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":"50 24","pages":""},"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":"47 22","pages":""},"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":"45 4","pages":""},"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}
Pub Date : 2024-02-09DOI: 10.21203/rs.3.rs-3871956/v1
K. Bujakowska, Riccardo Sangermano, Priya Gupta, Cherrell Price, Jinu Han, Julien Navarro, C. Condroyer, Emily Place, A. Antonio, Shizuo Mukai, Xavier Zanlonghi, J. Sahel, Jacque Duncan, Eric A. Pierce, Christina Zeitz, I. Audo, Rachel Huckfeldt
Abstract Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. The implementation of next-generation sequencing in routine diagnostics, together with advanced clinical phenotyping including multimodal retinal imaging, have contributed to the increase of reports describing novel genotype-phenotype associations and phenotypic expansions. In this study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with syndromic recessive Jeune syndrome. The most common retinal phenotypes were cone-rod and rod-cone dystrophies, but the clinical presentations were unified by their early onset as well as the severe impact on central visual function. Twelve variants were detected (three pathogenic, seven likely pathogenic, two of uncertain significance), eight of which were novel. One deep intronic change, c.373+91A>G, led to the creation of a cryptic splice acceptor site in intron four, followed by the inclusion of a 200-base pair pseudoexon and subsequent premature stop codon formation. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Meta-analysis of all published and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.
{"title":"Coding and non-coding variants in the ciliopathy gene CFAP410 cause early-onset non-syndromic retinal degeneration.","authors":"K. Bujakowska, Riccardo Sangermano, Priya Gupta, Cherrell Price, Jinu Han, Julien Navarro, C. Condroyer, Emily Place, A. Antonio, Shizuo Mukai, Xavier Zanlonghi, J. Sahel, Jacque Duncan, Eric A. Pierce, Christina Zeitz, I. Audo, Rachel Huckfeldt","doi":"10.21203/rs.3.rs-3871956/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3871956/v1","url":null,"abstract":"Abstract Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. The implementation of next-generation sequencing in routine diagnostics, together with advanced clinical phenotyping including multimodal retinal imaging, have contributed to the increase of reports describing novel genotype-phenotype associations and phenotypic expansions. In this study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with syndromic recessive Jeune syndrome. The most common retinal phenotypes were cone-rod and rod-cone dystrophies, but the clinical presentations were unified by their early onset as well as the severe impact on central visual function. Twelve variants were detected (three pathogenic, seven likely pathogenic, two of uncertain significance), eight of which were novel. One deep intronic change, c.373+91A>G, led to the creation of a cryptic splice acceptor site in intron four, followed by the inclusion of a 200-base pair pseudoexon and subsequent premature stop codon formation. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Meta-analysis of all published and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"42 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965200","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-3873514/v1
Jacco Boon, Nadia Soudani, T. Bricker, T. Darling, K. Seehra, Nita Patel, M. Guebre‐Xabier, Gale Smith, M. Suthar, Ali Ellebedy, Meredith E. Davis-Gardner
Abstract The continued emergence of SARS-CoV-2 variants necessitates updating COVID-19 vaccines to match circulating strains. The immunogenicity and efficacy of these vaccines must be tested in pre-clinical animal models. In Syrian hamsters, we measured the humoral and cellular immune response after immunization with the nanoparticle recombinant Spike (S) protein-based COVID-19 vaccine (Novavax, Inc.). We also compared the efficacy of the updated monovalent XBB.1.5 variant vaccine to previous COVID-19 vaccines for the induction of XBB.1.5 and EG.5.1 neutralizing antibodies and protection against a challenge with the EG.5.1 variant of SARS-CoV-2. Immunization induced high levels of spike-specific serum IgG and IgA antibodies, S-specific IgG and IgA antibody secreting cells, and antigen specific CD4 + T-cells. The XBB.1.5 and XBB.1.16 vaccines, but not the Prototype vaccine, induced high levels of neutralizing antibodies against XBB.1.5 and EG.5.1 variants of SARS-CoV-2. Upon challenge with the Omicron EG.5.1 variant, the XBB.1.5 and XBB.1.16 vaccines reduced the virus load in the lungs, nasal turbinates, trachea and nasal washes. The bivalent vaccine continued to offer protection in the trachea and lungs, but protection was reduced in the upper airways. In contrast, the monovalent Prototype vaccine no longer offered good protection, and breakthrough infections were observed in all animals and tissues. Thus, the protein-based XBB.1.5 vaccine is immunogenic and can protect against the Omicron EG.5.1 variant in the Syrian hamster model.
摘要 由于 SARS-CoV-2 变异株的不断出现，有必要更新 COVID-19 疫苗，使其与流行株相匹配。这些疫苗的免疫原性和有效性必须在临床前动物模型中进行测试。在叙利亚仓鼠身上，我们测量了纳米颗粒重组 Spike (S) 蛋白 COVID-19 疫苗（Novavax 公司）免疫后的体液和细胞免疫反应。我们还比较了最新单价XBB.1.5变异株疫苗与以前的COVID-19疫苗在诱导XBB.1.5和EG.5.1中和抗体方面的功效，以及对SARS-CoV-2的EG.5.1变异株挑战的保护作用。免疫诱导了高水平的尖峰特异性血清 IgG 和 IgA 抗体、S 特异性 IgG 和 IgA 抗体分泌细胞以及抗原特异性 CD4 + T 细胞。XBB.1.5和XBB.1.16疫苗（而非原型疫苗）可诱导高水平的针对XBB.1.5和EG.5.1变体的SARS-CoV-2中和抗体。在接种 Omicron EG.5.1 变异株后，XBB.1.5 和 XBB.1.16 疫苗可减少肺、鼻甲、气管和鼻腔冲洗液中的病毒载量。二价疫苗继续为气管和肺部提供保护，但对上呼吸道的保护作用减弱。相比之下，单价原型疫苗不再提供良好的保护，在所有动物和组织中都观察到了突破性感染。因此，基于蛋白质的XBB.1.5疫苗具有免疫原性，能够在叙利亚仓鼠模型中保护其免受Omicron EG.5.1变体的感染。
{"title":"Immunogenicity and efficacy of XBB.1.5 rS vaccine against EG.5.1 variant of SARS-CoV-2 in Syrian hamsters","authors":"Jacco Boon, Nadia Soudani, T. Bricker, T. Darling, K. Seehra, Nita Patel, M. Guebre‐Xabier, Gale Smith, M. Suthar, Ali Ellebedy, Meredith E. Davis-Gardner","doi":"10.21203/rs.3.rs-3873514/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3873514/v1","url":null,"abstract":"Abstract The continued emergence of SARS-CoV-2 variants necessitates updating COVID-19 vaccines to match circulating strains. The immunogenicity and efficacy of these vaccines must be tested in pre-clinical animal models. In Syrian hamsters, we measured the humoral and cellular immune response after immunization with the nanoparticle recombinant Spike (S) protein-based COVID-19 vaccine (Novavax, Inc.). We also compared the efficacy of the updated monovalent XBB.1.5 variant vaccine to previous COVID-19 vaccines for the induction of XBB.1.5 and EG.5.1 neutralizing antibodies and protection against a challenge with the EG.5.1 variant of SARS-CoV-2. Immunization induced high levels of spike-specific serum IgG and IgA antibodies, S-specific IgG and IgA antibody secreting cells, and antigen specific CD4 + T-cells. The XBB.1.5 and XBB.1.16 vaccines, but not the Prototype vaccine, induced high levels of neutralizing antibodies against XBB.1.5 and EG.5.1 variants of SARS-CoV-2. Upon challenge with the Omicron EG.5.1 variant, the XBB.1.5 and XBB.1.16 vaccines reduced the virus load in the lungs, nasal turbinates, trachea and nasal washes. The bivalent vaccine continued to offer protection in the trachea and lungs, but protection was reduced in the upper airways. In contrast, the monovalent Prototype vaccine no longer offered good protection, and breakthrough infections were observed in all animals and tissues. Thus, the protein-based XBB.1.5 vaccine is immunogenic and can protect against the Omicron EG.5.1 variant in the Syrian hamster model.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"46 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139964719","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 : 2024-02-08DOI: 10.21203/rs.3.rs-3932153/v1
Yinfei Kong, Erick G. Guerrero, J. Frimpong, Tenie Khachikian, Suojin Wang, Thomas A. D’Aunno, Daniel Howard
Abstract Background This study investigates the impact of workforce diversity, specifically staff identified as Black/African American, on retention in opioid use disorder (OUD) treatment, aiming to enhance patient outcomes. Employing a novel machine learning technique known as 'causal forest,' we explore heterogeneous treatment effects on retention. Methods We relied on four waves of the National Drug Abuse Treatment System Survey (NDATSS), a nationally representative longitudinal dataset of treatment programs. We analyzed OUD program data from the years 2000, 2005, 2014 and 2017 (n = 627). Employing the 'causal forest' method, we analyzed the heterogeneity in the relationship between workforce diversity and retention in OUD treatment. Interviews with program directors and clinical supervisors provided the data for this study. Results The results reveal diversity-related variations in the association with retention across 61 out of 627 OUD treatment programs (less than 10%). These programs, associated with positive impacts of workforce diversity, were more likely private-for-profit, newer, had lower percentages of Black and Latino clients, lower staff-to-client ratios, higher proportions of staff with graduate degrees, and lower percentages of unemployed clients. Conclusions While workforce diversity is crucial, our findings underscore that it alone is insufficient for improving retention in addiction health services research. Programs with characteristics typically linked to positive outcomes are better positioned to maximize the benefits of a diverse workforce in client retention. This research has implications for policy and program design, guiding decisions on resource allocation and workforce diversity to enhance retention rates among Black clients with OUDs.
{"title":"Identifying the Heterogeneity in the Association between Workforce Diversity and Retention in Opioid Treatment among Black clients","authors":"Yinfei Kong, Erick G. Guerrero, J. Frimpong, Tenie Khachikian, Suojin Wang, Thomas A. D’Aunno, Daniel Howard","doi":"10.21203/rs.3.rs-3932153/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3932153/v1","url":null,"abstract":"Abstract Background This study investigates the impact of workforce diversity, specifically staff identified as Black/African American, on retention in opioid use disorder (OUD) treatment, aiming to enhance patient outcomes. Employing a novel machine learning technique known as 'causal forest,' we explore heterogeneous treatment effects on retention. Methods We relied on four waves of the National Drug Abuse Treatment System Survey (NDATSS), a nationally representative longitudinal dataset of treatment programs. We analyzed OUD program data from the years 2000, 2005, 2014 and 2017 (n = 627). Employing the 'causal forest' method, we analyzed the heterogeneity in the relationship between workforce diversity and retention in OUD treatment. Interviews with program directors and clinical supervisors provided the data for this study. Results The results reveal diversity-related variations in the association with retention across 61 out of 627 OUD treatment programs (less than 10%). These programs, associated with positive impacts of workforce diversity, were more likely private-for-profit, newer, had lower percentages of Black and Latino clients, lower staff-to-client ratios, higher proportions of staff with graduate degrees, and lower percentages of unemployed clients. Conclusions While workforce diversity is crucial, our findings underscore that it alone is insufficient for improving retention in addiction health services research. Programs with characteristics typically linked to positive outcomes are better positioned to maximize the benefits of a diverse workforce in client retention. This research has implications for policy and program design, guiding decisions on resource allocation and workforce diversity to enhance retention rates among Black clients with OUDs.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"37 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965221","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 : 2024-02-08DOI: 10.21203/rs.3.rs-3871665/v1
Pradeep Varathan Pugalenthi, Bing He, Linhui Xie, K. Nho, A. Saykin, Jingwen Yan
Abstract Alzheimer’s disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWASs) have led to a significant set of SNPs associated with AD and related traits. GWAS hits usually emerge as clusters where a lead SNP with the highest significance is surrounded by other less significant neighboring SNPs. Although functionality is not guaranteed even with the strongest associations in GWASs, lead SNPs have historically been the focus of the field, with the remaining associations inferred to be redundant. Recent deep genome annotation tools enable the prediction of function from a segment of a DNA sequence with significantly improved precision, which allows in-silico mutagenesis to interrogate the functional effect of SNP alleles. In this project, we explored the impact of top AD GWAS hits on chromatin functions and whether it will be altered by the genetic context (i.e., alleles of neighboring SNPs). Our results showed that highly correlated SNPs in the same LD block could have distinct impacts on downstream functions. Although some GWAS lead SNPs showed dominant functional effects regardless of the neighborhood SNP alleles, several other SNPs did exhibit enhanced loss or gain of function under certain genetic contexts, suggesting potential additional information hidden in the LD blocks and the need for reanalysis of GWAS findings as clusters.
摘要 阿尔茨海默病（AD）是一种高度遗传性脑痴呆症，并伴有严重的认知功能障碍。大规模的全基因组关联研究（GWAS）发现了一系列与阿尔茨海默病及相关特征有关的重要 SNPs。全基因组关联研究的结果通常以基因簇的形式出现，在这些基因簇中，具有最高重要性的主要 SNP 被其他重要性较低的邻近 SNP 所包围。尽管在 GWAS 中，即使是关联性最强的 SNP 也不能保证其功能性，但主导 SNP 一直是该领域的研究重点，而其余的关联则被推断为多余的。最近的深度基因组注释工具可以从DNA序列的一个片段预测功能，其精确度大大提高，从而可以通过体内诱变来探究SNP等位基因的功能效应。在这个项目中，我们探讨了AD GWAS热门基因对染色质功能的影响，以及这种影响是否会因遗传背景（即相邻SNP的等位基因）而改变。我们的研究结果表明，同一LD区块中高度相关的SNP可能会对下游功能产生不同的影响。尽管一些 GWAS 的前导 SNPs 显示出显性功能效应，与邻近 SNP 的等位基因无关，但其他一些 SNPs 在某些遗传背景下确实表现出增强的功能丧失或增益，这表明 LD 区块中可能隐藏着额外的信息，因此有必要将 GWAS 研究结果作为群集进行重新分析。
{"title":"Deciphering the tissue-specific functional effect of Alzheimer risk SNPs with deep genome annotation","authors":"Pradeep Varathan Pugalenthi, Bing He, Linhui Xie, K. Nho, A. Saykin, Jingwen Yan","doi":"10.21203/rs.3.rs-3871665/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3871665/v1","url":null,"abstract":"Abstract Alzheimer’s disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWASs) have led to a significant set of SNPs associated with AD and related traits. GWAS hits usually emerge as clusters where a lead SNP with the highest significance is surrounded by other less significant neighboring SNPs. Although functionality is not guaranteed even with the strongest associations in GWASs, lead SNPs have historically been the focus of the field, with the remaining associations inferred to be redundant. Recent deep genome annotation tools enable the prediction of function from a segment of a DNA sequence with significantly improved precision, which allows in-silico mutagenesis to interrogate the functional effect of SNP alleles. In this project, we explored the impact of top AD GWAS hits on chromatin functions and whether it will be altered by the genetic context (i.e., alleles of neighboring SNPs). Our results showed that highly correlated SNPs in the same LD block could have distinct impacts on downstream functions. Although some GWAS lead SNPs showed dominant functional effects regardless of the neighborhood SNP alleles, several other SNPs did exhibit enhanced loss or gain of function under certain genetic contexts, suggesting potential additional information hidden in the LD blocks and the need for reanalysis of GWAS findings as clusters.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"37 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965226","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 : 2024-02-08DOI: 10.21203/rs.3.rs-3934937/v1
Grace X. Ma, Lin Zhu, Yin Tan, Phuong Do, Guercie Guerrier, Min Qi Wang, Minhhuyen Nguyen, Tam Tran, Philip Pham
Abstract Purpose The fecal immunochemical test (FIT) is a non-invasive method for colorectal cancer (CRC) screening, particularly effective in underserved Vietnamese American communities with low screening rates. This study reports on a culturally tailored multilevel intervention, incorporating FIT, aimed at increasing CRC screening among these populations aged 50 or above in the Greater Philadelphia metropolitan area. Methods From 2017 to 2020, we conducted a two-arm cluster randomized controlled trial to test the efficacy of a culturally tailored, multicomponent multilevel intervention aimed at increasing CRC screening uptake via enhanced self-awareness and self-efficacy, improved access to care, and changes in social norms and removal of stigma. The intervention group received multicomponent, multilevel CRC intervention including provision of a FIT self-sampling kit, with intervention approaches informed by the Centers for Disease Control's Clinical Preventive Services (CPS) Guidelines for adults 50+. The control group received only the CPS education. Results The study sample consisted of 746 eligible Vietnamese American participants recruited from 20 community-based organizations, with 95% having limited English proficiency. At 12-month follow-up, the intervention group showed substantially higher rates of FIT completion (89.56% vs. 7.59%, p < .001) and any CRC testing (91.48% vs. 42.41%, p < .001) compared to the control group. Conclusion The results suggest that the community-based, culturally-tailored multilevel intervention, which incorporates with FIT self-testing, effectively enhances CRC screening among low-income Vietnamese Americans. Additionally, these results underscore the significance of community-oriented strategies, like collaborating with relevant community-based organizations, in achieving CRC screening targets.
摘要 目的 粪便免疫化学检验（FIT）是一种无创的结肠直肠癌（CRC）筛查方法，对筛查率低、服务不足的越南裔美国人社区尤为有效。本研究报告了一项结合 FIT 的文化定制多层次干预措施，旨在提高大费城都市区 50 岁或以上人群的 CRC 筛查率。方法 从 2017 年到 2020 年，我们开展了一项双臂群组随机对照试验，以检验文化定制的多成分多层次干预措施的效果，该干预措施旨在通过增强自我意识和自我效能、改善就医途径、改变社会规范和消除耻辱感来提高 CRC 筛查的接受率。干预组接受多成分、多层次的 CRC 干预，包括提供 FIT 自我采样包，干预方法参考了美国疾病控制中心的《50 岁以上成人临床预防服务（CPS）指南》。对照组只接受 CPS 教育。结果 研究样本包括从 20 个社区组织招募的 746 名符合条件的美籍越南人，其中 95% 的人英语水平有限。在 12 个月的随访中，干预组的 FIT 完成率（89.56% vs. 7.59%，p < .001）和任何 CRC 检测率（91.48% vs. 42.41%，p < .001）均大大高于对照组。结论 结果表明，以社区为基础、根据文化定制的多层次干预措施，结合 FIT 自我检测，有效地提高了低收入越裔美国人的 CRC 筛查率。此外，这些结果还强调了以社区为导向的策略（如与相关社区组织合作）对实现 CRC 筛查目标的重要意义。
{"title":"Multilevel and multicomponent intervention to promote colorectal cancer screening among underserved Vietnamese Americans: A cluster randomized trial","authors":"Grace X. Ma, Lin Zhu, Yin Tan, Phuong Do, Guercie Guerrier, Min Qi Wang, Minhhuyen Nguyen, Tam Tran, Philip Pham","doi":"10.21203/rs.3.rs-3934937/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3934937/v1","url":null,"abstract":"Abstract Purpose The fecal immunochemical test (FIT) is a non-invasive method for colorectal cancer (CRC) screening, particularly effective in underserved Vietnamese American communities with low screening rates. This study reports on a culturally tailored multilevel intervention, incorporating FIT, aimed at increasing CRC screening among these populations aged 50 or above in the Greater Philadelphia metropolitan area. Methods From 2017 to 2020, we conducted a two-arm cluster randomized controlled trial to test the efficacy of a culturally tailored, multicomponent multilevel intervention aimed at increasing CRC screening uptake via enhanced self-awareness and self-efficacy, improved access to care, and changes in social norms and removal of stigma. The intervention group received multicomponent, multilevel CRC intervention including provision of a FIT self-sampling kit, with intervention approaches informed by the Centers for Disease Control's Clinical Preventive Services (CPS) Guidelines for adults 50+. The control group received only the CPS education. Results The study sample consisted of 746 eligible Vietnamese American participants recruited from 20 community-based organizations, with 95% having limited English proficiency. At 12-month follow-up, the intervention group showed substantially higher rates of FIT completion (89.56% vs. 7.59%, p < .001) and any CRC testing (91.48% vs. 42.41%, p < .001) compared to the control group. Conclusion The results suggest that the community-based, culturally-tailored multilevel intervention, which incorporates with FIT self-testing, effectively enhances CRC screening among low-income Vietnamese Americans. Additionally, these results underscore the significance of community-oriented strategies, like collaborating with relevant community-based organizations, in achieving CRC screening targets.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"38 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965138","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 : 2024-02-08DOI: 10.21203/rs.3.rs-3918063/v1
P. Meyer-Kalos, Grace Owens, Melissa Fisher, Lionel Wininger, Anne Williams-Wengerd, Kimberleigh Breen, Josephine Abate, Ariel Currie, Nathan Olinger, Sophia Vinogradov
Abstract Background: Measurement-based care (MBC) is an effective tool in the delivery of evidence-based practices (EBPs). MBC utilizes feedback loops to share information and drive changes throughout a learning healthcare system. Few studies have demonstrated this practice in team-based care for people with early psychosis. This paper describes the development of a personalized feedback report derived from routine assessments that is shared with clients and clinicians as part of a MBC process. Methods: We used a quasi pre-post comparison design with mixed methods to evaluate the implementation of a personalized feedback report at 5 early psychosis coordinated specialty care programs (CSC). We compared clients enrolled in CSC who did and did not receive a feedback report over the first 6 months of treatment. The sample included 204 clients: 146 who did not receive the feedback report and were enrolled over 2 years, and 58 who received the feedback report. A subset of 67 clients completed measures at both intake and 6-month follow-up, including 42 who received the report and 25 who did not. We compared the two groups with regard to self-reported symptoms, likelihood of completing treatment, and perception of shared decision making. . We conducted qualitative interviews with 5 clients and 5 clinicians to identify the benefits and challenges associated with the personalized feedback report. Results: People who received a personalized feedback report reported significant improvements in shared decision-making and had greater improvements over time in their intent to attend future treatment sessions. They engaged in more sessions for Supported Employment and Education (SEE), case management, and peer support, and fewer medication visits over the first 6 months of treatment. Both groups showed significant improvement in symptoms and functioning. Results from the qualitative analysis indicated that the experience of receiving the reports was valuable and validating for both patients and clinicians. Conclusions: A personalized feedback report was integrated into standard of care for early psychosis programs. This process may improve shared decision-making, strengthen the likelihood to stay in treatment, and increase engagement in psychosocial interventions. We posit that this process facilitates strengths-focused discussions, enhances intrinsic motivation, and strengthens the therapeutic alliance.
{"title":"Putting measurement-based care into action: A mixed methods study of the benefits of integrating routine client feedback in coordinated specialty care programs for early psychosis","authors":"P. Meyer-Kalos, Grace Owens, Melissa Fisher, Lionel Wininger, Anne Williams-Wengerd, Kimberleigh Breen, Josephine Abate, Ariel Currie, Nathan Olinger, Sophia Vinogradov","doi":"10.21203/rs.3.rs-3918063/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3918063/v1","url":null,"abstract":"Abstract Background: Measurement-based care (MBC) is an effective tool in the delivery of evidence-based practices (EBPs). MBC utilizes feedback loops to share information and drive changes throughout a learning healthcare system. Few studies have demonstrated this practice in team-based care for people with early psychosis. This paper describes the development of a personalized feedback report derived from routine assessments that is shared with clients and clinicians as part of a MBC process. Methods: We used a quasi pre-post comparison design with mixed methods to evaluate the implementation of a personalized feedback report at 5 early psychosis coordinated specialty care programs (CSC). We compared clients enrolled in CSC who did and did not receive a feedback report over the first 6 months of treatment. The sample included 204 clients: 146 who did not receive the feedback report and were enrolled over 2 years, and 58 who received the feedback report. A subset of 67 clients completed measures at both intake and 6-month follow-up, including 42 who received the report and 25 who did not. We compared the two groups with regard to self-reported symptoms, likelihood of completing treatment, and perception of shared decision making. . We conducted qualitative interviews with 5 clients and 5 clinicians to identify the benefits and challenges associated with the personalized feedback report. Results: People who received a personalized feedback report reported significant improvements in shared decision-making and had greater improvements over time in their intent to attend future treatment sessions. They engaged in more sessions for Supported Employment and Education (SEE), case management, and peer support, and fewer medication visits over the first 6 months of treatment. Both groups showed significant improvement in symptoms and functioning. Results from the qualitative analysis indicated that the experience of receiving the reports was valuable and validating for both patients and clinicians. Conclusions: A personalized feedback report was integrated into standard of care for early psychosis programs. This process may improve shared decision-making, strengthen the likelihood to stay in treatment, and increase engagement in psychosocial interventions. We posit that this process facilitates strengths-focused discussions, enhances intrinsic motivation, and strengthens the therapeutic alliance.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"37 21","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965219","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 : 2024-02-08DOI: 10.21203/rs.3.rs-3911823/v1
Sumayiya Nalubega, P. Kutyabami, Adeline Twimukye, D. Mafigiri, Nelson K. Sewankambo
Abstract Background Informed consent (IC) is a fundamental principle in medical ethics that upholds respect for patient autonomy. Although widely applied in healthcare, its feasibility and implementation in herbal medicine have been underexplored. This study therefore aimed to explore the practices and attitudes of herbalists regarding informed consent. Methods To achieve these objectives, a qualitative cross-sectional study was conducted from June to December 2020. Twenty-one in-depth interviews with herbalists and four key informant interviews with leaders of the different traditional medicine organizations were also conducted. The data were analyzed thematically using NVivo version 12 software. Results Sixteen of the twenty-one participants acquired oral herbal medicine knowledge from their relatives. Although a positive inclination toward obtaining IC was evident, the focus was on disclosing basic information. Discussions of alternative treatments and herbal specifics less frequent. Disease management decisions often involve shared responsibility within families or societies. Documented IC procedures are rare among herbalists, who deem consent forms unnecessary, although they recognize the potential benefits of IC in fostering trust and professionalism. Challenges hindering IC implementation included regulatory gaps, inadequate skills, and the absence of mechanisms to protect the intellectual property rights of herbal medicine. Conclusion This study illuminates how educational, cultural, familial, and regulatory factors influence herbalists' practices and attitudes toward informed consent.
{"title":"Practices and attitudes of herbalists regarding informed consent in Uganda: A qualitative study","authors":"Sumayiya Nalubega, P. Kutyabami, Adeline Twimukye, D. Mafigiri, Nelson K. Sewankambo","doi":"10.21203/rs.3.rs-3911823/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3911823/v1","url":null,"abstract":"Abstract Background Informed consent (IC) is a fundamental principle in medical ethics that upholds respect for patient autonomy. Although widely applied in healthcare, its feasibility and implementation in herbal medicine have been underexplored. This study therefore aimed to explore the practices and attitudes of herbalists regarding informed consent. Methods To achieve these objectives, a qualitative cross-sectional study was conducted from June to December 2020. Twenty-one in-depth interviews with herbalists and four key informant interviews with leaders of the different traditional medicine organizations were also conducted. The data were analyzed thematically using NVivo version 12 software. Results Sixteen of the twenty-one participants acquired oral herbal medicine knowledge from their relatives. Although a positive inclination toward obtaining IC was evident, the focus was on disclosing basic information. Discussions of alternative treatments and herbal specifics less frequent. Disease management decisions often involve shared responsibility within families or societies. Documented IC procedures are rare among herbalists, who deem consent forms unnecessary, although they recognize the potential benefits of IC in fostering trust and professionalism. Challenges hindering IC implementation included regulatory gaps, inadequate skills, and the absence of mechanisms to protect the intellectual property rights of herbal medicine. Conclusion This study illuminates how educational, cultural, familial, and regulatory factors influence herbalists' practices and attitudes toward informed consent.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"39 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965128","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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