581/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3748581/v1","url":null,"abstract":"Abstract Astrocytes safeguard the homeostasis of the central nervous system 1,2 . Despite their prominent morphological plasticity under conditions that challenge the brain’s adaptive capacity 3–5 , the classification of astrocytes, and relating their molecular make-up to spatially devolved neuronal operations that specify behavior or metabolism, remained mostly futile 6,7 . Although it seems unexpected in the era of single-cell biology, the lack of a major advance in stratifying astrocytes under physiological conditions rests on the incompatibility of ‘neurocentric’ algorithms that rely on stable developmental endpoints, lifelong transcriptional, neurotransmitter, and neuropeptide signatures for classification 6–8 with the dynamic functional states, anatomic allocation, and allostatic plasticity of astrocytes 1 . Simplistically, therefore, astrocytes are still grouped as ‘resting’ vs. ‘reactive’, the latter referring to pathological states marked by various inducible genes 3,9,10 . Here, we introduced a machine learning-based feature recognition algorithm that benefits from the cumulative power of published single-cell RNA-seq data on astrocytes as a reference map to stepwise eliminate pleiotropic and inducible cellular features. For the healthy hypothalamus, this walk-back approach revealed gene regulatory networks (GRNs) that specified subsets of astrocytes, and could be used as landmarking tools for their anatomical assignment. The core molecular censuses retained by astrocyte subsets were sufficient to stratify them by allostatic competence, chiefly their signaling and metabolic interplay with neurons. Particularly, we found differentially expressed mitochondrial genes in insulin-sensing astrocytes and demonstrated their reciprocal signaling with neurons that work antagonistically within the food intake circuitry. As a proof-of-concept, we showed that disrupting Mfn2 expression in astrocytes reduced their ability to support dynamic circuit reorganization, a time-locked feature of satiety in the hypothalamus, thus leading to obesity in mice. Overall, our results suggest that astrocytes in the healthy brain are fundamentally more heterogeneous than previously thought and topologically mirror the specificity of local neurocircuits.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139964814","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 : 2024-02-09DOI: 10.21203/rs.3.rs-3922904/v1
Michael Farzan, Andi Pan, Charles C. Bailey, T. Ou, Jinge Xu, Xin Liu, Baodan Hu, Gogce Crynen, Nickolas K. Skamangas, N. Bronkema, Mai H. Tran, Huihui Mu, Xia Zhang, Yiming Yin, Michael Alpert, Wenhui He
Abstract Many human proteins have been repurposed as biologics for clinical use. These proteins have been engineered with in vitro techniques that improve affinity for their ligands. However, these approaches do not select against properties that impair efficacy such as protease sensitivity or self-reactivity. Here we engineer the B-cell receptor of primary murine B cells to express a human protein biologic without disrupting their ability to affinity mature. Specifically, CD4 domains 1 and 2 (D1D2) of a half-life enhanced-HIV-1 entry inhibitor CD4-Ig (CD4-Ig-v0) were introduced into the heavy-chain loci of murine B cells, which were then adoptively transferred to wild-type mice. After immunization, transferred B cells proliferated, class switched, affinity matured, and efficiently produced D1D2-presenting antibodies. Somatic hypermutations found in the D1D2-encoding region of engrafted B cells improved binding affinity of CD4-Ig-v0 for the HIV-1 envelope glycoprotein (Env) and the neutralization potency of CD4-Ig-v0 by more than ten-fold across a global panel of HIV-1 isolates, without impairing its pharmacokinetic properties. Thus, affinity maturation of non-antibody protein biologics in vivo can guide development of more effective therapeutics.
摘要 许多人类蛋白质已被重新用作生物制剂用于临床。这些蛋白质经过体外技术的改造，提高了与配体的亲和力。然而，这些方法并不能避免蛋白酶敏感性或自身反应性等影响药效的特性。在这里，我们对原代小鼠 B 细胞的 B 细胞受体进行了改造，以表达一种人类蛋白生物制剂，而不破坏它们的亲合成熟能力。具体来说，我们将半衰期增强型艾滋病毒-1进入抑制剂CD4-Ig（CD4-Ig-v0）的CD4结构域1和2（D1D2）导入小鼠B细胞的重链位点，然后将其收养性转移给野生型小鼠。免疫后，转移的 B 细胞增殖、分类转换、亲和力成熟，并有效地产生了 D1D2 呈递抗体。在接种B细胞的D1D2编码区发现的体细胞高突变提高了CD4-Ig-v0与HIV-1包膜糖蛋白（Env）的结合亲和力以及CD4-Ig-v0在全球HIV-1分离株中的中和效力，提高幅度超过10倍，且不影响其药代动力学特性。因此，非抗体蛋白生物制剂在体内的亲和力成熟可以指导开发更有效的治疗方法。
{"title":"In vivo affinity maturation of the HIV-1 Env-binding domain of CD4","authors":"Michael Farzan, Andi Pan, Charles C. Bailey, T. Ou, Jinge Xu, Xin Liu, Baodan Hu, Gogce Crynen, Nickolas K. Skamangas, N. Bronkema, Mai H. Tran, Huihui Mu, Xia Zhang, Yiming Yin, Michael Alpert, Wenhui He","doi":"10.21203/rs.3.rs-3922904/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3922904/v1","url":null,"abstract":"Abstract Many human proteins have been repurposed as biologics for clinical use. These proteins have been engineered with in vitro techniques that improve affinity for their ligands. However, these approaches do not select against properties that impair efficacy such as protease sensitivity or self-reactivity. Here we engineer the B-cell receptor of primary murine B cells to express a human protein biologic without disrupting their ability to affinity mature. Specifically, CD4 domains 1 and 2 (D1D2) of a half-life enhanced-HIV-1 entry inhibitor CD4-Ig (CD4-Ig-v0) were introduced into the heavy-chain loci of murine B cells, which were then adoptively transferred to wild-type mice. After immunization, transferred B cells proliferated, class switched, affinity matured, and efficiently produced D1D2-presenting antibodies. Somatic hypermutations found in the D1D2-encoding region of engrafted B cells improved binding affinity of CD4-Ig-v0 for the HIV-1 envelope glycoprotein (Env) and the neutralization potency of CD4-Ig-v0 by more than ten-fold across a global panel of HIV-1 isolates, without impairing its pharmacokinetic properties. Thus, affinity maturation of non-antibody protein biologics in vivo can guide development of more effective therapeutics.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139964822","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 : 2024-02-09DOI: 10.21203/rs.3.rs-3924584/v1
Thang Le, Takeyuki Oba, Luke Couch, Lauren McInerney, Chiang-Shan R Li
Abstract Physical pain and negative emotions represent two distinct drinking motives that contribute to harmful alcohol use. Proactive avoidance which can reduce problem drinking in response to these motives appears to be impaired in problem drinkers. However, proactive avoidance and its underlying neural deficits have not been assessed experimentally. How these deficits inter-relate with drinking motives to influence alcohol use also remains unclear. The current study leveraged neuroimaging data collected in forty-one problem and forty-one social drinkers who performed a probabilistic learning go/nogo task that involved proactive avoidance of painful outcomes. We characterized the regional brain responses to proactive avoidance and identified the neural correlates of drinking to avoid physical pain and negative emotions. Behavioral results confirmed problem drinkers’ proactive avoidance deficits in learning rate and performance accuracy, both which were associated with greater alcohol use. Imaging findings in problem drinkers showed that negative emotions as a drinking motive predicted attenuated right insula activation during proactive avoidance. In contrast, physical pain motive predicted reduced right putamen response. These regions’ activations as well as functional connectivity with the somatomotor cortex also demonstrated a negative relationship with drinking severity and positive relationship with proactive avoidance performance. Path modeling further delineated the pathways through which physical pain and negative emotions, along with alcohol use severity, influenced the neural and behavioral measures of proactive avoidance. Taken together, the current findings provide experimental evidence for proactive avoidance deficits in problem drinkers and establish the link between their neural underpinnings and alcohol misuse.
{"title":"Deficits in proactive avoidance and neural responses to drinking motives in problem drinkers","authors":"Thang Le, Takeyuki Oba, Luke Couch, Lauren McInerney, Chiang-Shan R Li","doi":"10.21203/rs.3.rs-3924584/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3924584/v1","url":null,"abstract":"Abstract Physical pain and negative emotions represent two distinct drinking motives that contribute to harmful alcohol use. Proactive avoidance which can reduce problem drinking in response to these motives appears to be impaired in problem drinkers. However, proactive avoidance and its underlying neural deficits have not been assessed experimentally. How these deficits inter-relate with drinking motives to influence alcohol use also remains unclear. The current study leveraged neuroimaging data collected in forty-one problem and forty-one social drinkers who performed a probabilistic learning go/nogo task that involved proactive avoidance of painful outcomes. We characterized the regional brain responses to proactive avoidance and identified the neural correlates of drinking to avoid physical pain and negative emotions. Behavioral results confirmed problem drinkers’ proactive avoidance deficits in learning rate and performance accuracy, both which were associated with greater alcohol use. Imaging findings in problem drinkers showed that negative emotions as a drinking motive predicted attenuated right insula activation during proactive avoidance. In contrast, physical pain motive predicted reduced right putamen response. These regions’ activations as well as functional connectivity with the somatomotor cortex also demonstrated a negative relationship with drinking severity and positive relationship with proactive avoidance performance. Path modeling further delineated the pathways through which physical pain and negative emotions, along with alcohol use severity, influenced the neural and behavioral measures of proactive avoidance. Taken together, the current findings provide experimental evidence for proactive avoidance deficits in problem drinkers and establish the link between their neural underpinnings and alcohol misuse.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965060","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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