Pub Date : 2024-04-07DOI: 10.1101/2024.04.04.24305299
Gang Wang, Cedoljub Bundalovic-Torma, Sharanya Menon, Sabina Bruehlmann, Lynn Wilsack, Renata Rehak, Sahar Bagheri, Mohammad M. Banoei, Lawrence Lou, Yasmin Nasser, Matthew Woo, Ian Lewis, Kathy D. McCoy, Christopher N. Andrews
Objective The small intestine (SI) microbiome is increasingly implicated in both functional gastrointestinal (GI) disorders and a wide range of systemic diseases. However, owing to limitations of traditional GI sampling approaches, the SI remains challenging to directly access on a large scale. This work presents the Small Intestinal MicroBiome Aspiration Capsule (SIMBA) as an effective means for sampling SI luminal content.
{"title":"CLINICAL SAMPLING OF SMALL INTESTINE LUMINAL CONTENT FOR MICROBIOME MULTI-OMICS ANALYSIS: A PERFORMANCE ANALYSIS OF THE SMALL INTESTINE MICROBIOME ASPIRATION (SIMBA) CAPSULE AND BENCHMARKING AGAINST ENDOSCOPY","authors":"Gang Wang, Cedoljub Bundalovic-Torma, Sharanya Menon, Sabina Bruehlmann, Lynn Wilsack, Renata Rehak, Sahar Bagheri, Mohammad M. Banoei, Lawrence Lou, Yasmin Nasser, Matthew Woo, Ian Lewis, Kathy D. McCoy, Christopher N. Andrews","doi":"10.1101/2024.04.04.24305299","DOIUrl":"https://doi.org/10.1101/2024.04.04.24305299","url":null,"abstract":"<strong>Objective</strong> The small intestine (SI) microbiome is increasingly implicated in both functional gastrointestinal (GI) disorders and a wide range of systemic diseases. However, owing to limitations of traditional GI sampling approaches, the SI remains challenging to directly access on a large scale. This work presents the Small Intestinal MicroBiome Aspiration Capsule (SIMBA) as an effective means for sampling SI luminal content.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581493","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 : 2024-04-05DOI: 10.1101/2024.04.03.24305251
James Reigle, Oscar Lopez-Nunez, Erik Drysdale, Dua Abuquteish, Xiaoxuan Liu, Juan Putra, Lauren Erdman, Anne M. Griffiths, Surya Prasath, Iram Siddiqui, Jasbir Dhaliwal
Background Accurate identification of inflammatory cells from mucosal histopathology images is important in diagnosing ulcerative colitis. The identification of eosinophils in the colonic mucosa has been associated with disease course. Cell counting is not only time-consuming but can also be subjective to human biases. In this study we developed an automatic eosinophilic cell counting tool from mucosal histopathology images, using deep learning.
{"title":"Using Deep Learning to Automate Eosinophil Counting in Pediatric Ulcerative Colitis Histopathological Images","authors":"James Reigle, Oscar Lopez-Nunez, Erik Drysdale, Dua Abuquteish, Xiaoxuan Liu, Juan Putra, Lauren Erdman, Anne M. Griffiths, Surya Prasath, Iram Siddiqui, Jasbir Dhaliwal","doi":"10.1101/2024.04.03.24305251","DOIUrl":"https://doi.org/10.1101/2024.04.03.24305251","url":null,"abstract":"<strong>Background</strong> Accurate identification of inflammatory cells from mucosal histopathology images is important in diagnosing ulcerative colitis. The identification of eosinophils in the colonic mucosa has been associated with disease course. Cell counting is not only time-consuming but can also be subjective to human biases. In this study we developed an automatic eosinophilic cell counting tool from mucosal histopathology images, using deep learning.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"282 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581494","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 : 2024-04-03DOI: 10.1101/2024.04.02.24305212
Gang Wang, Sharanya Menon, Lynn Wilsack, Renata Rehak, Lawrence Lou, Christian Turbide, Jeremie Auger, Annie Tremblay, Olivier Mathieu, Sylvie Binda, Thomas A Tompkins, Sabina Bruehlmann, Christopher N Andrews
Few minimally invasive options for sampling the small intestinal (SI) luminal fluid exist to study the SI microbiota in health and disease. To address the lack of tools and methods to study GI regions that are difficult to access, Nimble Science developed a fully autonomous and passive sampling method, the Small Intestine MicroBiome Aspiration (SIMBATM) capsule, for convenient, high-quality, and reliable sampling to study the diet-microbiota interactions in the SI. The sealing efficacy and microbial DNA preservation capacity of the SIMBA capsules was first validated through in vitro simulation assays. Then, a clinical study was conducted with 20 healthy participants to validate the in vivo use of SIMBA capsules to reliably capture samples for SI microbiome analysis before and after an intervention (NCT04489329). Briefly, participants ingested the capsules at baseline and 7 days later, with a probiotic capsule containing a blend of L. rhamnosus R0011 and B. longum R0175. Following baseline SIMBA capsule ingestion, multiple low-dosage x-ray scans were performed to track the sampling location. Fecal samples corresponding with the baseline and intervention capsule were analyzed for comparison. The SIMBA capsules’ performance in vitro demonstrated the potential for contamination-free sampling with preservation of the microbial communities. Within the clinical study, the capsules performed safely and reliably for collection of SI content. X-ray tracking confirmed that 97.2% of the capsules completed sample collection in the SI regions before reaching the colon. Importantly, our data showed that the capsules sampled in the right area of the intestines and that baseline SIMBA microbiome profile is significantly different from fecal microbiome profile. SIMBA successfully detected a concurrent probiotic intervention in the small intestine, which was not detectable using stool samples. The high accuracy of sampling location and sealing efficacy of the SIMBA capsules makes them potentially useful research tools in clinical trials for studying diet-microbiota interactions in health and disease, and perhaps eventually for the clinical diagnosis of GI tract conditions affecting the SI such as SIBO.
在研究健康和疾病中的小肠微生物群时，几乎没有微创的小肠（SI）管腔液体采样方法。为了解决缺乏工具和方法来研究难以进入的消化道区域的问题，Nimble Science 公司开发了一种完全自主的被动采样方法--小肠微生物组抽吸（SIMBATM）胶囊，用于方便、高质量和可靠的采样，以研究小肠内饮食与微生物群之间的相互作用。首先通过体外模拟试验验证了 SIMBA 胶囊的密封效果和微生物 DNA 保存能力。然后，对 20 名健康参与者进行了一项临床研究，以验证在干预前后使用 SIMBA 胶囊可靠地采集样本用于 SI 微生物组分析（NCT04489329）。简而言之，参与者在基线和 7 天后分别摄入含有鼠李糖 R0011 和长球菌 R0175 混合菌株的益生菌胶囊。在基线摄入 SIMBA 胶囊后，进行了多次低剂量 X 射线扫描，以跟踪采样位置。对与基线胶囊和干预胶囊相对应的粪便样本进行分析比较。SIMBA 胶囊在体外的表现表明，它具有无污染采样和保存微生物群落的潜力。在临床研究中，胶囊在收集 SI 内容物方面的表现安全可靠。X 射线跟踪证实，97.2% 的胶囊在到达结肠前完成了 SI 区域的样本采集。重要的是，我们的数据显示，胶囊在肠道的正确区域采样，而且基线 SIMBA 微生物组图谱与粪便微生物组图谱有显著差异。SIMBA 成功检测到了小肠中同时存在的益生菌干预，而粪便样本则无法检测到。SIMBA 胶囊采样位置的高准确性和密封效果使其成为临床试验中有用的研究工具，用于研究饮食与微生物群在健康和疾病中的相互作用，并最终用于影响 SIBO 等消化道疾病的临床诊断。
{"title":"Spatially and Temporally Precise Microbiome Profiling in the Small Intestine using the SIMBA Capsule with X-ray tracking","authors":"Gang Wang, Sharanya Menon, Lynn Wilsack, Renata Rehak, Lawrence Lou, Christian Turbide, Jeremie Auger, Annie Tremblay, Olivier Mathieu, Sylvie Binda, Thomas A Tompkins, Sabina Bruehlmann, Christopher N Andrews","doi":"10.1101/2024.04.02.24305212","DOIUrl":"https://doi.org/10.1101/2024.04.02.24305212","url":null,"abstract":"Few minimally invasive options for sampling the small intestinal (SI) luminal fluid exist to study the SI microbiota in health and disease. To address the lack of tools and methods to study GI regions that are difficult to access, Nimble Science developed a fully autonomous and passive sampling method, the Small Intestine MicroBiome Aspiration (SIMBA<sup>TM</sup>) capsule, for convenient, high-quality, and reliable sampling to study the diet-microbiota interactions in the SI. The sealing efficacy and microbial DNA preservation capacity of the SIMBA capsules was first validated through <em>in vitro</em> simulation assays. Then, a clinical study was conducted with 20 healthy participants to validate the <em>in vivo</em> use of SIMBA capsules to reliably capture samples for SI microbiome analysis before and after an intervention (NCT04489329). Briefly, participants ingested the capsules at baseline and 7 days later, with a probiotic capsule containing a blend of <em>L. rhamnosus</em> R0011 and <em>B. longum</em> R0175. Following baseline SIMBA capsule ingestion, multiple low-dosage x-ray scans were performed to track the sampling location. Fecal samples corresponding with the baseline and intervention capsule were analyzed for comparison. The SIMBA capsules’ performance <em>in vitro</em> demonstrated the potential for contamination-free sampling with preservation of the microbial communities. Within the clinical study, the capsules performed safely and reliably for collection of SI content. X-ray tracking confirmed that 97.2% of the capsules completed sample collection in the SI regions before reaching the colon. Importantly, our data showed that the capsules sampled in the right area of the intestines and that baseline SIMBA microbiome profile is significantly different from fecal microbiome profile. SIMBA successfully detected a concurrent probiotic intervention in the small intestine, which was not detectable using stool samples. The high accuracy of sampling location and sealing efficacy of the SIMBA capsules makes them potentially useful research tools in clinical trials for studying diet-microbiota interactions in health and disease, and perhaps eventually for the clinical diagnosis of GI tract conditions affecting the SI such as SIBO.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"94 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581623","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 : 2024-03-26DOI: 10.1101/2024.03.23.24304787
Selena Chia, Tianruo Guo, Ewa M. Goldys, Sophie C. Payne, Nigel H. Lovell, Mohit N. Shivdasani, Fei Deng
Inflammatory bowel disease (IBD) is a chronic disorder associated with inflammation in the gastrointestinal tract, leading to a range of debilitating symptoms. Fecal calprotectin is an established biomarker for ulcerative colitis (UC), one of the main IBD diseases, which provides indications of the presence and severity of inflammation in the digestive tract. Enzyme-Linked Immunosorbent Assay (ELISA) as a gold standard approach for fecal calprotectin detection is time-consuming and impractical in point-of-care settings. Moreover, obtaining fecal samples from patients is challenging and inhibits longitudinal monitoring. To overcome these limitations, we designed a new approach for detecting calprotectin which leverages clustered regularly interspaced short palindromic repeats (CRISPR)/Cas technology. We successfully developed a portable tube-based CRISPR/Cas assay for point-of-care testing of calprotectin. This assay showed a detection range from 1-10000 ng/mL (over 4 log units), using both fluorescent and colorimetric analytical techniques. The established assay was further validated through measurements in mucosal samples obtained in an anesthetised preclinical rodent model of UC, with 2-3 times higher calprotectin concentration detected in UC rat samples compared to that of healthy control animals. This point-of-care test may provide a rapid, precise, and user-friendly approach for the diagnosis and monitoring of IBD through mucosal sample testing.
{"title":"A CRISPR mediated point-of-care assay for the detection of mucosal calprotectin in an animal model of ulcerative colitis","authors":"Selena Chia, Tianruo Guo, Ewa M. Goldys, Sophie C. Payne, Nigel H. Lovell, Mohit N. Shivdasani, Fei Deng","doi":"10.1101/2024.03.23.24304787","DOIUrl":"https://doi.org/10.1101/2024.03.23.24304787","url":null,"abstract":"Inflammatory bowel disease (IBD) is a chronic disorder associated with inflammation in the gastrointestinal tract, leading to a range of debilitating symptoms. Fecal calprotectin is an established biomarker for ulcerative colitis (UC), one of the main IBD diseases, which provides indications of the presence and severity of inflammation in the digestive tract. Enzyme-Linked Immunosorbent Assay (ELISA) as a gold standard approach for fecal calprotectin detection is time-consuming and impractical in point-of-care settings. Moreover, obtaining fecal samples from patients is challenging and inhibits longitudinal monitoring. To overcome these limitations, we designed a new approach for detecting calprotectin which leverages clustered regularly interspaced short palindromic repeats (CRISPR)/Cas technology. We successfully developed a portable tube-based CRISPR/Cas assay for point-of-care testing of calprotectin. This assay showed a detection range from 1-10000 ng/mL (over 4 log units), using both fluorescent and colorimetric analytical techniques. The established assay was further validated through measurements in mucosal samples obtained in an anesthetised preclinical rodent model of UC, with 2-3 times higher calprotectin concentration detected in UC rat samples compared to that of healthy control animals. This point-of-care test may provide a rapid, precise, and user-friendly approach for the diagnosis and monitoring of IBD through mucosal sample testing.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140298169","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 : 2024-03-26DOI: 10.1101/2024.03.21.24304701
ARNOLD W. LAMBISIA, Martin Mutunga, Esther N. Katama, Charles N Agoti, Charlotte J. Houldcroft
Background Although seven human adenovirus (HAdV) species are known to exist, only F (types 40 and 41) and G, are identified as diarrhoeal disease agents. The role of other HAdV species in diarrhoeal disease remains unclear and data of their prevalence is limited. We describe HAdV species and types in hospitalised children with diarrhoea in coastal Kenya. Methods 329 stool samples collected between June 2022 and August 2023 from children aged <13-years were screened for HAdV using quantitative polymerase chain reaction (qPCR). Positive HAdV cases were genotyped by adenovirus primers from the RespiCoV panel by amplification, next generation sequencing followed by phylogenetic analysis. Results 65 samples (20%) tested HadV positive from which five HAdV species were identified. Other than HAdV F, other species included A, B, C and D; these were detected as either mono-detections or coinfections. Six HAdV F identified by NGS had been missed by our q PCR typing method. This appeared to be as a result of a 133-nucleotide deletion in the long fiber protein which abrogated a primer and probe binding site. Based on VESIKARI scores grading of diarrhoeal disease severity, 93% of the HAdV cases presented with severe disease. One child with an HAdV F infection died. Conclusion Our study shows the enormous diversity and clinical characteristics of HAdV species in children with diarrhoea in coastal Kenya. These data offers an opportunity to improve current diagnostic assays, increase knowledge of HAdV in Africa for control of outbreaks in the future.
{"title":"Multi-species co-circulation of adenoviruses identified by next generation sequencing during an outbreak in coastal Kenya in 2023","authors":"ARNOLD W. LAMBISIA, Martin Mutunga, Esther N. Katama, Charles N Agoti, Charlotte J. Houldcroft","doi":"10.1101/2024.03.21.24304701","DOIUrl":"https://doi.org/10.1101/2024.03.21.24304701","url":null,"abstract":"Background\u0000Although seven human adenovirus (HAdV) species are known to exist, only F (types 40 and 41) and G, are identified as diarrhoeal disease agents. The role of other HAdV species in diarrhoeal disease remains unclear and data of their prevalence is limited. We describe HAdV species and types in hospitalised children with diarrhoea in coastal Kenya. Methods\u0000329 stool samples collected between June 2022 and August 2023 from children aged <13-years were screened for HAdV using quantitative polymerase chain reaction (qPCR). Positive HAdV cases were genotyped by adenovirus primers from the RespiCoV panel by amplification, next generation sequencing followed by phylogenetic analysis. Results\u000065 samples (20%) tested HadV positive from which five HAdV species were identified. Other than HAdV F, other species included A, B, C and D; these were detected as either mono-detections or coinfections. Six HAdV F identified by NGS had been missed by our q PCR typing method. This appeared to be as a result of a 133-nucleotide deletion in the long fiber protein which abrogated a primer and probe binding site. Based on VESIKARI scores grading of diarrhoeal disease severity, 93% of the HAdV cases presented with severe disease. One child with an HAdV F infection died. Conclusion\u0000Our study shows the enormous diversity and clinical characteristics of HAdV species in children with diarrhoea in coastal Kenya. These data offers an opportunity to improve current diagnostic assays, increase knowledge of HAdV in Africa for control of outbreaks in the future.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140298254","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 : 2024-03-21DOI: 10.1101/2024.03.20.24304332
Melina Thibault, Alan Barkun, Myriam Martel, Alton W. Russell
Background: Patients are referred for colonoscopy for symptom assessment, screening, and surveillance. Public health measures to mitigate the spread of the COVID−19 pandemic disrupted services and increased patient delays for colonoscopy services in Quebec. The differential impact of these interruptions by colonoscopy indication is largely unknown. Methods: Using 2018−2022 retrospective clinical data from two high-volume Montreal endoscopy centres and provincial administrative data, we characterized changes in colonoscopy wait times and the proportion of waitlisted patients who were delayed (wait time exceeded provincial guidelines) by procedure indication and demographics. We used regression to examine patient characteristics associated with delayed procedures during pre- and intra−COVID−19 periods. We used time series analysis to characterize trends in the proportion of waitlisted patients delayed. Results: The COVID-19−related public health measures resulted in record-high delays (median increase in wait times of 34−159% across indications). While older patients experienced longer wait times pre-pandemic, intra−COVID−19 wait times increased disproportionately for patients younger than 50. The proportion of waitlisted patients delayed peaked mid−2020 (56.9% for screening; 56.0% for symptom assessment patients). By early 2022, the proportion delayed had fallen to 37.3% for screening patients but remained at 53.8% for symptom assessment patients. Conclusions: In Quebec, intra-COVID-19 colonoscopy delays disproportionately impacted symptom assessment procedures and younger patients. Additional capacity or improved triaging may be needed to address persistent delays. Understanding the effects of the pandemic on colonoscopy services can help inform strategies to mitigate harms from on-going delays in Quebec.
{"title":"Impact of COVID-19 Pandemic on Colonoscopy Wait Times by Procedure Indication","authors":"Melina Thibault, Alan Barkun, Myriam Martel, Alton W. Russell","doi":"10.1101/2024.03.20.24304332","DOIUrl":"https://doi.org/10.1101/2024.03.20.24304332","url":null,"abstract":"Background: Patients are referred for colonoscopy for symptom assessment, screening, and surveillance. Public health measures to mitigate the spread of the COVID−19 pandemic disrupted services and increased patient delays for colonoscopy services in Quebec. The differential impact of these interruptions by colonoscopy indication is largely unknown. Methods: Using 2018−2022 retrospective clinical data from two high-volume Montreal endoscopy centres and provincial administrative data, we characterized changes in colonoscopy wait times and the proportion of waitlisted patients who were delayed (wait time exceeded provincial guidelines) by procedure indication and demographics. We used regression to examine patient characteristics associated with delayed procedures during pre- and intra−COVID−19 periods. We used time series analysis to characterize trends in the proportion of waitlisted patients delayed. Results: The COVID-19−related public health measures resulted in record-high delays (median increase in wait times of 34−159% across indications). While older patients experienced longer wait times pre-pandemic, intra−COVID−19 wait times increased disproportionately for patients younger than 50. The proportion of waitlisted patients delayed peaked mid−2020 (56.9% for screening; 56.0% for symptom assessment patients). By early 2022, the proportion delayed had fallen to 37.3% for screening patients but remained at 53.8% for symptom assessment patients. Conclusions: In Quebec, intra-COVID-19 colonoscopy delays disproportionately impacted symptom assessment procedures and younger patients. Additional capacity or improved triaging may be needed to address persistent delays. Understanding the effects of the pandemic on colonoscopy services can help inform strategies to mitigate harms from on-going delays in Quebec.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"221 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140205295","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}
Objective: Enteric nervous system dysfunction is linked to digestive and neurological disorders. Hirschsprung's disease (HSCR) is characterized by the loss of enteric neuron cells (ENCs) in the distal colon. Embryonic enteric neural crest cell (ENCC) migration defects contribute to HSCR development in some infants, but postnatal factors that regulate ENC fate are undetermined. We sought to establish how postnatal changes contribute to HSCR by profiling the colonic microenvironment of HSCR infants. Design: In this study, we recruited infants with HSCR, infants with anorectal malformations but normal ENC development (CT), and an group of age-matched healthy control subjects. Laboratory findings and clinical manifestations were recorded. Single-cell and spatial transcriptome sequencing were applied to colonic tissues from a sub-cohort of CT and HSCR infants. Patient specimens, a mouse model of neonatal ischemic enterocolitis, and Sox10 knockdown mouse (Sox10WT/MUT) were used to reveal the factors that leads to ENC loss in HSCR infants. Results: We discover that intestinal ischemia promotes CLDN1+ hypertrophic nerve trunk formation and ENC death. Mechanistically, ischemia leads to defective nitric oxide (NO) signaling in ENCs, which aggravates mitochondria damage and caspase-mediated apoptosis that can be ameliorated by a NO donor drug. Conclusion: We show that ischemia contributes to postnatal ENC loss in HSCR infants and suggest that NO donor drugs may alleviate ischemia-related ENC death.
{"title":"Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in Hirschsprung's disease","authors":"Deshu Xu, Weiwei Liang, Chaoting Lan, Lanying Li, Weiyong Zhong, Meng Yao, Xiaoyu Zuo, Jixiao Zeng, Wei Zhong, Qiang Wu, Andrew Lew, Wenhao Zhou, Huimin Xia, Fan Bai, Yuxia Zhang, Yan Zhang","doi":"10.1101/2024.03.14.24304192","DOIUrl":"https://doi.org/10.1101/2024.03.14.24304192","url":null,"abstract":"Objective: Enteric nervous system dysfunction is linked to digestive and neurological disorders. Hirschsprung's disease (HSCR) is characterized by the loss of enteric neuron cells (ENCs) in the distal colon. Embryonic enteric neural crest cell (ENCC) migration defects contribute to HSCR development in some infants, but postnatal factors that regulate ENC fate are undetermined. We sought to establish how postnatal changes contribute to HSCR by profiling the colonic microenvironment of HSCR infants. Design: In this study, we recruited infants with HSCR, infants with anorectal malformations but normal ENC development (CT), and an group of age-matched healthy control subjects. Laboratory findings and clinical manifestations were recorded. Single-cell and spatial transcriptome sequencing were applied to colonic tissues from a sub-cohort of CT and HSCR infants. Patient specimens, a mouse model of neonatal ischemic enterocolitis, and Sox10 knockdown mouse (Sox10WT/MUT) were used to reveal the factors that leads to ENC loss in HSCR infants. Results: We discover that intestinal ischemia promotes CLDN1+ hypertrophic nerve trunk formation and ENC death. Mechanistically, ischemia leads to defective nitric oxide (NO) signaling in ENCs, which aggravates mitochondria damage and caspase-mediated apoptosis that can be ameliorated by a NO donor drug.\u0000Conclusion: We show that ischemia contributes to postnatal ENC loss in HSCR infants and suggest that NO donor drugs may alleviate ischemia-related ENC death.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"111 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140167307","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 : 2024-03-16DOI: 10.1101/2024.03.15.24304354
Katarina B. Greer, Andrew E. Blum, Ashley L. Faulx, Erica M. Deming, Lauren L. Hricik, Hinnah Siddiqui, Brigid M. Wilson, Amitabh Chak
Background: While rates of Esophageal Adenocarcinoma (EAC) in the US continue to rise, many patients at risk of disease are not screened. EsoCheck (EC), a non-endoscopic esophageal balloon sampling device coupled with EsoGuard (EG), a DNA based screening assay, is an FDA-approved minimally invasive alternative to the traditional screening method of upper endoscopy. Aim: Aim To prospectively determine the diagnostic accuracy, tolerance, and acceptability of the EC/EG test in a screening population. Methods: We recruited Veterans who met the American College of Gastroenterology (ACG) Guideline criteria for endoscopic Barrett's Esophagus (BE) and EAC screening at Louis Stokes Cleveland Veteran Affairs Medical Center. All study participants completed unsedated EC guided distal esophageal sampling followed by a sedated esophagogastroduodenoscopy (EGD). Diagnostic yield of the EG assay and EGD was recorded and used in calculation of sensitivity and specificity of EC/EG in prospective screening. The abbreviated Spielberger State-Trait Anxiety Inventory (STAI-6) questionnaire was administered before and after completion of EC. Overall tolerance of EC sampling was evaluated on a 10-point Likert scale. Results: Results Esophageal cancer screening was accepted by 130/782 (16.6%) eligible veterans and we analyzed results of those who completed both screening tests (N = 124). Prevalence of BE/EAC among studied veterans was 12.9% (16/124), based on EGD. Sensitivity and specificity of EC/EG for EGD-detected BE/EAC were 92.9% (95% CI 66.1, 99.8) and 72.2% (95% CI 62.1, 80.8), respectively. Positive and negative predictive values were 32.5% (95% CI 18.6, 49.1) and 98.6% (95% CI 92.4, 100), respectively. Baseline STAI-6 scores were reflective of notable levels of anxiety among veterans in the peri-procedural setting. Mean post-procedure acceptability score for Esocheck test was 7.23 (SD 2.45). Conclusions: Conclusions Our data suggest excellent sensitivity and negative predictive value of EC/EG in a screening population of veterans, making this modality a powerful screening tool for BE and EAC.
背景：虽然美国食管腺癌（EAC）的发病率持续上升，但许多有患病风险的患者并未接受筛查。EsoCheck（EC）是一种非内镜食管球囊取样装置，与基于 DNA 的筛查化验 EsoGuard（EG）结合使用，是经美国 FDA 批准的微创检查方法，可替代传统的上内镜筛查方法。目的：旨在前瞻性地确定 EC/EG 检测在筛查人群中的诊断准确性、耐受性和可接受性。方法：我们在路易斯-斯托克斯-克利夫兰退伍军人事务医疗中心招募了符合美国胃肠病学院 (ACG) 内镜巴雷特食管 (BE) 和 EAC 筛查指南标准的退伍军人。所有参加研究的人员都在无镇静剂的情况下完成了 EC 引导下的食管远端取样，然后进行了镇静剂食管胃十二指肠镜检查 (EGD)。记录 EG 检测和 EGD 的诊断率，并用于计算前瞻性筛查中 EC/EG 的敏感性和特异性。在完成食管造影前后均进行了简短的斯皮尔伯格状态-行为焦虑量表（STAI-6）问卷调查。以 10 点李克特量表评估对 EC 抽样的总体耐受性。结果130/782（16.6%）名符合条件的退伍军人接受了食管癌筛查，我们分析了完成两项筛查的退伍军人（N = 124）的结果。根据胃肠道造影检查，所研究的退伍军人中BE/EAC的患病率为12.9%（16/124）。EC/EG对EGD检测出的BE/EAC的敏感性和特异性分别为92.9%（95% CI 66.1，99.8）和72.2%（95% CI 62.1，80.8）。阳性和阴性预测值分别为 32.5% (95% CI 18.6, 49.1) 和 98.6% (95% CI 92.4, 100)。基线 STAI-6 评分反映了退伍军人在手术前的显著焦虑水平。Esocheck测试的术后可接受性平均得分为7.23（标清2.45）。结论我们的数据表明，在退伍军人筛查人群中，EC/EG 具有极高的灵敏度和阴性预测价值，使其成为筛查 BE 和 EAC 的有力工具。
{"title":"Non-endoscopic screening for Barrett's esophagus and Esophageal Adenocarcinoma in at risk Veterans","authors":"Katarina B. Greer, Andrew E. Blum, Ashley L. Faulx, Erica M. Deming, Lauren L. Hricik, Hinnah Siddiqui, Brigid M. Wilson, Amitabh Chak","doi":"10.1101/2024.03.15.24304354","DOIUrl":"https://doi.org/10.1101/2024.03.15.24304354","url":null,"abstract":"Background: While rates of Esophageal Adenocarcinoma (EAC) in the US continue to rise, many patients at risk of disease are not screened. EsoCheck (EC), a non-endoscopic esophageal balloon sampling device coupled with EsoGuard (EG), a DNA based screening assay, is an FDA-approved minimally invasive alternative to the traditional screening method of upper endoscopy. Aim: Aim To prospectively determine the diagnostic accuracy, tolerance, and acceptability of the EC/EG test in a screening population. Methods: We recruited Veterans who met the American College of Gastroenterology (ACG) Guideline criteria for endoscopic Barrett's Esophagus (BE) and EAC screening at Louis Stokes Cleveland Veteran Affairs Medical Center. All study participants completed unsedated EC guided distal esophageal sampling followed by a sedated esophagogastroduodenoscopy (EGD). Diagnostic yield of the EG assay and EGD was recorded and used in calculation of sensitivity and specificity of EC/EG in prospective screening. The abbreviated Spielberger State-Trait Anxiety Inventory (STAI-6) questionnaire was administered before and after completion of EC. Overall tolerance of EC sampling was evaluated on a 10-point Likert scale. Results: Results Esophageal cancer screening was accepted by 130/782 (16.6%) eligible veterans and we analyzed results of those who completed both screening tests (N = 124). Prevalence of BE/EAC among studied veterans was 12.9% (16/124), based on EGD. Sensitivity and specificity of EC/EG for EGD-detected BE/EAC were 92.9% (95% CI 66.1, 99.8) and 72.2% (95% CI 62.1, 80.8), respectively. Positive and negative predictive values were 32.5% (95% CI 18.6, 49.1) and 98.6% (95% CI 92.4, 100), respectively. Baseline STAI-6 scores were reflective of notable levels of anxiety among veterans in the peri-procedural setting. Mean post-procedure acceptability score for Esocheck test was 7.23 (SD 2.45). Conclusions: Conclusions Our data suggest excellent sensitivity and negative predictive value of EC/EG in a screening population of veterans, making this modality a powerful screening tool for BE and EAC.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140154691","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 : 2024-03-16DOI: 10.1101/2024.03.15.24304344
Ekaterina Plys, Jean-Luc Bulliard, Aziz Chaouch, Marie-Anne Durand, Luuk van Duuren, Karen Brandle, Reto Auer, Florian Froehlich, Iris Lansdorp-Vogelaar, Douglas A Corley, Kevin Selby
Background & Aims: Colorectal cancer (CRC) screening relies primarily on colonoscopy and fecal immunochemical testing (FIT). Aligning utilization of these options with individual CRC risk (i.e. personalized screening) may maximize benefit with lower risks, individual burdens, and societal costs. We studied the effect of communicating personalized CRC risk and corresponding screening recommendations on appropriate screening uptake in an organized screening setting. Methods: Pilot randomized controlled trial among residents aged 50-69 years old not yet invited for screening in Vaud, Switzerland. The intervention was a mailed brochure communicating individual 15-year CRC risk and corresponding screening recommendation. The control group received a brochure comparing FIT and colonoscopy. The primary outcome was self-reported risk-appropriate screening (FIT if <3% risk, FIT or colonoscopy if ≥3% and <6%, colonoscopy if ≥6%), assessed by a mailed questionnaire at 6 months. A secondary outcome was overall screening uptake. Results: Of 5396 invitations, 1059 people responded (19%), of whom 258 were randomized to intervention and 257 to control materials (average 15-year risk 1.4% (SD 0.5), age 52.2 years (SD 2.2), 51% women). Risk-appropriate screening completion was 37% in the intervention group and 23% in the control group (absolute difference 14%, 95%CI 6%-22%, p<0.001). Overall screening uptake was 50% in the intervention and 49% in the control group (absolute difference 1%, 95CI -7%-10%, p=0.758). Conclusions: In a population not known to be at elevated CRC risk, brochures providing personalized CRC risk and screening recommendations improved risk-appropriate screening without impacting overall screening uptake. This approach could be helpful for aligning screening methods, risks, and benefits with cancer risk. Trial registration: Clinicaltrials.gov NCT05357508.
{"title":"Colorectal cancer screening based on predicted risk: a pilot randomized controlled trial","authors":"Ekaterina Plys, Jean-Luc Bulliard, Aziz Chaouch, Marie-Anne Durand, Luuk van Duuren, Karen Brandle, Reto Auer, Florian Froehlich, Iris Lansdorp-Vogelaar, Douglas A Corley, Kevin Selby","doi":"10.1101/2024.03.15.24304344","DOIUrl":"https://doi.org/10.1101/2024.03.15.24304344","url":null,"abstract":"Background & Aims: Colorectal cancer (CRC) screening relies primarily on colonoscopy and fecal immunochemical testing (FIT). Aligning utilization of these options with individual CRC risk (i.e. personalized screening) may maximize benefit with lower risks, individual burdens, and societal costs. We studied the effect of communicating personalized CRC risk and corresponding screening recommendations on appropriate screening uptake in an organized screening setting. Methods: Pilot randomized controlled trial among residents aged 50-69 years old not yet invited for screening in Vaud, Switzerland. The intervention was a mailed brochure communicating individual 15-year CRC risk and corresponding screening recommendation. The control group received a brochure comparing FIT and colonoscopy. The primary outcome was self-reported risk-appropriate screening (FIT if <3% risk, FIT or colonoscopy if ≥3% and <6%, colonoscopy if ≥6%), assessed by a mailed questionnaire at 6 months. A secondary outcome was overall screening uptake.\u0000Results: Of 5396 invitations, 1059 people responded (19%), of whom 258 were randomized to intervention and 257 to control materials (average 15-year risk 1.4% (SD 0.5), age 52.2 years (SD 2.2), 51% women). Risk-appropriate screening completion was 37% in the intervention group and 23% in the control group (absolute difference 14%, 95%CI 6%-22%, p<0.001). Overall screening uptake was 50% in the intervention and 49% in the control group (absolute difference 1%, 95CI -7%-10%, p=0.758).\u0000Conclusions: In a population not known to be at elevated CRC risk, brochures providing personalized CRC risk and screening recommendations improved risk-appropriate screening without impacting overall screening uptake. This approach could be helpful for aligning screening methods, risks, and benefits with cancer risk.\u0000Trial registration: Clinicaltrials.gov NCT05357508.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140154711","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 : 2024-03-15DOI: 10.1101/2024.03.14.24304260
Runhao Li, Saifei Liu, Kenny Yeo, Suzanne Edwards, Man Ying Li, Ryan Santos, Sima Kianpour Rad, Fangmeinuo Wu, Guy Maddern, Joanne Young, Yoko Tomita, Amanda Townsend, Kevin Fenix, Ehud Hauben, Timothy Price, Eric Smith
Secreted Frizzled-Related Protein 5 (SFRP5) modulates Wnt signalling pathways, affecting diverse biological processes. We assessed the diagnostic and prognostic value of circulating SFRP5 (cSFRP5) in colorectal cancer (CRC). Plasma cSFRP5 concentrations were measured using ELISA in healthy donors (n=133), individuals diagnosed with CRC (n=449), colorectal polyps (n=85), and medical conditions in other organs including cancer, inflammation, and benign states (n=64). Patients with CRC, polyps, and other conditions showed higher cSFRP5 levels than healthy individuals (p<0.0001). Receiver operating characteristic curves comparing healthy donors with medical conditions, polyps, and CRC were 0.814 (p<0.0001), 0.763 (p<0.0001), and 0.762 (p<0.0001), respectively. In CRC, cSFRP5 correlated with patient age (p<0.0001), tumour stage (p<0.0001), and histological differentiation (p=0.0273). Levels peaked in stage II versus I (p<0.0001), III (p=0.0007), or IV (p<0.0001), and were higher in stage III versus I (p=0.0007) and IV (p=0.0054), with no difference between I and IV. Elevated cSFRP5 levels predicted longer overall survival in stage II-III CRC (univariate: HR 1.82, 95% CI 1.02-3.26, p=0.024; multivariable: HR 2.34, 95% CI 1.12-4.88, p=0.015). This study confirms elevated cSFRP5 levels in CRC and reveals a correlation between elevated cSFRP5 and overall survival in stage II-III disease.
分泌型Frizzled相关蛋白5（SFRP5）可调节Wnt信号通路，影响多种生物过程。我们评估了循环 SFRP5（cSFRP5）在结直肠癌（CRC）中的诊断和预后价值。我们使用酶联免疫吸附法测定了健康捐献者（133 人）、确诊为 CRC 患者（449 人）、结直肠息肉患者（85 人）以及其他器官（包括癌症、炎症和良性状态）患者（64 人）的血浆 cSFRP5 浓度。与健康人相比，CRC、息肉和其他疾病患者的 cSFRP5 水平更高（p<0.0001）。将健康供体与病症、息肉和 CRC 进行比较的接收方操作特征曲线分别为 0.814（p<0.0001）、0.763（p<0.0001）和 0.762（p<0.0001）。在 CRC 中，cSFRP5 与患者年龄（p<0.0001）、肿瘤分期（p<0.0001）和组织学分化（p=0.0273）相关。在 II 期与 I 期（p<0.0001）、III 期（p=0.0007）或 IV 期（p<0.0001）相比，cSFRP5 水平达到峰值，III 期与 I 期（p=0.0007）和 IV 期（p=0.0054）相比，cSFRP5 水平更高，I 期与 IV 期之间没有差异。cSFRP5 水平升高预示着 II-III 期 CRC 的总生存期更长（单变量：HR 1.82，95% CI 1.02-3.26，p=0.024；多变量：HR 2.34，95% CI 1.02-3.26，p=0.024：HR 2.34，95% CI 1.12-4.88，p=0.015）。本研究证实了 CRC 中 cSFRP5 水平的升高，并揭示了 cSFRP5 升高与 II-III 期疾病总生存率之间的相关性。
{"title":"Circulating SFRP5 levels are elevated in colorectal cancer and correlate with overall survival in stage II-III disease","authors":"Runhao Li, Saifei Liu, Kenny Yeo, Suzanne Edwards, Man Ying Li, Ryan Santos, Sima Kianpour Rad, Fangmeinuo Wu, Guy Maddern, Joanne Young, Yoko Tomita, Amanda Townsend, Kevin Fenix, Ehud Hauben, Timothy Price, Eric Smith","doi":"10.1101/2024.03.14.24304260","DOIUrl":"https://doi.org/10.1101/2024.03.14.24304260","url":null,"abstract":"Secreted Frizzled-Related Protein 5 (SFRP5) modulates Wnt signalling pathways, affecting diverse biological processes. We assessed the diagnostic and prognostic value of circulating SFRP5 (cSFRP5) in colorectal cancer (CRC). Plasma cSFRP5 concentrations were measured using ELISA in healthy donors (n=133), individuals diagnosed with CRC (n=449), colorectal polyps (n=85), and medical conditions in other organs including cancer, inflammation, and benign states (n=64). Patients with CRC, polyps, and other conditions showed higher cSFRP5 levels than healthy individuals (p<0.0001). Receiver operating characteristic curves comparing healthy donors with medical conditions, polyps, and CRC were 0.814 (p<0.0001), 0.763 (p<0.0001), and 0.762 (p<0.0001), respectively. In CRC, cSFRP5 correlated with patient age (p<0.0001), tumour stage (p<0.0001), and histological differentiation (p=0.0273). Levels peaked in stage II versus I (p<0.0001), III (p=0.0007), or IV (p<0.0001), and were higher in stage III versus I (p=0.0007) and IV (p=0.0054), with no difference between I and IV. Elevated cSFRP5 levels predicted longer overall survival in stage II-III CRC (univariate: HR 1.82, 95% CI 1.02-3.26, p=0.024; multivariable: HR 2.34, 95% CI 1.12-4.88, p=0.015). This study confirms elevated cSFRP5 levels in CRC and reveals a correlation between elevated cSFRP5 and overall survival in stage II-III disease.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140154647","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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