bluuebunny/crossref_metadata_2025_split huggingface dataset:
Minimizing bias in massive multi-arm observational studies with BCAUS: balancing covariates automatically using supervision
Authors: Belthangady Chinmay , Stedden Will , Norgeot Beau 
Published: September 2021

Abstract
Background
Observational studies are increasingly being used to provide supplementary evidence in addition to Randomized Control Trials (RCTs) because they provide a scale and diversity of participants and outcomes that would be infeasible in an RCT. Additionally, they more closely reflect the settings in which the studied interventions will be applied in the future. Well-established propensity-score-based methods exist to overcome the challenges of working with observational data to estimate causal effects. These methods also provide quality assurance diagnostics to evaluate the degree to which bias has been removed and the estimates can be trusted. In large medical datasets it is common to find the same underlying health condition being treated with a variety of distinct drugs or drug combinations. Conventional methods require a manual iterative workflow, making them scale poorly to studies with many intervention arms. In such situations, automated causal inference methods that are compatible with traditional propensity-score-based workflows are highly desirable.

Methods
We introduce an automated causal inference method BCAUS, that features a deep-neural-network-based propensity model that is trained with a loss which penalizes both the incorrect prediction of the assigned treatment as well as the degree of imbalance between the inverse probability weighted covariates. The network is trained end-to-end by dynamically adjusting the loss term for each training batch such that the relative contributions from the two loss components are held fixed. Trained BCAUS models can be used in conjunction with traditional propensity-score-based methods to estimate causal treatment effects.

Results
We tested BCAUS on the semi-synthetic Infant Health & Development Program dataset with a single intervention arm, and a real-world observational study of diabetes interventions with over 100,000 individuals spread across more than a hundred intervention arms. When compared against other recently proposed automated causal inference methods, BCAUS had competitive accuracy for estimating synthetic treatment effects and provided highly concordant estimates on the real-world dataset but was an order-of-magnitude faster.

Conclusions
BCAUS is directly compatible with trusted protocols to estimate treatment effects and diagnose the quality of those estimates, while making the established approaches automatically scalable to an arbitrary number of simultaneous intervention arms without any need for manual iteration.
A Bayesian latent class mixture model with censoring for correlation analysis in antimicrobial resistance across populations
Authors: Zhang Min , Wang Chong , O’Connor Annette M. 
Published: September 2021

Abstract
Background
The emergence of antimicrobial resistance across populations is a global threat to public health. Surveillance programs often monitor human and animal populations to evaluate trends of emergence in these populations. Many national level antibiotic resistance surveillance programs quantify the proportion of resistant bacteria as a means of monitoring emergence and control measures. The reason for monitoring these different populations are many, including interest in similar changes in resistance which might provide insight into emergence and control options.

Methods
In this research, we developed a method to quantify the correlation in antimicrobial resistance across populations, for the conventionally unnoticed mean shift of the susceptible bacteria. With the proposed Bayesian latent class mixture model with censoring and multivariate normal hierarchy, we address several challenges associated with analyzing the minimum inhibitory concentration data.

Results
Application of this approach to the surveillance data from National Antimicrobial Resistance Monitoring System led to a detection of positive correlation in the central tendency of azithromycin resistance of the susceptible populations from Salmonella serotype Typhimurium across food animal and human populations.

Conclusions
Our proposed approach has been shown to be accurate and superior to the commonly used naïve estimation by simulation studies. Further implementation of this Bayesian model could serve as a useful tool to indicate the co-existence of antimicrobial resistance, and potentially a need of clinical intervention.
Spot specimen testing with GeneXpert MTB/RIF results compared to morning specimen in a programmatic setting in Cotonou, Benin
Authors: Massou Faridath , Fandohan Merlin , Wachinou Ablo Prudence , Agbla Schadrac Christin , Agodokpessi Gildas , Rigouts Leen , de Jong Bouke Catherine , Affolabi Dissou 
Published: September 2021

Abstract
Background
The diagnosis of tuberculosis (TB) using smear microscopy has been based on testing two specimens: one spot and one early morning sputa. Recently, the World Health Organization (WHO) has recommended to replace, whenever possible, microscopy with GeneXpert® MTB/RIF performed on a single specimen. However, as the bacterial load is higher in early morning specimens than in spot specimens, one could expect lower sensitivity of GeneXpert® MTB/RIF performed only on spot specimens. In this study, we compared results of GeneXpert® MTB/RIF on spot specimens versus early morning specimens, under programmatic conditions in Cotonou, Benin.

Methods
From June to September 2018, all sputa received from presumptive TB patients at the Supranational Reference Laboratory for Tuberculosis of Cotonou were included in the study. From each patient, two specimens were collected (one spot and one early morning) and GeneXpert® MTB/RIF was performed on both specimens.

Results
In total, 886 participants were included in the study, of whom 737 provided both sputa and 149 (16.8%) gave only the spot specimen. For the 737 participants who provided both sputa, GeneXpert® MTB/RIF was positive for both specimens in 152 participants; for three participants GeneXpert® MTB/RIF was positive on spot specimen but negative on morning specimen while for another three, the test was positive on morning specimen but negative on spot specimen. The overall percentage of agreement was excellent (99.2%) with a positive and negative percent agreement greater than 98%.

Conclusion
For TB diagnosis under programmatic conditions in Cotonou, GeneXpert® MTB/RIF in spot specimens gave similar results with the test in morning specimens. Performing GeneXpert® MTB/RIF in both specimens did not significantly increase the number of cases detected. To avoid losing patients from the diagnostic cascade, it is preferable to test sputa produced at the time of the first visit at the health center.
Patterns of engagement in HIV care during pregnancy and breastfeeding: findings from a cohort study in North-Eastern South Africa
Authors: Etoori David , Rice Brian , Reniers Georges , Gomez-Olive Francesc Xavier , Renju Jenny , Kabudula Chodziwadziwa Whiteson , Wringe Alison 
Published: September 2021

Abstract
Background
Eliminating mother-to-child transmission of HIV (MTCT) in sub-Saharan Africa is hindered by limited understanding of HIV-testing and HIV-care engagement among pregnant and breastfeeding women.

Methods
We investigated HIV-testing and HIV-care engagement during pregnancy and breastfeeding from 2014 to 2018 in the Agincourt Health and Demographic Surveillance System (HDSS). We linked HIV patient clinic records to HDSS pregnancy data. We modelled time to a first recorded HIV-diagnosis following conception, and time to antiretroviral therapy (ART) initiation following diagnosis using Kaplan-Meier methods.
We performed sequence and cluster analyses for all pregnancies linked to HIV-related clinic data to categorise MTCT risk period engagement patterns and identified factors associated with different engagement patterns using logistic regression.
We determined factors associated with ART resumption for women who were lost to follow-up (LTFU) using Cox regression.

Results
Since 2014, 15% of 10,735 pregnancies were recorded as occurring to previously (51%) or newly (49%) HIV-diagnosed women. New diagnoses increased until 2016 and then declined. We identified four MTCT risk period engagement patterns (i) early ART/stable care (51.9%), (ii) early ART/unstable care (34.1%), (iii) late ART initiators (7.6%), and (iv) postnatal seroconversion/early, stable ART (6.4%). Year of delivery, mother’s age, marital status, and baseline CD4 were associated with these patterns. A new pregnancy increased the likelihood of treatment resumption following LTFU.

Conclusion
Almost half of all pregnant women did not have optimal ART coverage during the MTCT risk period. Programmes need to focus on improving retention, and leveraging new pregnancies to re-engage HIV-positive women on ART.
Can TSH level and premenstrual spotting constitute a non-invasive marker for the diagnosis of endometriosis?
Authors: Birke Lena , Baston-Büst Dunja M. , Kruessel Jan-Steffen , Fehm Tanja N. , Bielfeld Alexandra P. 
Published: September 2021

Abstract
Background
To date, there is no reliable non-invasive marker for the early detection and diagnosis of endometriosis available possibly resulting in a delayed diagnosis and consequently an unnecessary long ordeal for the individual woman. Therefore, the primary objective of the current study was to evaluate whether the combination of a thyroid-stimulating hormone (TSH) level > 2.5 µlU/ml and premenstrual spotting could serve as non-invasive markers of endometriosis. A secondary objective was to determine whether typical symptoms of endometriosis like dysmenorrhea and/or dyspareunia could increase the diagnostic reliability.

Methods
We conducted a retrospective, case–control study with 167 female patients at the Department of OB/GYN and REI (UniKiD) of the medical center of the University of Düsseldorf, between January 2015 and December 2016. 107 women with surgically confirmed endometriosis were compared to 60 without endometriosis (controls). To evaluate the diagnostic accuracy, we considered sensitivity, specificity and predictive values. In order to assess the association between the non-invasive markers and endometriosis an odds ratio (OR) with a 95% confidence interval was calculated.

Results
In our cohort, diagnosis of endometriosis with non-invasive markers according to their sensitivity yielded the following ranking: increased TSH level, premenstrual spotting, combination of both previous parameters, addition of dysmenorrhea, addition of dyspareunia and combination of all parameters.

Conclusion
The existence of endometriosis should be taken into consideration when a patient suffers from thyroid dysfunction and premenstrual spotting. Apart from an increased TSH level, the presence of premenstrual spotting underlines the possible diagnosis of endometriosis with non-invasive markers and therefore, the patient´s history needs to be taken into account carefully.
Trial registration The retrospective study was approved by the Ethics Committee of the medical faculty of the Heinrich-Heine University, Düsseldorf, Germany, Registration number Düsseldorf: 5371R (approved: April 04th, 2016). Since the design of the study was retrospective no written informed consent was necessary.
Variation in referrals from primary care to scheduled paediatric services in North and East Scotland -a cross-sectional study
Authors: Dick Smita , Crabb Ryen , McFaul Claire , MacRae Clare , Wilson Philip , Turner Steve 
Published: September 2021

Abstract
Background
Factors contributing to decisions to refer children for scheduled appointments at medical paediatric outpatient clinics are not well understood. Our aim was to describe practice-level characteristics associated with referrals to general paediatric clinics.

Methods
In this cross-sectional study the setting was general practices in three health boards in Scotland, NHS Grampian, NHS Highland and NHS Tayside The outcome was average annual number of referrals per 1000 children between 2011 and 2017. Univariate and multivariate analyses related the outcome to practice characteristics. For each practice the following characteristics were determined: distance from hospital; area deprivation; number of children registered; presence of ≥ 1 general practitioner with a child health interest and practice ownership.

Results
There were 62 practices in NHS Grampian, 63 in NHS Highland, and 65 in NHS Tayside; representative annual number of referrals to paediatric clinics per capita were 22, 34, and 35/1000 respectively. In the multivariate model, the number of referrals was inversely related to number of children in the practice (0.8 % fall per 1000 children [95 % confidence interval, CI, 0.5, 1.1]) and was higher from practices in the more deprived areas by a mean 55 % [95 % CI 9, 121] compared to less deprived areas. The number of referrals from a practice rose by 0.91 % [95 % CI 0.86, 0.97] for each additional partner in the practice.

Conclusion
Some practice-level characteristics were related to the standardised number of referrals, and associations differed between regions.
Synthesis of (−)−deoxypodophyllotoxin and (−)−epipodophyllotoxin via a multi-enzyme cascade in E. coli
Authors: Decembrino Davide , Raffaele Alessandra , Knöfel Ronja , Girhard Marco , Urlacher Vlada B. 
Published: September 2021

Abstract
Background
The aryltetralin lignan (−)−podophyllotoxin is a potent antiviral and anti-neoplastic compound that is mainly found in Podophyllum plant species. Over the years, the commercial demand for this compound rose notably because of the high clinical importance of its semi-synthetic chemotherapeutic derivatives etoposide and teniposide. To satisfy this demand, (−)−podophyllotoxin is conventionally isolated from the roots and rhizomes of Sinopodophyllum hexandrum, which can only grow in few regions and is now endangered by overexploitation and environmental damage. For these reasons, targeting the biosynthesis of (−)−podophyllotoxin precursors or analogues is fundamental for the development of novel, more sustainable supply routes.

Results
We recently established a four-step multi-enzyme cascade to convert (+)−pinoresinol into (−)−matairesinol in E. coli. Herein, a five-step multi-enzyme biotransformation of (−)−matairesinol to (−)−deoxypodophyllotoxin was proven effective with 98 % yield at a concentration of 78 mg/L. Furthermore, the extension of this cascade to a sixth step leading to (−)−epipodophyllotoxin was evaluated. To this end, seven enzymes were combined in the reconstituted pathway involving inter alia three plant cytochrome P450 monooxygenases, with two of them being functionally expressed in E. coli for the first time.

Conclusions
Both, (−)−deoxypodophyllotoxin and (−)−epipodophyllotoxin, are direct precursors to etoposide and teniposide. Thus, the reconstitution of biosynthetic reactions of Sinopodophyllum hexandrum as an effective multi-enzyme cascade in E. coli represents a solid step forward towards a more sustainable production of these essential pharmaceuticals.
The pattern of romantic and sexual related experiences among Chinese young adolescents: an exploration with multi-group latent class analysis
Authors: Yu Chunyan , Lou Chaohua , Lian Qiguo , Tu Xiaowen , Zhang Jiashuai , Zuo Xiayun 
Published: September 2021

Abstract
Background
Studies on very young adolescents’ romantic and sexual experiences would help inform the context in which early sex arises. However, such studies are scant in China due to sparse data and cultural issues.

Method
This study used the GEAS baseline data conducted among1776 adolescents in Shanghai. Multi-group latent class analysis was used to explore adolescents’ romantic and sexual experiences patterns and subgroups. Multi-nominal logistic regression was performed to identify the factors distinguishing different subgroups subsequently.

Results
There were gender differences in the lifetime prevalence for very young adolescents’ romantic and sexual-related behaviors. The Multi-group latent class analysis indicated that the participants could be classified into three classes: general group, early romance group, and sex exploratory group. Multi-nominal logistic regression showed youth in the early romance group were more likely to had friends of both gender, ever had a romantic relationship, and had more autonomy in deciding where to go than the general group; while male respondents in the sex exploratory group were older, ever had a romantic relationship, believed that boys should be more sexually active and more proactive than girls, had more autonomy on deciding where to go, and perceived less school connection and neighborhood cohesion. Female respondents in the sex exploratory group were older and less empowered in decision-making than the general group.

Conclusions
The result provides a picture of romantic and sexual behavior patterns among both gender of very young adolescents in China. Current sex education needs not only to be culturally appropriate but also to address the harm of gender inequality and stereotypes, as well as to provide accessible and supportive services to help young adolescents personalize their received information and strengthen their skills in communication, decision making, and critical thinking.
Investigating receptor-mediated antibody transcytosis using blood–brain barrier organoid arrays
Authors: Simonneau Claire , Duschmalé Martina , Gavrilov Alina , Brandenberg Nathalie , Hoehnel Sylke , Ceroni Camilla , Lassalle Evodie , Kassianidou Elena , Knoetgen Hendrik , Niewoehner Jens , Villaseñor Roberto 
Published: September 2021

Abstract
Background
The pathways that control protein transport across the blood–brain barrier (BBB) remain poorly characterized. Despite great advances in recapitulating the human BBB in vitro, current models are not suitable for systematic analysis of the molecular mechanisms of antibody transport. The gaps in our mechanistic understanding of antibody transcytosis hinder new therapeutic delivery strategy development.

Methods
We applied a novel bioengineering approach to generate human BBB organoids by the self-assembly of astrocytes, pericytes and brain endothelial cells with unprecedented throughput and reproducibility using micro patterned hydrogels. We designed a semi-automated and scalable imaging assay to measure receptor-mediated transcytosis of antibodies. Finally, we developed a workflow to use CRISPR/Cas9 gene editing in BBB organoid arrays to knock out regulators of endocytosis specifically in brain endothelial cells in order to dissect the molecular mechanisms of receptor-mediated transcytosis.

Results
BBB organoid arrays allowed the simultaneous growth of more than 3000 homogenous organoids per individual experiment in a highly reproducible manner. BBB organoid arrays showed low permeability to macromolecules and prevented transport of human non-targeting antibodies. In contrast, a monovalent antibody targeting the human transferrin receptor underwent dose- and time-dependent transcytosis in organoids. Using CRISPR/Cas9 gene editing in BBB organoid arrays, we showed that clathrin, but not caveolin, is required for transferrin receptor-dependent transcytosis.

Conclusions
Human BBB organoid arrays are a robust high-throughput platform that can be used to discover new mechanisms of receptor-mediated antibody transcytosis. The implementation of this platform during early stages of drug discovery can accelerate the development of new brain delivery technologies.
Research led by people who use drugs: centering the expertise of lived experience
Authors: Salazar Zach R. , Vincent Louise , Figgatt Mary C. , Gilbert Michael K. , Dasgupta Nabarun 
Published: September 2021

Abstract
Background
Research collaborations between people who use drugs (PWUD) and researchers are largely underutilized, despite the long history of successful, community-led harm reduction interventions and growing health disparities experienced by PWUD. PWUD play a critical role in identifying emerging issues in the drug market, as well as associated health behaviors and outcomes. As such, PWUD are well positioned to meaningfully participate in all aspects of the research process, including population of research questions, conceptualization of study design, and contextualization of findings.

Main body
We argue PWUD embody unparalleled and current insight to drug use behaviors, including understanding of novel synthetic drug bodies and the dynamics at play in the drug market; they also hold intimate and trusting relationships with other PWUD. This perfectly situates PWUD to collaborate with researchers in investigation of drug use behaviors and development of harm reduction interventions. While PWUD have a history of mistrust with the medical community, community-led harm reduction organizations have earned their trust and are uniquely poised to facilitate research projects. We offer the North Carolina Survivors Union as one such example, having successfully conducted a number of projects with reputable research institutions. We also detail the fallacy of meaningful engagement posed by traditional mechanisms of capturing community voice. As a counter, we detail the framework developed and implemented by the union in hopes it may serve as guidance for other community-led organizations. We also situate research as a mechanism to diversify the job opportunities available to PWUD and offer a real-time example of the integration of these principles into public policy and direct service provision.

Conclusion
In order to effectively mitigate the risks posed by the fluid and volatile drug market, research collaborations must empower PWUD to play meaningful roles in the entirety of the research process. Historically, the most effective harm reduction interventions have been born of the innovation and heart possessed by PWUD; during the current overdose crisis, there is no reason to believe they will not continue to be.