Pub Date : 2024-08-12DOI: 10.1101/2024.08.11.24311846
M. Mori, Y. Mori, Nakao Yuki, Shintaro Mandai, T. Fujiki, Hiroaki Kikuchi, Fumiaki Ando, K. Susa, Takayasu Mori, Y. Waseda, S. Yoshida, Y. Fujii, E. Sohara, Shinichi Uchida
Introduction: Organoids are miniature organs produced by newly emerging technologies. Kidney organoids originated from human inducible pluripotent stem cells (iPSCs) were developed to recapitulate renal diseases. However, producing iPSC kidney organoids from multiple individuals at the same time and in a uniform condition is still impossible. Here, we report adult renal tubular organoids, "tubuloids", established from primary renal epithelial cells from multiple human individuals in a uniform manner. Methods: Kidneys obtained from patients due to the surgery for malignancy were minced into small pieces, and primary renal epithelial tubule cells are cultured. 4 patients had normal kidney function and 4 had mild chronic kidney disease (CKD). Growth factors were added to the primary cultured cells at the same time and Matrigel was added to these 8 lines. Results: Primary cultured renal epithelial cells from normal kidneys showed a large number of fine, swollen epithelial appearance. On the other hand, primary cultured kidney epithelial cells from mild CKD kidneys were smaller and slightly elongated than those of normal kidneys. The growth speed was faster in normal kidney cells than in mild CKD cells. At the beginning of the three-dimensionalization (day 0), normal renal tubuloids grew faster than mild CKD tubuloids. The difference in size between normal tubuloids and mild CKD ones became less noticeable on day 5. Both types of tubuloids reached almost same size on day 10. All 8 strains are of different human origin, and uniform tubuloids could be produced at the same time and in a uniform protocol. Conclusion: In terms of pathological models, the differences between mouse models and humans cannot be ignored, and there is a great need for a more human-like model of human pathology from both medical and research perspectives. Our renal tubular organoids can be produced in a uniform manner at the same time. It is expected to be used as a new type of convenient human pathological model.
{"title":"Adult renal tubular organoids can be produced from different human individuals in a completely same protocol","authors":"M. Mori, Y. Mori, Nakao Yuki, Shintaro Mandai, T. Fujiki, Hiroaki Kikuchi, Fumiaki Ando, K. Susa, Takayasu Mori, Y. Waseda, S. Yoshida, Y. Fujii, E. Sohara, Shinichi Uchida","doi":"10.1101/2024.08.11.24311846","DOIUrl":"https://doi.org/10.1101/2024.08.11.24311846","url":null,"abstract":"Introduction: Organoids are miniature organs produced by newly emerging technologies. Kidney organoids originated from human inducible pluripotent stem cells (iPSCs) were developed to recapitulate renal diseases. However, producing iPSC kidney organoids from multiple individuals at the same time and in a uniform condition is still impossible. Here, we report adult renal tubular organoids, \"tubuloids\", established from primary renal epithelial cells from multiple human individuals in a uniform manner. Methods: Kidneys obtained from patients due to the surgery for malignancy were minced into small pieces, and primary renal epithelial tubule cells are cultured. 4 patients had normal kidney function and 4 had mild chronic kidney disease (CKD). Growth factors were added to the primary cultured cells at the same time and Matrigel was added to these 8 lines. Results: Primary cultured renal epithelial cells from normal kidneys showed a large number of fine, swollen epithelial appearance. On the other hand, primary cultured kidney epithelial cells from mild CKD kidneys were smaller and slightly elongated than those of normal kidneys. The growth speed was faster in normal kidney cells than in mild CKD cells. At the beginning of the three-dimensionalization (day 0), normal renal tubuloids grew faster than mild CKD tubuloids. The difference in size between normal tubuloids and mild CKD ones became less noticeable on day 5. Both types of tubuloids reached almost same size on day 10. All 8 strains are of different human origin, and uniform tubuloids could be produced at the same time and in a uniform protocol. Conclusion: In terms of pathological models, the differences between mouse models and humans cannot be ignored, and there is a great need for a more human-like model of human pathology from both medical and research perspectives. Our renal tubular organoids can be produced in a uniform manner at the same time. It is expected to be used as a new type of convenient human pathological model.","PeriodicalId":18505,"journal":{"name":"medRxiv","volume":"11 35","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919455","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 : 2024-08-12DOI: 10.1101/2024.08.12.24311730
Charles Whittaker, Gregory Barnsley, D. Mesa, D. Laydon, Chee Wah Tan, Feng Zhu, Rob Johnson, P. Doohan, G. Nedjati-Gilani, P. Winskill, Alexandra B. Hogan, A. Deol, Christinah Mukandavire, Katharina Hauck, David Chien, Boon Lye, Lin-Fa Wang, Oliver J Watson, Azra C Ghani
COVID-19 has underscored the need for more timely access to vaccines during future pandemics. This has motivated development of broad-spectrum vaccines providing protection against viral families, which could be stockpiled ahead of an outbreak and deployed rapidly following detection. We use mathematical modelling to evaluate the utility of a broadly protective sarbecovirus vaccine (BPSV) during a hypothetical SARS-X outbreak, including ring-vaccination, spatial targeting and mass vaccination of high-risk populations. Our results show BPSV ring- or spatially-targeted vaccination strategies are unlikely to contain a SARS-CoV-2-like virus but could contain or slow the spread of a SARS-CoV-1-like virus. Vaccination of high-risk populations with the BPSV ahead of a virus-specific vaccine (VSV) becoming available could substantially reduce mortality. For a 250-day VSV development timeline, BPSV availability reduced infection-related deaths in our model by 54% on average, though exact impact depended on the non-pharmaceutical intervention (NPI) scenario considered. We further show that BPSV availability enables shorter and less stringent NPIs to be imposed whilst limiting disease burden to that observed in the VSV-only scenario, though results are sensitive to vaccine properties (e.g. efficacy), health system capabilities (e.g. vaccination rollout speed) and the assumed timeline to VSV availability. Our modelling suggests that availability of a BPSV for those aged 60+ years could have averted 40-65% of COVID-19 deaths during the pandemic's first year, though exact impact depends on the size of the maintained stockpile. Our work highlights significant potential impact of a BPSV, but that achieving this impact depends on investment into health systems enabling rapid and equitable access during future SARS-X pandemics.
{"title":"Quantifying the impact of a broadly protective sarbecovirus vaccine in a future SARS-X pandemic","authors":"Charles Whittaker, Gregory Barnsley, D. Mesa, D. Laydon, Chee Wah Tan, Feng Zhu, Rob Johnson, P. Doohan, G. Nedjati-Gilani, P. Winskill, Alexandra B. Hogan, A. Deol, Christinah Mukandavire, Katharina Hauck, David Chien, Boon Lye, Lin-Fa Wang, Oliver J Watson, Azra C Ghani","doi":"10.1101/2024.08.12.24311730","DOIUrl":"https://doi.org/10.1101/2024.08.12.24311730","url":null,"abstract":"COVID-19 has underscored the need for more timely access to vaccines during future pandemics. This has motivated development of broad-spectrum vaccines providing protection against viral families, which could be stockpiled ahead of an outbreak and deployed rapidly following detection. We use mathematical modelling to evaluate the utility of a broadly protective sarbecovirus vaccine (BPSV) during a hypothetical SARS-X outbreak, including ring-vaccination, spatial targeting and mass vaccination of high-risk populations. Our results show BPSV ring- or spatially-targeted vaccination strategies are unlikely to contain a SARS-CoV-2-like virus but could contain or slow the spread of a SARS-CoV-1-like virus. Vaccination of high-risk populations with the BPSV ahead of a virus-specific vaccine (VSV) becoming available could substantially reduce mortality. For a 250-day VSV development timeline, BPSV availability reduced infection-related deaths in our model by 54% on average, though exact impact depended on the non-pharmaceutical intervention (NPI) scenario considered. We further show that BPSV availability enables shorter and less stringent NPIs to be imposed whilst limiting disease burden to that observed in the VSV-only scenario, though results are sensitive to vaccine properties (e.g. efficacy), health system capabilities (e.g. vaccination rollout speed) and the assumed timeline to VSV availability. Our modelling suggests that availability of a BPSV for those aged 60+ years could have averted 40-65% of COVID-19 deaths during the pandemic's first year, though exact impact depends on the size of the maintained stockpile. Our work highlights significant potential impact of a BPSV, but that achieving this impact depends on investment into health systems enabling rapid and equitable access during future SARS-X pandemics.","PeriodicalId":18505,"journal":{"name":"medRxiv","volume":"41 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919196","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 : 2024-08-12DOI: 10.1101/2024.08.11.24311833
A. Arzanipour
Heart disease remains a leading cause of mortality worldwide, necessitating robust methods for its early detection and intervention. This study employs a comprehensive approach to identify and analyze critical features contributing to heart disease. Using a dataset of 270 patients, three well-known feature importance techniques--Boruta, Information Gain, and Lasso Regression--are applied to determine the top five features for heart disease detection. Following the identification of these key features, the g-computation method, a causal inference technique, is utilized to explore the causal relationships between these features and the presence of heart disease. The findings provide valuable insights into not only the features that are highly correlated with chronic heart disease but also those that have a direct causal impact on the classification of patients. This integrated approach enhances the understanding of heart disease etiology and can inform more effective diagnostic and therapeutic strategies.
{"title":"Integrating feature importance techniques and causal inference to enhance early detection of heart disease","authors":"A. Arzanipour","doi":"10.1101/2024.08.11.24311833","DOIUrl":"https://doi.org/10.1101/2024.08.11.24311833","url":null,"abstract":"Heart disease remains a leading cause of mortality worldwide, necessitating robust methods for its early detection and intervention. This study employs a comprehensive approach to identify and analyze critical features contributing to heart disease. Using a dataset of 270 patients, three well-known feature importance techniques--Boruta, Information Gain, and Lasso Regression--are applied to determine the top five features for heart disease detection. Following the identification of these key features, the g-computation method, a causal inference technique, is utilized to explore the causal relationships between these features and the presence of heart disease. The findings provide valuable insights into not only the features that are highly correlated with chronic heart disease but also those that have a direct causal impact on the classification of patients. This integrated approach enhances the understanding of heart disease etiology and can inform more effective diagnostic and therapeutic strategies.","PeriodicalId":18505,"journal":{"name":"medRxiv","volume":"6 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919936","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 : 2024-08-12DOI: 10.1101/2024.08.11.24311833
A. Arzanipour
Heart disease remains a leading cause of mortality worldwide, necessitating robust methods for its early detection and intervention. This study employs a comprehensive approach to identify and analyze critical features contributing to heart disease. Using a dataset of 270 patients, three well-known feature importance techniques--Boruta, Information Gain, and Lasso Regression--are applied to determine the top five features for heart disease detection. Following the identification of these key features, the g-computation method, a causal inference technique, is utilized to explore the causal relationships between these features and the presence of heart disease. The findings provide valuable insights into not only the features that are highly correlated with chronic heart disease but also those that have a direct causal impact on the classification of patients. This integrated approach enhances the understanding of heart disease etiology and can inform more effective diagnostic and therapeutic strategies.
{"title":"Integrating feature importance techniques and causal inference to enhance early detection of heart disease","authors":"A. Arzanipour","doi":"10.1101/2024.08.11.24311833","DOIUrl":"https://doi.org/10.1101/2024.08.11.24311833","url":null,"abstract":"Heart disease remains a leading cause of mortality worldwide, necessitating robust methods for its early detection and intervention. This study employs a comprehensive approach to identify and analyze critical features contributing to heart disease. Using a dataset of 270 patients, three well-known feature importance techniques--Boruta, Information Gain, and Lasso Regression--are applied to determine the top five features for heart disease detection. Following the identification of these key features, the g-computation method, a causal inference technique, is utilized to explore the causal relationships between these features and the presence of heart disease. The findings provide valuable insights into not only the features that are highly correlated with chronic heart disease but also those that have a direct causal impact on the classification of patients. This integrated approach enhances the understanding of heart disease etiology and can inform more effective diagnostic and therapeutic strategies.","PeriodicalId":18505,"journal":{"name":"medRxiv","volume":"20 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919170","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 : 2024-08-12DOI: 10.1101/2024.08.11.24311826
Adenike Oluwakemi, PhD. Ogah. PhD, Dr Chrispin Mwando, Dr Kenneth Chanda, Dr Selia Nganjo
Background Limited data is available regarding the prevalence of neonatal anemia and its associated risk factors in areas with constrained resources. Subject and methods In a cross-sectional study, data pertaining to socio-demographic and clinical characteristics of 489 mother-singleton, term newborn pairs were consecutively collected from the admission wards of six public hospitals in Lusaka. The information was then analyzed to determine the prevalence of newborn anemia and its associated risk factors. Newborn and maternal anemia were defined as hemoglobin levels below 15g/dl and 11g/dl, respectively. The relationship between the variables was explored using Chi-square tests and a binary logistic regression model. The findings were reported in terms of p-values, odds ratios, and 95% confidence intervals. Results The prevalence of anemia and severe anemia in newborns was 72.4% and 2.5% respectively, while in mothers it was 30.5% and 14.7% respectively. Delayed cord clamping was performed in 71.4% of the deliveries, and 86.5% of newborns had their hemoglobin levels estimated between 4-6 hours after birth. Maternal pre-delivery hemoglobin data were obtained from the hospital records of 246 (49.7%) out of the 489 mothers in the study. The majority (63.4%) of maternal hemoglobin levels were determined more than 4 weeks before delivery, and this infrequent hemoglobin assessment was significantly associated with newborn anemia (p<0.001; OR 3.60; 95% CI 1.81, 7.14). Additionally, 11% of the 489 mothers had underlying medical conditions, which were also significantly associated with newborn anemia (p=0.019; OR=2.96; [95%CI 1.20, 7.32]). The top three maternal medical conditions were HIV (35.2%), hypertension (25.9%), and Hepatitis B virus infection (13%). Maternal age was significantly associated with newborn anemia, with teenage pregnancy posing the highest risk (93.8%; p<0.001; OR 5.68; [95%CI 1.94, 16.60]). Furthermore, primiparous (p<0.001; OR 5.46 [95% CI 2.02, 14.93]), para 2 (p=0.014; OR=2.11 [95% CI 1.16, 3.83]), and multiparous (p=0.009; OR=4.77; [95% CI 1.48, 15.35]) mothers were more likely to produce anemic newborns compared to other parity. Newborns born before 40 weeks gestation were 3.11 times (95% CI 1.75, 5.52) more likely to have anemia, p<0.001, compared to full-term babies. Normal birthweight babies were less likely to become anemic compared to low birthweight babies (p=0.003; OR=0.31 [95% CI 0.14, 0.68]). Conclusion Enhanced antenatal care for pregnant mothers in resource-limited settings is essential, with particular focus on maternal hemoglobin, nutrition, and medical conditions. Attention should also be given to teenage pregnancy, primiparous and multiparous mothers, as well as preterm and low birthweight babies, to prevent newborn anemia and consequently reduce infant morbidity and mortality.
背景 在资源有限的地区，有关新生儿贫血患病率及其相关风险因素的数据十分有限。研究对象和方法 在一项横断面研究中，研究人员从卢萨卡六家公立医院的入院病房中连续收集了 489 对母亲-胎儿、足月新生儿的社会人口学和临床特征数据。然后对这些信息进行分析，以确定新生儿贫血症的发病率及其相关风险因素。新生儿和产妇贫血分别定义为血红蛋白水平低于 15g/dl 和 11g/dl。利用卡方检验和二元逻辑回归模型探讨了变量之间的关系。研究结果以 p 值、几率比和 95% 置信区间表示。结果 新生儿贫血和严重贫血的发生率分别为 72.4% 和 2.5%，而母亲贫血和严重贫血的发生率分别为 30.5% 和 14.7%。71.4%的分娩延迟了脐带夹闭，86.5%的新生儿在出生后 4-6 小时内进行了血红蛋白水平评估。在 489 名产妇中，有 246 名（49.7%）产妇的分娩前血红蛋白数据来自医院记录。大多数（63.4%）产妇的血红蛋白水平是在分娩前 4 周以上测定的，而这种不频繁的血红蛋白评估与新生儿贫血有显著关联（P<0.001；OR 3.60；95% CI 1.81，7.14）。此外，489 位母亲中有 11% 的人患有基础疾病，这也与新生儿贫血显著相关（p=0.019；OR=2.96；[95%CI 1.20，7.32]）。产妇的前三种疾病分别是艾滋病（35.2%）、高血压（25.9%）和乙型肝炎病毒感染（13%）。产妇年龄与新生儿贫血密切相关，其中少女怀孕的风险最高（93.8%；P<0.001；OR 5.68；[95%CI 1.94，16.60]）。此外，初产妇（p<0.001；OR 5.46 [95% CI 2.02，14.93]）、二产妇（p=0.014；OR=2.11 [95% CI 1.16，3.83]）和多产妇（p=0.009；OR=4.77；[95% CI 1.48，15.35]）与其他产次的母亲相比，更容易生出贫血的新生儿。与足月儿相比，妊娠 40 周前出生的新生儿患贫血症的几率是足月儿的 3.11 倍（95% CI 1.75，5.52），P<0.001。与低出生体重儿相比，正常出生体重儿贫血的几率较低（P=0.003；OR=0.31 [95% CI 0.14, 0.68]）。结论 在资源有限的环境中，加强对孕妇的产前保健至关重要，尤其要关注孕妇的血红蛋白、营养和医疗状况。还应关注少女怀孕、初产妇和多产妇以及早产儿和低出生体重儿，以预防新生儿贫血，从而降低婴儿发病率和死亡率。
{"title":"Factors determining hemoglobin levels in vaginally delivered term newborns at public hospitals in Lusaka, Zambia","authors":"Adenike Oluwakemi, PhD. Ogah. PhD, Dr Chrispin Mwando, Dr Kenneth Chanda, Dr Selia Nganjo","doi":"10.1101/2024.08.11.24311826","DOIUrl":"https://doi.org/10.1101/2024.08.11.24311826","url":null,"abstract":"Background Limited data is available regarding the prevalence of neonatal anemia and its associated risk factors in areas with constrained resources. Subject and methods In a cross-sectional study, data pertaining to socio-demographic and clinical characteristics of 489 mother-singleton, term newborn pairs were consecutively collected from the admission wards of six public hospitals in Lusaka. The information was then analyzed to determine the prevalence of newborn anemia and its associated risk factors. Newborn and maternal anemia were defined as hemoglobin levels below 15g/dl and 11g/dl, respectively. The relationship between the variables was explored using Chi-square tests and a binary logistic regression model. The findings were reported in terms of p-values, odds ratios, and 95% confidence intervals. Results The prevalence of anemia and severe anemia in newborns was 72.4% and 2.5% respectively, while in mothers it was 30.5% and 14.7% respectively. Delayed cord clamping was performed in 71.4% of the deliveries, and 86.5% of newborns had their hemoglobin levels estimated between 4-6 hours after birth. Maternal pre-delivery hemoglobin data were obtained from the hospital records of 246 (49.7%) out of the 489 mothers in the study. The majority (63.4%) of maternal hemoglobin levels were determined more than 4 weeks before delivery, and this infrequent hemoglobin assessment was significantly associated with newborn anemia (p<0.001; OR 3.60; 95% CI 1.81, 7.14). Additionally, 11% of the 489 mothers had underlying medical conditions, which were also significantly associated with newborn anemia (p=0.019; OR=2.96; [95%CI 1.20, 7.32]). The top three maternal medical conditions were HIV (35.2%), hypertension (25.9%), and Hepatitis B virus infection (13%). Maternal age was significantly associated with newborn anemia, with teenage pregnancy posing the highest risk (93.8%; p<0.001; OR 5.68; [95%CI 1.94, 16.60]). Furthermore, primiparous (p<0.001; OR 5.46 [95% CI 2.02, 14.93]), para 2 (p=0.014; OR=2.11 [95% CI 1.16, 3.83]), and multiparous (p=0.009; OR=4.77; [95% CI 1.48, 15.35]) mothers were more likely to produce anemic newborns compared to other parity. Newborns born before 40 weeks gestation were 3.11 times (95% CI 1.75, 5.52) more likely to have anemia, p<0.001, compared to full-term babies. Normal birthweight babies were less likely to become anemic compared to low birthweight babies (p=0.003; OR=0.31 [95% CI 0.14, 0.68]). Conclusion Enhanced antenatal care for pregnant mothers in resource-limited settings is essential, with particular focus on maternal hemoglobin, nutrition, and medical conditions. Attention should also be given to teenage pregnancy, primiparous and multiparous mothers, as well as preterm and low birthweight babies, to prevent newborn anemia and consequently reduce infant morbidity and mortality.","PeriodicalId":18505,"journal":{"name":"medRxiv","volume":"8 45","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919500","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 : 2024-08-12DOI: 10.1101/2024.08.12.24311345
Joakim B. Stenbäck, Daniel Schmidt, Ulrika Noborg, Joel Gustafsson, Peter Norberg, Maria E Andersson, Michael X Fu, Heli Harvala, Johan Ringlander
Deep sequencing of the whole hepatitis B virus genome increases the analytical resolution and has the potential to improve molecular epidemiology investigations. The aim of this work was to develop and evaluate the performance of such deep sequencing using the Nanopore technology. The method includes an initial PCR step to generate two overlapping amplicons that cover the whole HBV genome, followed by sequencing using the Nanopore rapid barcoding kit that allows parallel analysis of several samples in one reaction. The libraries can be sequenced with the standard Nanopore flow cell on MiniIon or GridIon devices, as well as the Flongle. The performance of the method was evaluated by comparing Nanopore and Sanger sequences or qPCR results from 64 clinical samples. The Nanopore-derived consensus sequences were, on average, 99.9% similar to those from Sanger sequencing and the full HBV genome was determined in samples with HBV DNA levels of approximately 3 log10 IU/mL with MagNA pure 96 extraction and < 2 log10 IU/mL using a high-volume manual extraction protocol on a subset of samples from patients with very low viral load (1.62-3.74 IU/mL). A perfect agreement with Sanger/qPCR-derived genotype was seen. The cost of sequencing per genome using the Nanopore method is low, ranging of 6-37 euros. We conclude that whole-genome sequencing of HBV with Nanopore is well suited for genomic characterization, antiviral resistance mutation analysis and genotyping of HBV in a routine laboratory setting
{"title":"Accurate and cost-efficient whole genome sequencing of hepatitis B virus using Nanopore","authors":"Joakim B. Stenbäck, Daniel Schmidt, Ulrika Noborg, Joel Gustafsson, Peter Norberg, Maria E Andersson, Michael X Fu, Heli Harvala, Johan Ringlander","doi":"10.1101/2024.08.12.24311345","DOIUrl":"https://doi.org/10.1101/2024.08.12.24311345","url":null,"abstract":"Deep sequencing of the whole hepatitis B virus genome increases the analytical resolution and has the potential to improve molecular epidemiology investigations. The aim of this work was to develop and evaluate the performance of such deep sequencing using the Nanopore technology. The method includes an initial PCR step to generate two overlapping amplicons that cover the whole HBV genome, followed by sequencing using the Nanopore rapid barcoding kit that allows parallel analysis of several samples in one reaction. The libraries can be sequenced with the standard Nanopore flow cell on MiniIon or GridIon devices, as well as the Flongle. The performance of the method was evaluated by comparing Nanopore and Sanger sequences or qPCR results from 64 clinical samples. The Nanopore-derived consensus sequences were, on average, 99.9% similar to those from Sanger sequencing and the full HBV genome was determined in samples with HBV DNA levels of approximately 3 log10 IU/mL with MagNA pure 96 extraction and < 2 log10 IU/mL using a high-volume manual extraction protocol on a subset of samples from patients with very low viral load (1.62-3.74 IU/mL). A perfect agreement with Sanger/qPCR-derived genotype was seen. The cost of sequencing per genome using the Nanopore method is low, ranging of 6-37 euros. We conclude that whole-genome sequencing of HBV with Nanopore is well suited for genomic characterization, antiviral resistance mutation analysis and genotyping of HBV in a routine laboratory setting","PeriodicalId":18505,"journal":{"name":"medRxiv","volume":"8 41","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919503","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 : 2024-08-12DOI: 10.1101/2024.08.12.24311851
Ali N. M. Gubran¹ Naif, Mohammed Al-Haidary², Marwa Faisal, M. Bajubair³, Afrah Mohsen, Ali Algibary³, Manal Galeb, Mhmad Ali³, Marwa Fuad, Othman Ali³, Naif Mohammed Al-Haidary
Background: Intestinal parasite infection is a significant public health problem worldwide. This study aimed to determine the prevalence of intestinal parasites among primary school children, identify the most common types of parasites, and identify the risk factors contributing to infection in Aden, Yemen. Methodology/Principal Findings: An analytical cross-sectional study was conducted on 201 school children in Aden, Yemen. Stool specimens were collected and tested using direct methods (saline and iodine preparations) and sedimentation concentration techniques. Data analysis was performed using SPSS (Version 21) with p <= 0.05 considered statistically significant. The overall prevalence of intestinal parasites was 47.3%; 35.8% had a single parasite and 11.5% had multiple parasites. Higher rates were observed among female schoolchildren (51.2%), children whose mothers had primary education (51.3%), secondary education (50%), housewives (48.5%), and children aged >9 years (50%). The most predominant parasite was Entamoeba histolytica/dispar (36.3%). There was no significant association between the identified risk factors and intestinal parasitic infections. Conclusions/Significance: The prevalence rate of intestinal parasites is high in Aden, Yemen, with Entamoeba histolytica/dispar being the most dominant parasite. The highest rates were found among female schoolchildren, those whose mothers were housewives with primary or secondary education, and children aged >9 years.
{"title":"Intestinal Parasites among Primary School Children in Aden, Yemen","authors":"Ali N. M. Gubran¹ Naif, Mohammed Al-Haidary², Marwa Faisal, M. Bajubair³, Afrah Mohsen, Ali Algibary³, Manal Galeb, Mhmad Ali³, Marwa Fuad, Othman Ali³, Naif Mohammed Al-Haidary","doi":"10.1101/2024.08.12.24311851","DOIUrl":"https://doi.org/10.1101/2024.08.12.24311851","url":null,"abstract":"Background: Intestinal parasite infection is a significant public health problem worldwide. This study aimed to determine the prevalence of intestinal parasites among primary school children, identify the most common types of parasites, and identify the risk factors contributing to infection in Aden, Yemen. Methodology/Principal Findings: An analytical cross-sectional study was conducted on 201 school children in Aden, Yemen. Stool specimens were collected and tested using direct methods (saline and iodine preparations) and sedimentation concentration techniques. Data analysis was performed using SPSS (Version 21) with p <= 0.05 considered statistically significant. The overall prevalence of intestinal parasites was 47.3%; 35.8% had a single parasite and 11.5% had multiple parasites. Higher rates were observed among female schoolchildren (51.2%), children whose mothers had primary education (51.3%), secondary education (50%), housewives (48.5%), and children aged >9 years (50%). The most predominant parasite was Entamoeba histolytica/dispar (36.3%). There was no significant association between the identified risk factors and intestinal parasitic infections. Conclusions/Significance: The prevalence rate of intestinal parasites is high in Aden, Yemen, with Entamoeba histolytica/dispar being the most dominant parasite. The highest rates were found among female schoolchildren, those whose mothers were housewives with primary or secondary education, and children aged >9 years.","PeriodicalId":18505,"journal":{"name":"medRxiv","volume":"23 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919135","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 : 2024-08-12DOI: 10.1101/2024.08.12.24311869
A. W. Jung, I. Louloudis, S. Brunak, L. Mortensen
Electronic health records can be used to track diagnoses and drug prescriptions in large heterogeneous populations over time. Coupled with recent advances in causal inference from observational data, these records offer new opportunities to emulate clinical trials and identify potential targets for drug repositioning. Here, we run a hypothesis generating cohort study of Danes aged 50 to 80 years from 2001 to 2015 (n = 2,512,380), covering a total of 23,371,354 years of observations. We examine prescription drugs at ATC level-4 and their effect on 9 major disease outcomes. Using Bayesian time-varying Cox regression and longitudinal minimum loss estimation, our analysis successfully reproduces known drug-disease associations from clinical trials, such as the reduction in the 3-year absolute risk of death associated with Statins (ATC:C10AA) -0.8% (95% CI =[-1.2%, -0.5%]) and -0.8% (95% CI =[-1.3%, -0.2%]) for females and males, respectively. Additionally, we discovered novel associations that suggest potential repositioning opportunities. For instance, Statins were associated with a reduction in the 3-year absolute risk of dementia by -0.3% (95% CI =[-0.5%, -0.1%]) for females and -0.2% (95% CI =[-0.4%, 0.1%]) for males. Furthermore, Biguanides (ATC:P01BB) stands out as a particularly interesting candidate with absolute risk reductions across various outcomes. In total, we identified 76 potential drug-disease pairs for further investigation. However, it should be stressed that the emulation of clinical trials here is solely of hypothesis generating nature and identified effects need to be corroborated with additional evidence, preferably from RTCs, as the risk of confounding by indication in this study is substantial. In summary, this study provides a large-scale screen of prescribed drugs and their effect on major debilitating disease in the Danish health registries. This provides an additional source of information that can be used in the search for possible repositioning candidates.
电子健康记录可用于长期跟踪大量异质人群的诊断和药物处方。这些记录与观察数据因果推断的最新进展相结合，为模拟临床试验和确定药物重新定位的潜在目标提供了新的机会。在此，我们对 2001 年至 2015 年期间年龄在 50 岁至 80 岁之间的丹麦人（n = 2,512,380 人）进行了一项假设生成队列研究，共覆盖 23,371,354 年的观察数据。我们研究了 ATC 4 级处方药及其对 9 种主要疾病结果的影响。利用贝叶斯时变 Cox 回归和纵向最小损失估计，我们的分析成功地再现了临床试验中已知的药物-疾病关联，如他汀类药物（ATC：C10AA）对女性和男性的 3 年绝对死亡风险分别降低了 -0.8%（95% CI =[-1.2%，-0.5%]）和 -0.8%（95% CI =[-1.3%，-0.2%]）。此外，我们还发现了一些新的关联，表明可能存在重新定位的机会。例如，他汀类药物可使女性和男性3年痴呆绝对风险分别降低-0.3% (95% CI =[-0.5%, -0.1%])和-0.2% (95% CI =[-0.4%, 0.1%])。此外，双胍类药物（ATC:P01BB）作为一种特别有趣的候选药物，在各种结果中都能降低绝对风险。我们总共确定了 76 种潜在的药物-疾病配对，以供进一步研究。不过，需要强调的是，本研究中对临床试验的模仿仅是假设性的，确定的效果还需要更多的证据来证实，最好是从临床试验中获得，因为本研究中适应症混淆的风险很大。总之，本研究对丹麦健康登记中的处方药及其对主要衰弱性疾病的影响进行了大规模筛查。这为寻找可能的重新定位候选药物提供了额外的信息来源。
{"title":"Targeted inference to identify drug repositioning candidates in the Danish health registries","authors":"A. W. Jung, I. Louloudis, S. Brunak, L. Mortensen","doi":"10.1101/2024.08.12.24311869","DOIUrl":"https://doi.org/10.1101/2024.08.12.24311869","url":null,"abstract":"Electronic health records can be used to track diagnoses and drug prescriptions in large heterogeneous populations over time. Coupled with recent advances in causal inference from observational data, these records offer new opportunities to emulate clinical trials and identify potential targets for drug repositioning. Here, we run a hypothesis generating cohort study of Danes aged 50 to 80 years from 2001 to 2015 (n = 2,512,380), covering a total of 23,371,354 years of observations. We examine prescription drugs at ATC level-4 and their effect on 9 major disease outcomes. Using Bayesian time-varying Cox regression and longitudinal minimum loss estimation, our analysis successfully reproduces known drug-disease associations from clinical trials, such as the reduction in the 3-year absolute risk of death associated with Statins (ATC:C10AA) -0.8% (95% CI =[-1.2%, -0.5%]) and -0.8% (95% CI =[-1.3%, -0.2%]) for females and males, respectively. Additionally, we discovered novel associations that suggest potential repositioning opportunities. For instance, Statins were associated with a reduction in the 3-year absolute risk of dementia by -0.3% (95% CI =[-0.5%, -0.1%]) for females and -0.2% (95% CI =[-0.4%, 0.1%]) for males. Furthermore, Biguanides (ATC:P01BB) stands out as a particularly interesting candidate with absolute risk reductions across various outcomes. In total, we identified 76 potential drug-disease pairs for further investigation. However, it should be stressed that the emulation of clinical trials here is solely of hypothesis generating nature and identified effects need to be corroborated with additional evidence, preferably from RTCs, as the risk of confounding by indication in this study is substantial. In summary, this study provides a large-scale screen of prescribed drugs and their effect on major debilitating disease in the Danish health registries. This provides an additional source of information that can be used in the search for possible repositioning candidates.","PeriodicalId":18505,"journal":{"name":"medRxiv","volume":"39 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919008","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 : 2024-08-12DOI: 10.1101/2024.08.11.24311834
Meghan Ford, Ryan Truong, Bruce Knox, Susan A. Bartels, Colleen Davidson, Michele Cole, Logan Jackson, Eva Purkey, Imaan Bayoumi
Background: Substance use disorders (SUD) significantly impact the physical, social, and mental health of individuals, their families, and the wider community. Parental substance use can lead to long-term social and health problems for children. Examining resilience and its determinants among families directly affected by SUD (e.g., having a parent who misuses substances) or indirectly exposed to substance use (e.g., living in a community impacted by drug use) may uncover valuable insights to support families addressing SUD. The existing literature does not adequately address substance use within the context of families with young children and community resilience. The current study aims to enhance our understanding of the daily impact of family member substance use (direct substance use) or exposure to substance use within the community (indirect substance use) on children and families through qualitative interviews. Methods: The present study was a qualitative secondary analysis. Families were recruited within the Kingston, Frontenac, Lennox, and Addington area during 2022 and 2023 with a focus on maximum variation. Families were eligible to participate if they: 1) included at least one adult caring for a child under 18; 2) had a history of adversity; 3) were interested in participating; and 4) could consent to all parts of the study. Arts-based qualitative methods and community based participatory methods were employed. Participating families created a visual timeline, participated in a focus group discussion, and an individual interview. The qualitative transcripts were then analyzed following reflexive thematic analysis. Findings: Six families (12 adults, 4 children) were included in the secondary analysis. The analysis generated four themes: (1) How children affect resilience in families affected by SUD; (2) Service needs of parents with SUD to enhance family resilience; (3) The role of social support in family resilience; and (4) How perceptions of safety and trust challenge community resilience. The main limitation of this study was a small sample size. Conclusions: The study highlights the significant impact of family and community on the resilience of individuals affected by SUD. It emphasizes the importance of developing addictions services and social environments that are supportive of families with young children. These spaces should be designed to be substance-free, inclusive, and welcoming to children. Additionally, there is a need to improve service navigation and address the barriers to care commonly experienced by individuals affected by SUD.
背景：药物使用失调（SUD）对个人、其家庭和更广泛的社区的身体、社会和心理健康造成严重影响。父母使用药物会给孩子带来长期的社会和健康问题。研究直接受药物滥用影响（如父母一方滥用药物）或间接受药物滥用影响（如生活在受药物滥用影响的社区）的家庭的复原力及其决定因素，可能会为支持家庭解决药物滥用问题提供有价值的见解。现有文献没有充分论述有幼儿的家庭和社区复原力背景下的药物使用问题。本研究旨在通过定性访谈，加深我们对家庭成员药物使用（直接药物使用）或在社区内接触药物使用（间接药物使用）对儿童和家庭的日常影响的了解。研究方法本研究为二次定性分析。在 2022 年和 2023 年期间，在金斯顿、弗朗特纳克、伦诺克斯和爱丁顿地区招募家庭，重点关注最大差异。符合以下条件的家庭有资格参与1) 至少有一名成年人照顾 18 岁以下的儿童；2) 有逆境史；3) 有兴趣参与；4) 可以同意参与研究的所有部分。研究采用了基于艺术的定性方法和基于社区的参与方法。参与研究的家庭制作了一份可视化时间表，参加了一次焦点小组讨论和一次个人访谈。然后对定性记录进行了反思性主题分析。研究结果二次分析包括六个家庭（12 个成人，4 个儿童）。分析产生了四个主题：(1) 儿童如何影响受 SUD 影响的家庭的复原力；(2) 患有 SUD 的父母在提高家庭复原力方面的服务需求；(3) 社会支持在家庭复原力中的作用；(4) 安全感和信任感如何挑战社区复原力。本研究的主要局限性在于样本量较小。结论：本研究强调了家庭和社区对受 SUD 影响的个人的复原力的重要影响。它强调了发展支持有幼儿家庭的戒毒服务和社会环境的重要性。这些场所的设计应该不含药物、具有包容性并欢迎儿童的到来。此外，还需要改善服务导航，解决受药物滥用影响的个人在接受护理时通常会遇到的障碍。
{"title":"Its because they are my kids and I love them\": The impact of family and community substance use on children and families","authors":"Meghan Ford, Ryan Truong, Bruce Knox, Susan A. Bartels, Colleen Davidson, Michele Cole, Logan Jackson, Eva Purkey, Imaan Bayoumi","doi":"10.1101/2024.08.11.24311834","DOIUrl":"https://doi.org/10.1101/2024.08.11.24311834","url":null,"abstract":"Background: Substance use disorders (SUD) significantly impact the physical, social, and mental health of individuals, their families, and the wider community. Parental substance use can lead to long-term social and health problems for children. Examining resilience and its determinants among families directly affected by SUD (e.g., having a parent who misuses substances) or indirectly exposed to substance use (e.g., living in a community impacted by drug use) may uncover valuable insights to support families addressing SUD. The existing literature does not adequately address substance use within the context of families with young children and community resilience. The current study aims to enhance our understanding of the daily impact of family member substance use (direct substance use) or exposure to substance use within the community (indirect substance use) on children and families through qualitative interviews. Methods: The present study was a qualitative secondary analysis. Families were recruited within the Kingston, Frontenac, Lennox, and Addington area during 2022 and 2023 with a focus on maximum variation. Families were eligible to participate if they: 1) included at least one adult caring for a child under 18; 2) had a history of adversity; 3) were interested in participating; and 4) could consent to all parts of the study. Arts-based qualitative methods and community based participatory methods were employed. Participating families created a visual timeline, participated in a focus group discussion, and an individual interview. The qualitative transcripts were then analyzed following reflexive thematic analysis. Findings: Six families (12 adults, 4 children) were included in the secondary analysis. The analysis generated four themes: (1) How children affect resilience in families affected by SUD; (2) Service needs of parents with SUD to enhance family resilience; (3) The role of social support in family resilience; and (4) How perceptions of safety and trust challenge community resilience. The main limitation of this study was a small sample size. Conclusions: The study highlights the significant impact of family and community on the resilience of individuals affected by SUD. It emphasizes the importance of developing addictions services and social environments that are supportive of families with young children. These spaces should be designed to be substance-free, inclusive, and welcoming to children. Additionally, there is a need to improve service navigation and address the barriers to care commonly experienced by individuals affected by SUD.","PeriodicalId":18505,"journal":{"name":"medRxiv","volume":"40 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919203","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 : 2024-08-12DOI: 10.1101/2024.08.11.24311823
Mohammadreza Mohebbi, Mojtaba Lotfaliany, Martin O’Hely, Jessica Batti, M. Kotowicz, Lucy Saunders, Richard Page, Sally Beatti, Wolfgang Marx, F. Jacka, Postdoctoral Mojtaba Lotfaliany, Research, Postdoctoral Martin O’Hely, Research Fellow c. Mark, Professor d. Michael Kotowicz, Berk, Research Sally Beattie, Affiliate, Dr Amelia J McGuinness
Objective: To compare the effects of consuming food-based versus supplement-based very low-energy diet (VLED) programs on gut microbiome composition in women with a high body mass index (BMI). Design: An investigator-initiated, single-blind, two-arm, parallel-group randomised controlled-feeding trial with computer-generated 1:1 randomisation. From May 2021 to February 2022, women aged 30-65 years with BMI 30-45 kg/m2 were recruited from southwest Victoria, Australia, and randomised to a three-week food-based or supplement-based VLED program. The primary outcome was between-group differential change in faecal microbiome alpha diversity (Shannon index) from baseline to week three, assessed using shotgun metagenomics. Outcome assessors, study investigators, and analysing statisticians were blinded to group allocation until analysis completion. Allocation concealment was managed by an independent researcher using a computer software system. Modified intention-to-treat (mITT) analyses using linear mixed-effects regression models estimated mean between-group differential changes, reported as beta-coefficient point estimates ({beta}) and 95% confidence intervals (95%CI), adjusted for multiple comparisons. Results: Forty-seven participants were randomised (food-based: n=23, supplement-based: n=24). Of the 45 participants analysed, there was a between-group differential change in the Shannon index (mITT {beta}: 0.37, 95%CI: 0.15 to 0.60) from baseline to week three, with a greater increase in the food-based group (mean change: 0.26, 95%CI: 0.09 to 0.44; n=23) versus supplement-based group (mean change: -0.10, 95%CI: -0.25 to 0.05; n=22). There were 27 non-serious adverse events (food-based: 8, supplement-based: 19), all non-serious. Conclusion: A food-based VLED, with more whole food components and fewer highly processed industrial ingredients, increases gut microbiome diversity more than a supplement-based VLED.
{"title":"The effects of food-based versus supplement-based very low-energy diets on gut microbiome composition and health outcomes in women with high body mass index (The MicroFit Study): a randomised controlled trial","authors":"Mohammadreza Mohebbi, Mojtaba Lotfaliany, Martin O’Hely, Jessica Batti, M. Kotowicz, Lucy Saunders, Richard Page, Sally Beatti, Wolfgang Marx, F. Jacka, Postdoctoral Mojtaba Lotfaliany, Research, Postdoctoral Martin O’Hely, Research Fellow c. Mark, Professor d. Michael Kotowicz, Berk, Research Sally Beattie, Affiliate, Dr Amelia J McGuinness","doi":"10.1101/2024.08.11.24311823","DOIUrl":"https://doi.org/10.1101/2024.08.11.24311823","url":null,"abstract":"Objective: To compare the effects of consuming food-based versus supplement-based very low-energy diet (VLED) programs on gut microbiome composition in women with a high body mass index (BMI). Design: An investigator-initiated, single-blind, two-arm, parallel-group randomised controlled-feeding trial with computer-generated 1:1 randomisation. From May 2021 to February 2022, women aged 30-65 years with BMI 30-45 kg/m2 were recruited from southwest Victoria, Australia, and randomised to a three-week food-based or supplement-based VLED program. The primary outcome was between-group differential change in faecal microbiome alpha diversity (Shannon index) from baseline to week three, assessed using shotgun metagenomics. Outcome assessors, study investigators, and analysing statisticians were blinded to group allocation until analysis completion. Allocation concealment was managed by an independent researcher using a computer software system. Modified intention-to-treat (mITT) analyses using linear mixed-effects regression models estimated mean between-group differential changes, reported as beta-coefficient point estimates ({beta}) and 95% confidence intervals (95%CI), adjusted for multiple comparisons. Results: Forty-seven participants were randomised (food-based: n=23, supplement-based: n=24). Of the 45 participants analysed, there was a between-group differential change in the Shannon index (mITT {beta}: 0.37, 95%CI: 0.15 to 0.60) from baseline to week three, with a greater increase in the food-based group (mean change: 0.26, 95%CI: 0.09 to 0.44; n=23) versus supplement-based group (mean change: -0.10, 95%CI: -0.25 to 0.05; n=22). There were 27 non-serious adverse events (food-based: 8, supplement-based: 19), all non-serious. Conclusion: A food-based VLED, with more whole food components and fewer highly processed industrial ingredients, increases gut microbiome diversity more than a supplement-based VLED.","PeriodicalId":18505,"journal":{"name":"medRxiv","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919324","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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