bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simulating genetic risk scores from summary statistics with an application to type 1 diabetes
Authors: Squires Steven , Weedon Michael N. , Oram Richard A. 
Published: May 2024

AbstractMotivationGenetic risk scores (GRS) summarise genetic data into a single number and allow for discrimination between cases and controls. Many applications of GRSs would benefit from comparisons with multiple datasets to assess quality of the GRS across different groups. However, genetic data is often unavailable. If summary statistics of the genetic data could be used to simulate GRSs more comparisons could be made, potentially leading to improved research.ResultsWe present a methodology that utilises only summary statistics of genetic data to simulate GRSs with an example of a type 1 diabetes (T1D) GRS. An example on European populations of the mean T1D GRS for real and simulated data are 10.31 (10.12-10.48) and 10.38 (10.24-10.53) respectively. An example of a case-control set for T1D has a area under the receiver operating characteristic curve of 0.917 (0.903-0.93) for real data and 0.914 (0.898-0.929) for simulated data.AvailabilityThe code is available athttps://github.com/stevensquires/simulating_genetic_risk_scores.Contacts.squires@exeter.ac.uk
Remote Ischemic Conditioning for Neonatal Hypoxic-Ischemic Encephalopathy: A Safety and Feasibility Trial
Authors: Lo Emily , Cizmeci Mehmet N. , Wilson Diane , Ly Linh G. , El-Shahed Amr , Offringa Martin , Pierro Agostino , Kalish Brian T. 
Published: May 2024

ABSTRACTObjectiveTo test the hypothesis that remote ischemic conditioning (RIC) is safe and feasible as an adjunctive neuroprotective treatment in neonates with hypoxic-ischemic encephalopathy (HIE) during therapeutic hypothermia (TH).Study designIn this prospective, randomized, safety and dose escalation study in 32 neonates with HIE undergoing TH at a single quaternary referral NICU, four cohorts of consecutive patients received escalating therapy as follows: the first cohort of four patients received 3 minutes of limb ischemia by inflating a blood pressure cuff followed by 3 minutes of reperfusion; the second cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion; the third cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion on days 1 and 2 of TH; and the last cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion on days 1, 2, and 3 of TH. For patients randomized to the control arm (n=16), a blood pressure cuff was applied without inflation. Each patient received 4 cycles of RIC or sham. Clinical, biochemical, and safety outcomes were monitored in both groups.ResultsAll patients received the designated RIC therapy without interruption or delay on days 1-3 of TH. RIC was not associated with increased pain, vascular, cutaneous, muscular, or neural safety events. There was no difference in the incidence of seizures, brain injury, or mortality between the two groups with the escalation of RIC dose and frequency.ConclusionRIC is a safe and feasible adjunctive therapy for neonates with HIE undergoing TH. Future studies to investigate the potential efficacy of RIC for HIE are warranted.
Enhancing Healthcare Accessibility: A Comprehensive Usability Study of Pathpoint® eDerma Software
Authors: Subramaniyan Balamurugan , Naqvi Atlas , Mohamud Muna , Mahapatra Piyush 
Published: May 2024

AbstractThis research presents a comprehensive usability evaluation of Pathpoint® eDerma Software, conducted in accordance with IEC 62366-1:2015 standards. The study encompasses four diverse user groups, that includes administrators, medical photographers, dermatologists, and patients, ensuring a holistic assessment of the software’s usability and effectiveness. Through a combination of quantitative metrics and qualitative feedback, the study explores various aspects such as accessibility, navigation, safety, and user satisfaction. Potential risks to user experience and patient data security are identified and addressed to ensure compliance with safety standards. The findings highlight the software’s effectiveness in facilitating remote assessments, streamlining workflows, and improving patient care. This research contributes valuable insights to the ongoing refinement and optimisation of eDerma Software, aiming to enhance its usability, safety, and overall effectiveness in real-world healthcare settings.
EEG Correlates of Delayed Emergence after Remimazolam-Induced Anaesthesia Compared to Propofol
Authors: Lee Yeji , Park Sujung , Kim Hyoungkyu , Kim Jeongmin , Kim Eun Jung , Park Youngjai , Lee Uncheol , Kwon Jeongwook , Moon Joon-Young , Koo Bon-Nyeo 
Published: May 2024

AbstractBackgroundDelayed emergence from anaesthesia presents clinical challenges, including prolonged stays in the post-anaesthesia care unit (PACU). The neurobiological mechanisms underlying delayed emergence, particularly in remimazolam-induced anaesthesia, remain poorly understood. This study aimed to elucidate these mechanisms by comparing remimazolam and propofol anaesthesia, focusing on prefrontal electroencephalogram (EEG).MethodsPatients (age > 18,n= 48) underwent laparoscopic cholecystectomy randomly received remimazolam or propofol general anaesthesia. Power spectrogram analysis and functional connectivity measures, phase lag entropy (PLE) and phase lag index (PLI), were employed to the prefrontal EEG data collected at baseline, unconsciousness, and emergence. Correlation between EEG measures and Patient State Index (PSI) at PACU, as well as time to Aldrete 9, were compared.ResultsPSI values (P< 0.0001,P= 0.006) and time to Aldrete 9 at PACU (P< 0.001) revealed slower recovery in remimazolam-induced anaesthesia. Remimazolam group exhibited residual effects in power at theta (P= 0.018) and alpha (Ps< 0.001) bands and lower PLE during emergence in the alpha (P< 0.0001,P= 0.015) and beta (P= 0.016,P< 0.001) bands. Delayed consciousness recovery (time to Aldrete 9) under remimazolam was significantly correlated with PLE (Pearson’sr= -.78,P< 0.0001), and PLI (Pearson’sr= .69,P= 0.028) in the alpha band during deep anaesthesia.ConclusionDynamic changes in prefrontal EEG and the correlation analyses show the potential of EEG in predicting emergence speed, providing insights into the neurobiological mechanisms of short-term delayed emergence in remimazolam anaesthesia.
Mentorship in Health Research Institutions in Africa: A Systematic Review of Approaches, Benefits, Successes, Gaps and Challenges
Authors: Ng’oda Maurine , Gatheru Peter Muriuki , Oyeyemi Oyetunde , Busienei Phylis , Karugu Caroline H. , Mugo Sharon , Okoth Lilian , Nampijja Margaret , Kiwuwa-Muyingo Sylvia , Wado Yohaness Dibaba , Kitsao-Wekulo Patricia , Asiki Gershim , Gitau Evelyn 
Published: May 2024

AbstractBackgroundIn Africa, where the burden of diseases is disproportionately high, significant challenges arise from a shortage of skilled researchers, lack of research funding, and limited mentorship opportunities. The continent faces a substantial gap in research output largely attributed to the dearth of mentorship opportunities for early career researchers.ObjectiveTo explore existing mentorship approaches, identify challenges, gaps, successes, and benefits, and provide insights for strengthening mentorship programs in African health research institutions.MethodsWe registered the review protocol on the International Prospective Register of Systematic Reviews [CRD42021285018] and searched six electronic databases – EMBASE, AJOL, Web of Science, PubMed, DOAJ and JSTOR from inception to 10 November 2023, for studies published in English reporting on approaches of mentorship in health research in African countries. We also searched grey literature repositories, institutional websites, and reference lists of included studies for additional literature. Two independent reviewers conducted screening of titles and abstracts of identified studies, full-text screening, assessment of methodological quality, and data extraction. We assessed study quality against the Mixed Methods Appraisal Tool (MMAT). We resolved any disagreements through discussion and consensus. We employed a narrative approach to synthesize the findings.ResultsWe retrieved 1799 articles and after screening, included 21 studies in the review. The reviewers identified 20 mentorship programs for health researchers (N=1198) in 12 African countries mostly focusing on early career researchers and junior faculty members. A few included mid-career and senior researchers. We categorized the programs under three key mentoring approaches: international collaborative programs, regional and in-country collaborations, and specialized capacity-building initiatives. Our review highlighted the following successes and benefits of health research mentorship programs: the establishment of collaborations and partnerships, development of research programs and capacities, improvement of individual skills and confidence, increased publications, and successful grant applications. The gaps identified were limited funding, lack of a mentorship culture, negative attitudes towards research careers, and lack of prioritization of research mentorship.ConclusionOur review highlights a diverse landscape of health research mentorship aspects predominantly targeting early career researchers and heavily driven by the North. There is a need for locally driven mentorship initiatives in Africa to strengthen mentorship in order to advance health research in the region.
Effects of prenatal small-quantity lipid-based nutrient supplements on pregnancy, birth and infant outcomes: a systematic review and meta-analysis of individual participant data from randomized controlled trials in low- and middle-income countries
Authors: Dewey Kathryn G. , Wessells K. Ryan , Arnold Charles D. , Adu-Afarwuah Seth , Arnold Benjamin F. , Ashorn Ulla , Ashorn Per , Garcés Ana , Huybregts Lieven , Krebs Nancy F. , Lartey Anna , Leroy Jef L. , Maleta Kenneth , Matias Susana L. , Moore Sophie E. , Mridha Malay K. , Okronipa Harriet , Stewart Christine P. 
Published: May 2024

AbstractBackgroundUndernutrition during pregnancy increases the risk of giving birth to a small vulnerable newborn. Small-quantity lipid-based nutrient supplements (SQ-LNS) contain both macro- and micronutrients and can help prevent nutritional deficiencies during pregnancy and lactation.ObjectivesWe examined effects of SQ-LNS provided to pregnant women, compared to a) iron and folic acid or standard of care (IFA/SOC) or b) multiple micronutrient supplements (MMS), and identified characteristics that modified effects of SQ-LNS on birth outcomes.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 4 randomized controlled trials of SQ-LNS provided to pregnant women (n = 5,273). We generated study-specific and subgroup estimates of SQ-LNS compared with IFA/SOC or MMS and pooled the estimates. In sensitivity analyses, we examined whether results differed depending on methods for gestational age dating, birth anthropometry, or study design.ResultsSQ-LNS (vs IFA/SOC) increased birth weight (mean difference: +49g; 95% CI: 26, 71g), duration of gestation (+0.12 wk; 95% CI: 0.01, 0.24 wk), and all birth anthropometric z-scores (+0.10-0.13 SD); it reduced risk of low birthweight by 11%, newborn stunting by 17%, newborn wasting by 11%, and small head size by 11%. Only 2 trials compared SQ-LNS and MMS; birth outcomes did not differ except for a marginal increase in head circumference for gestational age (+0.11; 95% CI: -0.01, 0.23). Effect estimates for SQ-LNS vs IFA/SOC were greater among female infants and among women with body mass index < 20 kg/m2, inflammation, malaria, or household food insecurity. Effect estimates for SQ-LNS vs MMS were greater among female infants, first-born infants, and women < 25 y.ConclusionsSQ-LNS had positive impacts on multiple outcomes compared to IFA/SOC, but further research directly comparing SQ-LNS and MMS is needed. Targeting SQ-LNS to vulnerable subgroups may be worth considering. Analysis registered atwww.crd.york.ac.uk/PROSPERO(CRD42021283391).
Human genetics implicate thromboembolism in the pathogenesis of long COVID in individuals of European ancestry
Authors: Schuermans Art , Verstraete Andreas , Lammi Vilma , Nakanishi Tomoko , Ardissino Maddalena , Van den Eynde Jef , Sun Benjamin B. , Georgakis Marios K. , Guillen-Guio Beatriz , Wain Louise V. , Brightling Christopher E. ,   PHOSP-COVID Collaborative Group, Van Weyenbergh Johan , Lewandowski Adam J. , Raman Betty , Zeberg Hugo , Ollila Hanna M. , Burgess Stephen , Natarajan Pradeep , Honigberg Michael C. , Freson Kathleen , Vanassche Thomas , Verhamme Peter 
Published: May 2024

AbstractSARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organs. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and thromboembolism; however, compelling evidence from humans is limited and causal associations remain unclear. Here, we tested the association of thromboembolism-related genetic variants with long COVID in the Long COVID Host Genetics Initiative (ncases=3,018;ncontrols=994,582). Primary analyses revealed that each unit increase in the log-odds of genetically predicted venous thromboembolism risk was associated with 1.21-fold odds of long COVID (95%CI: 1.08-1.35;P=1.2×10-3). This association was independent of acute COVID-19 severity, robust across genetic instruments and methods, and replicated in external datasets for both venous thromboembolism and long COVID. Downstream analyses using gene-specific instruments, along with protein and gene expression data, suggested the protease-activated receptor 1 (PAR-1) as a potential molecular contributor to long COVID. These findings provide human genetic evidence implicating thromboembolism in long COVID pathogenesis.
Assessment of Cardiovascular Disease Risk Factors in Korean Children: Impact of Various Pediatric Hypertension Guidelines and Application of the Korean Blood Pressure Reference
Authors: Kim Jeong Yeon , Park Sangshin , Cho Heeyeon 
Published: May 2024

AbstractBackgroundThe global prevalence of pediatric hypertension (HTN) is increasing and is a significant precursor of cardiovascular disease (CVD). We performed a comparative analysis of two guidelines for pediatric HTN: the 2017 American Academy of Pediatrics (AAP) and the 2016 European Society for Hypertension (ESH); the Korean blood pressure (BP) reference was applied to the Korean pediatric population.MethodsData from 2,060 children and adolescents aged 10-18 years from the Korean National Health and Nutrition Examination Survey (2016-2018) were analyzed. BP was classified according to the AAP, ESH, and Korea Regional BP Classification (KRC). High BP was defined as BP exceeding the normotensive range.ResultsThe prevalence of high BP in Korean youth was notably higher in the AAP group than that in the ESH group (19.5% vs. 10.6%, p<0.0001). There were variations in the prevalence based on age, sex, and obesity. No significant disparities were observed between the AAP and KRC groups in terms of high BP prevalence. The application of the AAP and KRC demonstrated a more comprehensive reflection of CVD risk factors, including obesity and metabolic profiles, compared to the ESH. The KRC showed a tendency for more non-obese individuals to be categorized as having elevated BP, although this difference was not statistically significant.ConclusionsThis study advocates the adoption of the KRC for defining pediatric HTN in Korea. The KRC identified individuals with CVD risk as having a high BP, which raises the potential of the KRC for early intervention in CVD risk control.
Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells
Authors: Wang Peng , Wood Olivia , Choleva Lauryn , Liu Hongtao , Karakose Esra , Lambertini Luca , Pillard Aidan , Wu Vickie , Garcia-Ocana Adolfo , Scott Donald K. , Kumar Kunal , DeVita Robert J. , Stewart Andrew F. 
Published: May 2024

AbstractThe small molecule DYRK1A inhibitor, harmine, induces human beta cell proliferation, expands beta cell mass, enhances expression of beta cell phenotypic genes, and improves human beta cell function in vitroandin vivo. It is unknown whether the “pro-differentiation effect” is a DYRK1A inhibitor class-wide effect. Here we compare multiple commonly studied DYRK1A inhibitors. Harmine, 2-2c and 5-IT increase expression of PDX1, MAFA, NKX6.1, SLC2A2, PCSK1, MAFB, SIX2, SLC2A2, SLC30A8, ENTPD3 in normal and T2D human islets. Unexpectedly, GNF4877, CC-401, INDY, CC-401 and Leucettine fail to induce expression of these essential beta cell molecules. Remarkably, the pro-differentiation effect is independent of DYRK1A inhibition: although silencing DYRK1A induces human beta cell proliferation, it has no effect on differentiation; conversely, harmine treatment enhances beta cell differentiation in DYRK1A-silenced islets. A careful screen of multiple DYRK1A inhibitor kinase candidate targets was unable to identify pro-differentiation pathways. Overall, harmine, 2-2c and 5-IT are unique among DYRK1A inhibitors in their ability to enhance both beta cell proliferation and differentiation. While beta cellproliferationis mediated by DYRK1A inhibition,the pro-differentiationeffects of harmine,2-2cand 5-IT are distinct, and unexplained in mechanistic terms. These considerations have important implications for DYRK1A inhibitor pharmaceutical development.
Bacterial sensor evolved by decreasing complexity
Authors: Monteagudo-Cascales Elizabet , Gavira José A. , Xing Jiawei , Velando Félix , Matilla Miguel A. , Zhulin Igor B. , Krell Tino 
Published: May 2024

AbstractBacterial receptors feed into multiple signal transduction pathways that regulate a variety of cellular processes including gene expression, second messenger levels and motility. Receptors are typically activated by signal binding to ligand binding domains (LBD). Cache domains are omnipresent LBDs found in bacteria, archaea, and eukaryotes, including humans. They form the predominant family of extracytosolic bacterial LBDs and were identified in all major receptor types. Cache domains are composed of either a single (sCache) or a double (dCache) structural module. The functional relevance of bimodular LBDs remains poorly understood. Here, we identify the PacF chemoreceptor in the phytopathogenPectobacterium atrosepticumthat recognizes formate at the membrane distal module of its dCache domain, triggering chemoattraction. We further demonstrate that a family of formate-specific sCache domains has evolved from a dCache domain, exemplified by PacF, by losing the membrane proximal module. By solving high-resolution structures of two family members in complex with formate, we show that the molecular basis for formate binding at sCache and dCache domains is highly similar, despite their low sequence identity. The apparent loss of the membrane proximal module may be related to the observation that dCache domains bind ligands typically at the membrane distal module, whereas the membrane proximal module is not involved in signal sensing. This work advances our understanding of signal sensing in bacterial receptors and suggests that evolution by reducing complexity may be a common trend shaping their diversity.SignificanceMany bacterial receptors contain multi-modular sensing domains indicative of complex sensory processes. The presence of more than one sensing module likely permits the integration of multiple signals, although, the molecular detail and functional relevance for these complex sensors remain poorly understood. Bimodular sensory domains are likely to have arisen from the fusion or duplication of monomodular domains. Evolution by increasing complexity is generally believed to be a dominant force. Here we reveal the opposite – how a monomodular sensing domain has evolved from a bimodular one. Our findings will thus motivate research to establish whether evolution by decreasing complexity is typical of other sensory domains.
Comparative transcriptomics reveal a highly polymorphicXanthomonasHrpG virulence regulon
Authors: Quiroz Monnens Thomas , Roux Brice , Cunnac Sébastien , Charbit Erika , Carrère Sébastien , Lauber Emmanuelle , Jardinaud Marie-Françoise , Darrasse Armelle , Arlat Matthieu , Szurek Boris , Pruvost Olivier , Jacques Marie-Agnès , Gagnevin Lionel , Koebnik Ralf , Noël Laurent D. , Boulanger Alice 
Published: May 2024

ABSTRACTBacteria of the genusXanthomonascause economically significant diseases in various crops. Their virulence is dependent on the translocation of type III effectors (T3Es) into plant cells by the type III secretion system (T3SS), a process regulated by the master response regulator HrpG. Although HrpG has been studied for over two decades, its regulon across diverseXanthomonasspecies, particularly beyond type III secretion, remains understudied. In this study, we conducted transcriptome sequencing to explore the HrpG regulons of 17Xanthomonasstrains, encompassing six species and nine pathovars, each exhibiting distinct host and tissue specificities. We employed constitutive expression of plasmid-bornehrpG*, which encodes a constitutively active form of HrpG, to induce the regulon. Our findings reveal substantial inter- and intra-specific diversity in the HrpG* regulons across the strains. Besides 21 genes directly involved in the biosynthesis of the T3SS, the core HrpG* regulon is limited to only five additional genes encoding the transcriptional activator HrpX, the two T3E proteins XopR and XopL, a major facility superfamily (MFS) transporter, and the phosphatase PhoC. Interestingly, genes involved in chemotaxis and genes encoding enzymes with carbohydrate-active and proteolytic activities are variably regulated by HrpG*. The diversity in the HrpG* regulon suggests that HrpG-dependent virulence inXanthomonasmight be achieved through several distinct strain-specific strategies, potentially reflecting adaptation to diverse ecological niches. These findings enhance our understanding of the complex role of HrpG in regulating various virulence and adaptive pathways, extending beyond T3Es and the T3SS.IMPORTANCEIn the decades since its discovery, HrpG and its role in the regulation of the type III secretion system (T3SS) and its associated type III effectors (T3Es) inXanthomonashas been the subject of extensive research. Despite notable progress in understanding its molecular regulatory mechanisms, the full spectrum of processes under control of HrpG, particularly beyond the T3SS and T3Es, and the degree of regulatory conservation across plant-pathogenicXanthomonasspecies, remained unclear. To address this knowledge gap, we systematically compared the transcriptomes of 17Xanthomonasstrains, expressing a constitutively active form of HrpG, called HrpG*. We showed that HrpG* regulates different physiological processes other than the T3SS and T3Es and that this regulation shows substantial variation across the different strains. Taken together, our results provide new insights intoXanthomonas-plant interactions through the regulation of different metabolic and virulence pathways by the master response regulator HrpG.