bluuebunny/crossref_metadata_2025 huggingface dataset:
3D chromatin architecture, BRD4, and Mediator have distinct roles in regulating genome-wide transcriptional bursting and gene network
Authors: Trzaskoma Pawel , Jung SeolKyoung , Pękowska Aleksandra , Bohrer Christopher H. , Wang Xiang , Naz Faiza , Dell’Orso Stefania , Dubois Wendy D. , Olivera Ana , Vartak Supriya V. , Zhao Yongbing , Nayak Subhashree , Overmiller Andrew , Morasso Maria I. , Sartorelli Vittorio , Larson Daniel R. , Chow Carson C. , Casellas Rafael , O’Shea John J.
Published: August 2024

Discontinuous transcription is evolutionarily conserved and a fundamental feature of gene regulation; yet, the exact mechanisms underlying transcriptional bursting are unresolved. Analyses of bursting transcriptome-wide have focused on the role of cis-regulatory elements, but other factors that regulate this process remain elusive. We applied mathematical modeling to single-cell RNA sequencing data to infer bursting dynamics transcriptome-wide under multiple conditions to identify possible molecular mechanisms. We found that Mediator complex subunit 26 (MED26) primarily regulates frequency, MYC regulates burst size, while cohesin and Bromodomain-containing protein 4 (BRD4) can modulate both. Despite comparable effects on RNA levels among these perturbations, acute depletion of MED26 had the most profound impact on the entire gene regulatory network, acting downstream of chromatin spatial architecture and without affecting TATA box–binding protein (TBP) recruitment. These results indicate that later steps in the initiation of transcriptional bursts are primary nodes for integrating gene networks in single cells.
Three separate pathways in
Rhizobium leguminosarum
maintain phosphatidylcholine biosynthesis, which is required for symbiotic nitrogen fixation with clover
Authors: Kleetz Julia , Mizza Ann-Sophie , Shevyreva Irina , Welter Leon , Brocks Claudia , Hemschemeier Anja , Aktas Meriyem , Narberhaus Franz
Published: August 2024

Phosphatidylcholine (PC) is critical for the nitrogen-fixing symbiosis between rhizobia and legumes. We characterized three PC biosynthesis pathways in
Rhizobium leguminosarum
and evaluated their impact on nitrogen fixation in clover nodules. In the presence of choline, a PC synthase catalyzes the condensation of cytidine diphosphate-diacylglycerol with choline to produce PC. In the presence of lyso-PC, acyltransferases acylate this mono-acylated phospholipid to PC. The third pathway relies on phospholipid
N
-methyltransferases (Pmts), which sequentially methylate phosphatidylethanolamine (PE) through three rounds of methylation, yielding PC via the intermediates monomethyl-PE and dimethyl-PE. In
R. leguminosarum
, at least three Pmts participate in this methylation cascade. To elucidate the functions of these enzymes, we recombinantly produced and biochemically characterized them. We moved on to determine the phospholipid profiles of
R. leguminosarum
mutant strains harboring single and combinatorial deletions of PC biosynthesis genes. The cumulative results show that PC production occurs through the combined action of multiple enzymes, each with distinct substrate and product specificities. The methylation pathway emerges as the dominant PC biosynthesis route, and we pinpoint PmtS2, which catalyzes all three methylation steps, as the enzyme responsible for providing adequate PC amounts for a functional nitrogen-fixing symbiosis with clover.

IMPORTANCE

Understanding the molecular mechanisms of symbiotic nitrogen fixation has important implications for sustainable agriculture. The presence of the phospholipid phosphatidylcholine (PC) in the membrane of rhizobia is critical for the establishment of productive nitrogen-fixing root nodules on legume plants. The reasons for the PC requirement are unknown. Here, we employed
Rhizobium leguminosarum
and clover as model system for a beneficial plant-microbe interaction. We found that
R. leguminosarum
produces PC by three distinct pathways. The relative contribution of these pathways to PC formation was determined in an array of single, double, and triple mutant strains. Several of the PC biosynthesis enzymes were purified and biochemically characterized. Most importantly, we demonstrated the essential role of PC formation by
R. leguminosarum
in nitrogen fixation and pinpointed a specific enzyme indispensable for plant-microbe interaction. Our study offers profound insights into bacterial PC biosynthesis and its pivotal role in biological nitrogen fixation.
Holistic understanding of trimethoprim resistance in
Streptococcus pneumoniae
using an integrative approach of genome-wide association study, resistance reconstruction, and machine learning
Authors: Pham Nguyen-Phuong , Gingras Hélène , Godin Chantal , Feng Jie , Groppi Alexis , Nikolski Macha , Leprohon Philippe , Ouellette Marc
Published: August 2024

Antimicrobial resistance (AMR) is a public health threat worldwide. Next-generation sequencing (NGS) has opened unprecedented opportunities to accelerate AMR mechanism discovery and diagnostics. Here, we present an integrative approach to investigate trimethoprim (TMP) resistance in the key pathogen
Streptococcus pneumoniae
. We explored a collection of 662
S
.
pneumoniae
genomes by conducting a genome-wide association study (GWAS), followed by functional validation using resistance reconstruction experiments, combined with machine learning (ML) approaches to predict TMP minimum inhibitory concentration (MIC). Our study showed that multiple additive mutations in the
folA
and
sulA
loci are responsible for TMP non-susceptibility in
S. pneumoniae
and can be used as key features to build ML models for digital MIC prediction, reaching an average accuracy within ±1 twofold dilution factor of 86.3%. Our roadmap of
in silico
analysis—wet-lab validation—diagnostic tool building could be adapted to explore AMR in other combinations of bacteria–antibiotic.

IMPORTANCE

In the age of next-generation sequencing (NGS), while data-driven methods such as genome-wide association study (GWAS) and machine learning (ML) excel at finding patterns, functional validation can be challenging due to the high numbers of candidate variants. We designed an integrative approach combining a GWAS on
S. pneumoniae
clinical isolates, followed by whole-genome transformation coupled with NGS to functionally characterize a large set of GWAS candidates. Our study validated several phenotypic
folA
mutations beyond the standard Ile100Leu mutation, and showed that the overexpression of the
sulA
locus produces trimethoprim (TMP) resistance in
Streptococcus pneumoniae
. These validated loci, when used to build ML models, were found to be the best inputs for predicting TMP minimal inhibitory concentrations. Integrative approaches can bridge the genotype-phenotype gap by biological insights that can be incorporated in ML models for accurate prediction of drug susceptibility.
Demographic and zoological drivers of infectome diversity in companion cats with ascites
Authors: Sun Yankuo , Xing Jiabao , Xu Sijia , Li Yue , Zhong Jianhao , Gao Han , Cheng Song , Dong Jun , Zhang Tianyou , Lu Gang , Baele Guy , Zhang Guihong
Published: August 2024

Cats (
Felidae
) have become an integral part of many households. However, our understanding of the full spectrum of pathogens affecting cats (referred to as the infectome) is limited, mainly due to the inadequacy of commonly used diagnostic tools in capturing the complete diversity of potential pathogens and the prevalence of pathogen co-infections. In this study, we employed a meta-transcriptomic approach to simultaneously characterize the infectome contributing to different disease syndromes and to investigate spatial, demographic, and ecological factors influencing pathogen diversity and community composition in a cohort of 27 hospitalized cats and seven stray cats. We identified 15 species of pathogens, with
Candidatus Rickettsia tarasevichiae
and
Tritrichomonas foetus
representing potential spillover risks. Importantly, although most cases of ascites hyperplasia were explained by coinfection with multiple pathogens, we identified the potential novel clinical outcomes of
M. aubagnense
infection among cats. We demonstrated that the increase in infectome diversity can be explained by a variety of predictors including age growth, temperature increase, and a higher proportion of females, with age growth presenting the strongest effect. Fine-scale analysis indicated that a higher diversity of infectomes were harbored in young cats rather than adult ones. Our results demonstrated that most feline diseases are better explained by the presence of virus–bacteria or virus–virus coinfection. This study serves as a timely endorsement for clinical diagnosis by vets to consider the cause of a disease based on a panel of cryptical co-infecting pathogens rather than on individual infectious agents.

IMPORTANCE

Frequent studies reported the risks of cats as an intermediate host of zoonotic pathogens (e.g., SARS-CoV-2). Cats have a physically close interaction with their owners through activities like petting, kissing, and being licked on the cheek and hands. However, there are still limited studies that systematically investigate the infectome structure of cats. In this study, we employed a meta-transcriptomics approach to characterize 15 species of pathogens in cats, with
Candidatus Rickettsia tarasevichiae
first characterizing infection in diseased cats. Most feline diseases were better explained by the presence of virus–bacteria or virus–virus coinfection. The increase in infectome diversity could be influenced by a variety of predictors including age growth, temperature increase, and a higher proportion of females. A higher diversity of pathogens was harbored in young cats rather than adults. Importantly, we showed the value of linking the modern influx of meta-transcriptomics with comparative ecology and demography and of utilizing it to affirm that ecological and demographic variations impact the total infectome.
Evolution and uranium mineralization of the northern Ordos Basin revealed by detrital zircons of the Jurassic strata
Authors: Liu Yuan , Liu Hang , Jiao Yang-Quan , Zhao Jun-Hong
Published: August 2024

Stable sedimentary basins with complex evolutionary histories generally develop various epigenetic resources, such as sandstone-type uranium deposits. However, the genetic linkage between basin evolution and subsequent uranium mineralization remains unclear. Detrital zircon is a robust mineral, and its U-Pb ages and Lu-Hf isotopes are essential for tracing the evolution of sedimentary basins. The Ordos Basin is the largest intracontinental basin and uranium deposit region in the North China Craton. It consists of Cambrian to Ordovician marine deposits and Carboniferous to Jurassic terrestrial successions, and the origins of the terrigenous clastic sequences are dominantly influenced by the neighboring orogenic belts. This study presents new whole-rock elemental data, detrital zircon U-Pb ages, and Lu-Hf isotopes for the sandstones from the Jurassic Zhiluo Formation of the northern Ordos Basin. With data from the Paleozoic sedimentary rocks of the basin and the southern Central Asian Orogenic Belt, this study aimed to determine sediment provenances, the evolution of the northern Ordos Basin, and the potential implications for uranium mineralization. Detrital zircons from the Zhiluo Formation are generally rounded and preserve magmatic zoning structures. Their ages display four populations, 330–245 Ma, 470–350 Ma, 2100–1650 Ma, and 2750–2200 Ma, which are consistent with the tectono-thermal events of the Central Asian Orogenic Belt and the Yinshan Belt to the north, and the Alxa Block to the northwest. Both their detrital zircon ages and εHf(t) values are similar to those of the underlying sedimentary rocks. In addition, the formation has recycled carbonaceous debris, diverse clastic fragments, and Triassic fossils, and its sandstones show low index of compositional variability values (0.79–0.97) and high SiO2/Al2O3 (5.33–7.25) and Th/Sc (0.71–1.97) ratios. These lines of evidence suggest that the detritus of the Zhiluo Formation was partially derived from the underlying sedimentary strata. It should be noted that the Paleozoic to Mesozoic strata of the northern Ordos Basin also have detrital zircon age patterns and εHf(t) values similar to those of the southern Central Asian Orogenic Belt, and the secular evolution of the Ordos Basin is therefore considered to have been controlled by subduction of the Paleo-Asian Ocean and collision between the Central Asian Orogenic Belt and the North China Craton, as well as the post-collisional crustal extension that ensued. The carbonaceous debris in the Zhiluo Formation provided a reductive environment for the subsequent crystallization of reducing minerals and uranium mineralization.
Efficacy of weekly dose of 1% atropine for myopia control in Chinese children
Authors: Du Linlin , Ding Li , Chen Jun , Wang Jingjing , Yang Jinliuxing , Liu Sichen , Xu Xun , He Xiangui , Huang Jiannan , Zhu Mengjun
Published: August 2024

Purpose

To assess the effect of weekly 1% atropine use on children’s myopia progression and whether the effect is sustainable.

Methods

Medical records of myopic children aged 3–15 years receiving weekly 1% atropine for more than 1 year were retrospectively reviewed. Axial length (AL) and spherical equivalent refraction (SER) at every visit were collected. The changes in AL or SER over time were analysed using generalised estimating equation. The related factors of myopic progression were performed by multiple linear regression. The performance of short-term AL change to predict atropine-poor responders (AL change >0.2 mm/year) was assessed using receiver operating characteristic analysis.

Results

A total of 694 participants with a mean age of 8.83 years were included. The participants with follow-up time reached 1, 2, 3 and 4 years were 256 (36.9%), 250 (36.0%), 143 (20.6%) and 45 (6.5%) separately. The cumulative change in AL was 0.05 mm, 0.24 mm, 0.47 mm, 0.56 mm separately for 1-year, 2-year, 3-year and 4- year treatment. Approximate 0.20 mm elongation per year was observed since the second-year of the treatment. Older age and lower initial myopic refraction were independently associated with less myopic progression. A decrease in AL of more than 0.04 mm during the initial 2 months could serve as an indicator for identifying fast progressors (AL change >0.2 mm/year) over a 2-year period, with sensitivity and specificity rates of 0.78 and 0.73, respectively.

Conclusion

Weekly 1% atropine may be a potentially effective treatment with longer lasting effects for children with myopia control especially in those with older age and lower myopia.
Retinoblastoma survival and enucleation outcomes in 41 countries from the African continent
Authors: Nishath Thamanna , Stacey Andrew W , Steinberg David , Foster Allen , Bowman Richard , Essuman Vera , Fabian Ido Didi
Published: August 2024

Background

Retinoblastoma is the most common intraocular malignancy in childhood. Despite one-third of cases occurring in Africa, little is known of the outcomes on the continent. This study aims to explore survival and globe salvage outcomes and identify their risk factors across a large cohort of patients from the African continent.

Methods

A 3-year prospective, observational study was conducted. Kaplan-Meier survival analysis was used to investigate the risk of globe loss and death from retinoblastoma in Africa. Cox regression was used to identify risk factors associated with these outcomes.

Results

A total of 958 patients from 41 African countries and 66 participating centres were enrolled in the study. The survival rate was 78.2% at 1 year and 66.2% at 3 years after diagnosis. Cox regression showed a higher risk of death with the most advanced clinical stage (cT4, HR=6.29 vs cT2, p<0.001). The risk of losing at least one eye after diagnosis was 50% within 4 months and 72.6% within 3 years. Higher risk of enucleation was associated with a higher clinical stage compared with cT1 (cT3, HR=4.11, p=0.001; cT4, HR=3.77, p=0.005).

Conclusion

Nearly one in every four children diagnosed with retinoblastoma in African participating centres succumb to retinoblastoma within 1 year. There is also high morbidity associated with the diagnosis as a large majority of patients require eye removal surgery. The outcome of disease in children with retinoblastoma in Africa is poor compared with other continents and requires prompt intervention by increasing efforts to improve survival and eye salvage outcomes.
Ankle-GO score is associated with the probability of becoming coper after lateral ankle sprain: a 1-year prospective cohort study
Authors: Picot Brice , Fourchet François , Rauline Gauthier , Freiha Kinan , Wikstrom Erik , Lopes Ronny , Hardy Alexandre
Published: August 2024

Objective

To analyse the association between Ankle-GO score during the return to sport process and the probability of becoming a coper 1 year after lateral ankle sprain (LAS). Copers were defined as patients returning to their preinjury sport without loss of function and reporting no episodes of reinjury or giving-way.

Methods

Two months after a LAS, patients performed the Ankle-GO assessment which includes a cluster of four functional tests and two self-reported questionnaires for a maximum score of 25 points. One year after injury, participants were classified as copers or non-copers. Eight potential predictive variables associated with coper status were compared between the groups. Receiver operating characteristic curves (area under the curve (AUC)) and multivariable logistic regression models with OR and 95% CIs were used to determine the association of potential factors, including the Ankle-GO score, with copers.

Results

64 patients (56% females; age 33.7±13.2 years) completed the Ankle-GO-GO at 2 months postinjury. At 1 year postinjury, 10 patients (15%) were lost to follow-up, and only 17 of 54 patients (31%) became copers. Two-month Ankle-GO score was higher among copers (9.9±4.9 points vs 6.9±3.7, p=0.015) and was associated with future coper status at 1 year (AUC=0.70). Patients with an Ankle-GO score above 11 points and male patients were more likely to become copers (OR=12.1; 95% CI 2.5 to 59, p=0.002 and OR=5.2; 95% CI 1.2 to 22.4, p=0.026, respectively).

Conclusion

The Ankle-GO may help identify patients more likely to become copers within a year of injury. Those with low Ankle-GO scores and female patients should receive additional rehabilitation to increase the odds of becoming a coper.
Centre-based childcare in early childhood and child obesity: systematic review and meta-analysis protocol
Authors: Kucab Michaela , Keown-Stoneman Charles D G , Birken Catherine , Perlman Michal , Parsons Janet , Maguire Jonathon L
Published: August 2024

Objectives

Centre-based childcare has been identified as a promising environment for obesity prevention in early childhood, but the longitudinal relationships between attending centre-based childcare and child obesity are not well understood. The objective of this systematic review is to evaluate the longitudinal associations between centre-based childcare attendance in early childhood and child body mass index compared with other childcare settings or parental care. Subgroup analyses will also be conducted to determine if socioeconomic factors and characteristics of the childcare setting modify the relationships.

Methods

Databases that will be searched include MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Database and Web of Science. Longitudinal prospective cohort studies, retrospective cohort studies, case–control studies and intervention trials conducted in middle-income and high-income countries will be included in the search strategy. Sensitivity and subgroup analyses will be conducted to explore factors that may modify the findings. Study selection, data extraction, risk of bias and quality of evidence assessments will be conducted independently and in duplicate by two reviewers. Risk of bias will be assessed using the Risk Of Bias In Non-randomized Studies - of Exposure tool. Meta-analysis will be conducted using random effects models to account for between-study variation. Heterogeneity across included studies will be estimated using the I
2
statistic. If meta-analysis is not possible, a narrative summary will be provided. The quality of the evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation tool.

Ethics and dissemination

Ethical approval is not required for this study since no data will be collected. Findings aim to inform interventions and guide efforts in childcare settings to support optimal child growth. Results will be published in a peer-reviewed journal. Results may be of relevance for childcare and public health policy, researchers, parents and healthcare practitioners.

PROSPERO registration number

CRD42023436911.
Balancing key stakeholder priorities and ethical principles to design a trial comparing intervention or expectant management for early-onset selective fetal growth restriction in monochorionic twin pregnancy: FERN qualitative study
Authors: Mitchell Tracy Karen , Popa Mariana , Ashcroft Richard Edmund , Prasad Smriti , Sharp Andrew , Carnforth Christine , Turner Mark , Khalil Asma , Fenwick Natasha , Leven Shauna ,   The FERN study team, Woolfall Kerry
Published: August 2024

Objectives

As part of the FERN feasibility study, this qualitative research aimed to explore parents’ and clinicians’ views on the acceptability, feasibility and design of a randomised controlled trial (RCT) of active intervention versus expectant management in monochorionic (MC) diamniotic twin pregnancies with early-onset (prior to 24 weeks) selective fetal growth restriction (sFGR). Interventions could include laser treatment or selective termination which could lead to the death or serious disability of one or both twins.

Design

Qualitative semi-structured interviews with parents and clinicians. Data were analysed using reflexive thematic analysis and considered against the Principles of Biomedical Ethics.

Participants and setting

We interviewed 19 UK parents experiencing (six mothers, two partners) or had recently experienced (eight mothers, three partners) early-onset sFGR in MC twin pregnancy and 14 specialist clinicians from the UK and Europe.

Results

Participants viewed the proposed RCT as ‘ethically murky’ because they believed that the management of sFGR in MC twin pregnancy should be individualised according to the type and severity of sFGR. Clinicians prioritised the gestational age, size, decrease in growth velocity, access to the placental vessels and acceptability of intervention for parents. Discussions and decision-making about selective termination appeared to cause long-term harm (maleficence). The most important outcome for parents and clinicians was ‘live birth’. For clinicians, this was the live birth of at least one twin. For parents, this meant the live birth of both twins, even if this meant that their babies had neurodevelopmental impairment or disabilities.

Conclusions

All three pregnancy management approaches for sFGR in MC twin pregnancy carry risks and benefits, and the ultimate goal for parents is to receive individualised care to achieve the best possible outcome for both twins. An RCT was not acceptable to parents or clinicians or seen as ethically appropriate. Alternative study designs should be considered to answer this important research question.
Parental mental health during preconception years in association with offspring attention deficit hyperactivity disorder (ADHD): a systematic review protocol
Authors: Ann Johns Ditty , Quirk Shae E , Pasco Julie A , Hyde Natalie K , Williams Lana J
Published: August 2024

Introduction

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition prevalent in both children and adults. With growing awareness of the importance of the preconception period in health, it is essential to understand whether preconception parental mental health and related factors are related to onset of offspring ADHD. This protocol presents the methodology for undertaking a systematic review to investigate associations between parental mental health and/or psychotropic use during the preconception years and offspring ADHD.

Methods and analysis

Peer-reviewed literature will be identified by searching relevant electronic databases including Medline complete, Embase, PsycINFO and CINAHL; reference lists of eligible articles will be hand searched and grey literature considered. Eligible study designs include population-based and/or clinically based cohort or case–control studies. The primary exposure and outcome of interest is parental history of mental health conditions in the preconception period and offspring ADHD, respectively (ie, according to semistructured interviews/confirmed diagnosis by a relevant health professional or screening instruments). Critical appraisal will be undertaken. A descriptive synthesis will be presented including characteristics of the included studies, critical appraisal scores and a summary of main findings (eg, presented in tables, text and figures). A meta-analysis will be conducted, if possible, and statistical techniques will be employed if heterogeneity is detected.

Ethics and dissemination

Ethical permissions are not required for this systematic review since the study will only use published data. Findings from this systematic review will be published in a peer-reviewed scientific journal/presented at national and international conferences relevant to the field.

PROSPERO registration number

CRD42023460379.
Animations to communicate public health prevention messages: a realist review protocol
Authors: McCorry Kathleen , Maniatopoulos Gregory , Errington Linda , Land Ellie , Craig Michael , Vijaykumar Santosh , Bärnighausen Till , O'Brien Nicola
Published: August 2024

Introduction

With digital and social media advances, animated health communications (health animations) are highly prevalent globally, yet the evidence base underpinning them remains unclear and limited. While individual studies have attempted to explore the effectiveness, acceptability and usability of specific features of health animations, there is substantial heterogeneity in study design, comparators and the animation design and content. Consequently, there is a need to synthesise evidence of health animations using an approach that recognises this contextual complexity, which may affect their impact.

Methods and analysis

This project aims to understand why, how, for whom, to what extent and in which contexts health animations are expected to promote preventive health behaviours. We will conduct a realist review following Pawson’s five iterative stages to (1) define the review scope and locate existing theories; (2) search for evidence; (3) select and appraise evidence; (4) extract data and (5) synthesise data and refine theory. Engagement with stakeholders involved in developing, testing, implementing or commissioning health communications, including animations, will allow the initial programme theory to be tested and refined. The findings will be reported in accordance with Realist and Meta-narrative Evidence Syntheses: Evolving Standards.

Ethics and dissemination

Ethical approval for the public stakeholder work was provided by the Northumbria University Research Ethics Committee. We will disseminate the findings widely through outputs tailored to target specific professional, public and patient audiences. Dissemination will occur through stakeholder engagement as part of the research, a peer-reviewed publication and conference presentations.

PROSPERO registration number

CRD42023447127.
Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) using dose–volume constraints development: a study protocol
Authors: Simões Rita , Gulliford Sarah , Seddon Beatrice , Dehbi Hakim-Moulay , Robinson Martin , Forsyth Sharon , Hughes Ana , Gaunt Piers , Nguyen Thuy-Giang , Elston Stephanie , Mohammed Kabir , Zaidi Shane , Miles Elizabeth , Hoskin Peter , Harrington Kevin , Miah Aisha
Published: August 2024

Introduction

Radiotherapy improves local tumour control in patients with soft tissue sarcoma of the extremities (STSE) but it also increases the probability of long-term toxicities such as tissue fibrosis, joint stiffness and lymphoedema. The use of radiation dose and volume thresholds, called dose constraints, may potentially reduce the development of toxicities in STSE. The aim of this study is to determine predictors of radiotherapy-related side effects for STSE.

Methods and analysis

Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) is a multicentre observational study comprising two cohorts (PredicT A and B). PredicT A, a retrospective analysis of the UK VorteX (NCT00423618) and IMRiS clinical trials (NCT02520128), is aimed at deriving a statistical model for development of dose–volume constraints. This model will use receiving operator characteristics and multivariate analysis to predict radiotherapy side effects and patient-reported outcomes. PredicT B, a prospective cohort study of 150 patients with STSE, is aimed at testing the validity of those dose–volume constraints. PredicT B is open and planned to complete recruitment by September 2024.

Ethics and dissemination

PredicT B has received ethical approval from North West - Liverpool Central Research Ethics Committee (20/NW/0267). Participants gave informed consent to participate in the study before taking part. We will disseminate our findings via publications, presentations, national and international conference meetings and engage with local charities.

Trial registration number

NCT05978024.
Evidence-informed, experience-based co-design: a novel framework integrating research evidence and lived experience in priority-setting and co-design of health services
Authors: Morley Claire , Jose Kim , Hall Sonj E , Shaw Kelly , McGowan Deirdre , Wyss Martina , Winzenberg Tania
Published: August 2024

Objective

To describe a new co-design framework termed Evidence-informed, Experience-based Co-design (E2CD).

Background

Involving consumers and clinicians in planning, designing and implementing services results in the end-product being more likely to meet the needs of end-users and increases the likelihood of their uptake and sustainability. Different forms and definitions of co-design have been described in the literature and have had varying levels of success in health service redesign. However, many fall short of including people with lived experience in all aspects of the process, particularly in setting priorities for service (re)design. In addition, health services need to deliver evidence-based care as well as care that meets the needs of users, yet few ways of integrating research evidence into co-design processes are described. This paper describes a new framework to approach co-design which addresses these issues. We believe that it offers a roadmap to address some of healthcare’s most wicked problems and potentially improve outcomes for some of the most vulnerable people in our society. We use improving services for people with high healthcare service utilisation as a working example of the Framework’s application.

Conclusion

Evidence-informed experience-based co-design has the potential to be used as a framework for co-design that integrates research evidence with lived experience and provides people with lived experience a central role in decision-making about prioritising and designing services to meet their needs.
Study protocol: diagnostic accuracy study comparing Cy-Tb and STANDARD F TB-Feron FIA tests for tuberculosis infection diagnosis in Vietnam
Authors: Nguyen Han Thi , Vo Luan Nguyen Quang , Codlin Andrew , Forse Rachel , Wingfield Tom , Sidney Kristi , MacLean Emily Lai-Ho , Creswell Jacob , Kirubi Beatrice , Davies Forsman Lina
Published: August 2024

Introduction

The large reservoir of tuberculosis (TB) infections is one of the main reasons for the persistent incidence of TB. Accurate diagnostic tests are crucial to correctly identify and treat people with TB infection, which is vital to eliminate TB globally. The rdESAT-6 and rCFP-10 (Cy-Tb) injection (‘Cy-Tb’), a TB-specific antigen skin test and STANDARD F TB-Feron FIA (‘Standard F TB’) measuring interferon-gamma by fluorescence immunoassay assay are two novel tools for the diagnosis of TB infection which offer advantages compared with current tests in low-resource settings and reduced costs to both health systems and TB-affected people. The proposed study aims to evaluate the diagnostic accuracy of these two new tests for TB infection diagnosis.

Methods and analysis

This cross-sectional study aims to assess the diagnostic accuracy for TB infection of the Cy-Tb skin test and Standard F TB assay (investigational tests) compared with the QuantiFERON-TB Gold Plus (QFT-Plus) assay as the immunological reference standard. Three different cohorts of study participants will be recruited at the Vietnam National Lung Hospital: adults with bacteriologically confirmed pulmonary TB (n=100), household contacts of people with TB (n=200) and people without TB infection (n=50). All consenting participants will undergo simultaneous testing with Cy-Tb, Standard F TB and QFT-Plus. The primary endpoint is the diagnostic accuracy of the Cy-Tb skin test and Standard F TB assay, expressed as sensitivity and specificity against the reference standard.

Ethics and dissemination

Ethical approval was granted by the Vietnam National Lung Hospital Institutional Review Board (65/23/CN-HDDD-BVPTU) and the Swedish Ethical Review Authority (Dnr 2023-04271-01). Study results will be disseminated to the scientific community and policymakers through scientific publications.

Trial registration number

NCT06221735
.
Antibiotic use in public hospitals in Vietnam between 2018 and 2022: a retrospective study
Authors: Dat Vu Quoc
Published: August 2024

Objective

To assess the patterns of antibiotic consumption and expenditure in Vietnam.

Design

This was a cross-sectional study.

Setting

This study used data of antibiotic procurement that was publicly announced from 2018 to 2022 as a proxy for antibiotic consumption.

Participants

This study included winning bids from 390 procurement units in 63 provinces in Vietnam for 5 years with a total expenditure of US$ 12.8 billions that represented for approximately 20–30% of the national funds spend on medicines.

Interventions

Antibiotics were classified by WHO AWaRe (Access, Watch and Reserve) classification.

Outcome measures

The primary outcomes were the proportions of antibiotic consumptions in number of defined daily doses (DDD) and expenditures.

Results

There was a total of 2.54 million DDDs of systemic antibiotics, which accounted for 24.7% (US $3.16 billions) of total expenditure for medicines purchased by these public health facilities. The overall proportion of Access group antibiotics ranges from 40.9% to 53.8% of the total antibiotic consumption over 5 years.

Conclusion

This analysis identifies an unmet target of at least 60% of the total antibiotic consumption being Access group antibiotics and an unreasonable share of expenditure for non-essential antibiotics in public hospitals in Vietnam.
Teletherapy to address language disparities in deaf and hard-of-hearing children: study protocol for an inclusive multicentre clinical trial
Authors: Naugle Kendyl , Stephans Jihyun , Lazar Ann , Kearns Joy M , Coulthurst Sarah , Tebb Kathleen P , Chan Dylan K
Published: August 2024

Introduction

Children who are deaf or hard-of-hearing (DHH) are at risk for speech and language delay. Language outcomes are worse in DHH children from lower socioeconomic backgrounds, due in part to disparities in access to specialised speech-language therapy. Teletherapy may help improve access to this specialised care and close this language gap. Inclusion of diverse DHH children in prospective randomised clinical trials has been challenging but is necessary to address disparities and pursue hearing health equity. Stakeholder input regarding decisions on study design elements, including comparator groups, masking, assessments and compensation, is necessary to design inclusive studies. We have designed an inclusive, equitable comparativeness effectiveness trial to address disparities in paediatric hearing health. The specific aims of the study are to determine the effect of access to and utilisation of speech-language teletherapy in addressing language disparities in low-income children who are DHH.

Methods and analysis

After stakeholder input and pilot data collection, we designed a randomised clinical trial and concurrent longitudinal cohort trial to be conducted at four tertiary children’s hospitals in the USA. Participants will include 210 DHH children aged 0–27 months. 140 of these children will be from lower income households, who will be randomised 1:1 to receive usual care versus usual care plus access to supplemental speech-language teletherapy. 70 children from higher income households will be simultaneously recruited as a comparison cohort. Primary outcome measure will be the Preschool Language Scales Auditory Comprehension subscale standard score, with additional speech, language, hearing and quality of life validated measures as secondary outcomes.

Ethics and dissemination

This study was approved by the Institutional Review Boards of the participating sites: the University of California, San Francisco (19-28356), Rady Children’s Hospital (804651) and Seattle Children’s Hospital (STUDY00003750). Parents of enrolled children will provide written informed consent for their child’s participation. Professional and parent stakeholder groups that have been involved throughout the study design will facilitate dissemination and implementation of study findings via publication and through national and regional organisations.

Trial registration number

NCT04928209.
Perspectives of parents with lived experience of cytomegalovirus infection, on universal newborn screening for congenital cytomegalovirus (cCMV) in Canada: a patient-led qualitative study
Authors: Beaulieu Laija , Bruce Marcia , Tiedemann Barbara , Chishti Rabea , Iyiola Iqmat , Penny Sarah , Leroux Caroline , Nielssen Ingrid , Santana Maria Jose , Castillo Eliana
Published: August 2024

Objective

To understand parental perspectives regarding universal newborn screening (UNS) for congenital cytomegalovirus (cCMV) in Canada.

Design

A qualitative, patient-led study using the Patient and Community Engagement Research approach consisting of online focus groups and in-depth individual interviews to understand parental preferences regarding UNS for cCMV. Data were analysed iteratively using inductive thematic analysis and narrative story analysis.

Setting

Canada-wide study conducted via video conference from October to December 2023.

Patients

12 participants from five Canadian provinces who self-identified as 18 years of age or older and as having parental lived experience with cytomegalovirus (CMV) or cCMV participated in the study.

Results

We identified three themes: (1) attitudes about UNS for cCMV, including participants’ unanimous support for UNS and confirmation that parental anxiety is not a deterrent for screening, (2) cCMV diagnosis, including the importance of coupling cCMV diagnosis with access to treatment and medical support and (3) awareness of cCMV, where participants shared their frustration about the lack of public and pregnant people’s awareness of cCMV.

Conclusions

Parental anxiety is not a deterrent for UNS for cCMV. Children with cCMV and their families deserve every opportunity to attain their best possible outcomes. UNS offers children with cCMV access to early intervention if they need it, and also helps to raise awareness and education to prevent future CMV infections.
How can we better engage female athletes? A novel approach to health and performance education in adolescent athletes
Authors: Roche Megan , McIntyre Abby , Oliver Carolyn , Sainani Kristin , Boyd Tatum , Stoner Austin , Kraus Emily
Published: August 2024

Objectives

To evaluate the impact of a video series versus online pamphlets/blog posts on Female Athlete Triad (Triad) and Relative Energy Deficiency in Sport (REDs) knowledge in high school female runners.

Methods

Runners from 10 US schools were cluster-randomised into groups to either watch videos or read pamphlets on Triad/REDs, nutrition, menstrual cycle, bone health and mental health. Changes in knowledge and interest were assessed using generalised estimating equations.

Results

Forty-five runners were in the video intervention group (mean age=16.0) and 39 in the control (mean age=15.7). Both groups showed knowledge gains for all topics, except for mental health, where knowledge was already high. The intervention group’s knowledge increase (means=75.7 and 93.3) was not significantly higher than the control’s (means=77.9 and 93.6) (p=0.149). However, the intervention group had stronger scores on behavioural impact, information novelty and interest (means=3.77, 3.93 and 4.14) compared with the control’s (means=3.36, 3.48 and 3.52) (p≤0.05, p≤0.05 and p≤0.001).

Conclusion

Both videos and pamphlets improved knowledge of Triad/REDs and female athlete science, however videos had a greater influence on athletes’ engagement and behavioural intentions.
Age-related patterns of microbial dysbiosis in multiplex inflammatory bowel disease families
Authors: Jacobs Jonathan P , Spencer Elizabeth A , Helmus Drew S , Yang Julianne C , Lagishetty Venu , Bongers Gerold , Britton Graham , Gettler Kyle , Reyes-Mercedes Pamela , Hu Jianzhong , Hart Amy , Lamousé-Smith Esi , Wehkamp Jan , Landers Carol , Debbas Philip , Torres Joana , Colombel Jean-Frederic , Cho Judy , Peter Inga , Faith Jeremiah , Braun Jonathan , Dubinsky Marla
Published: August 2024

Objective

IBD is characterised by dysbiosis, but it remains unclear to what extent dysbiosis develops in unaffected at-risk individuals. To address this, we investigated age-related patterns of faecal and serum markers of dysbiosis in high-risk multiplex IBD families (two or more affected first-degree relatives).

Design

Faecal and serum samples were collected from multiplex IBD and control families (95 IBD, 292 unaffected, 51 controls). Findings were validated in independent cohorts of 616 and 1173 subjects including patients with IBD, infants born to mothers with IBD and controls. 16S rRNA gene sequencing and global untargeted metabolomics profiling of faeces and serum were performed.

Results

Microbial and metabolomic parameters of dysbiosis progressively decreased from infancy until age 8. This microbial maturation process was slower in infants born to mothers with IBD. After age 15, dysbiosis steadily increased in unaffected relatives throughout adulthood. Dysbiosis was accompanied by marked shifts in the faecal metabolome and, to a lesser extent, the serum metabolome. Faecal and serum metabolomics dysbiosis indices were validated in an independent cohort. Dysbiosis was associated with elevated antimicrobial serologies but not with faecal calprotectin. Dysbiosis metrics differentiated IBD from non-IBD comparably to serologies, with a model combining calprotectin, faecal metabolomics dysbiosis index and serology score demonstrating highest accuracy.

Conclusion

These findings support that dysbiosis exists as a pre-disease state detectable by faecal and serum biomarkers for IBD risk prediction. Given the expansion of disease-modifying agents and non-invasive imaging, the indices developed here may facilitate earlier diagnoses and improved management in at-risk individuals.
Persistence of residual shunt at 6 and 12 months after transoesophageal echocardiography-guided percutaneous closure of a patent foramen ovale for cryptogenic stroke
Authors: Witte Lars S , el Bouziani Abdelhak , Beijk Marcel A M , Robbers-Visser Danielle , Coutinho Jonathan M , Tijssen Jan G P , Straver Bart , Bouma Berto J , de Winter Robbert J
Published: August 2024

Background

Young patients suffering from cryptogenic stroke alongside a patent foramen ovale (PFO) are often considered for percutaneous device closure to reduce the risk of stroke recurrence. Residual right-to-left shunt after device closure may persist in approximately a quarter of the patients at 6 months, and some may close at a later time point. This study aimed to assess the prevalence and persistence of residual right-to-left shunt after percutaneous PFO closure.

Methods

Consecutive patients undergoing transoesophageal echocardiography-guided PFO closure for cryptogenic stroke between 2006 and 2021, with echocardiographic follow-up including contrast bubble study and Valsalva manoeuvre, were enrolled. Follow-up transthoracic echocardiography was performed at 6 months and repeated at 12 months in case of residual right-to-left shunt. Primary outcomes included the prevalence and grade of residual right-to-left shunt at 6 and 12 months after percutaneous PFO closure.

Results

227 patients were included with a mean age of 43±11 years and 50.2% were women. At 6-month follow-up, 72.7% had no residual right-to-left shunt, 12.3% small residual right-to-left shunt, 6.6% moderate residual right-to-left shunt and 8.4% large residual right-to-left shunt. At 12-month follow-up, the presence of residual right-to-left shunt in all patients was 12.3%, of whom 6.6% had small residual right-to-left shunt, 2.6% had moderate residual right-to-left shunt and 3.1% had large residual right-to-left shunt.

Conclusions

Residual right-to-left shunts are common at 6 months after percutaneous closure of PFO. However, the majority are small and two-thirds of residual right-to-left shunts achieve complete closure between 6 and 12 months.
Concurrent Binary Trees for Large-Scale Game Components
Authors: Benyoub Anis , Dupuy Jonathan
Published: August 2024

A concurrent binary tree (CBT) is a GPU-friendly data-structure suitable for the generation of bisection based terrain tessellations, i.e., adaptive triangulations over square domains. In this paper, we expand the benefits of this data-structure in two respects. First, we show how to bring bisection based tessellations to arbitrary polygon meshes rather than just squares. Our approach consists of mapping a triangular subdivision primitive, which we refer to as a bisector, to each halfedge of the input mesh. These bisectors can then be subdivided adaptively to produce conforming triangulations solely based on halfedge operators. Second, we alleviate a limitation that restricted the triangulations to low subdivision levels. We do so by using the CBT as a memory pool manager rather than an implicit encoding of the triangulation as done originally. By using a CBT in this way, we concurrently allocate and/or release bisectors during adaptive subdivision using shared GPU memory. We demonstrate the benefits of our improvements by rendering planetary scale geometry out of very coarse meshes. Performance-wise, our triangulation method evaluates in less than 0.2ms on console-level hardware.