bluuebunny/crossref_metadata_2025 huggingface dataset:
A realist approach to implementation fidelity in a mixed-method evaluation of electronic decision support systems to improve the quality of antenatal care in Nepal
Authors: Radovich Emma , Karki Sulata , Das Seema , Shakya Rajani , McCarthy Ona L. , Shrestha Abha , Calvert Clara , Campbell Oona M. R. , Penn-Kekana Loveday
Published: May 2024

Background

Understanding implementation fidelity, or adherence to the intervention-as-intended, is essential to interpreting the results of evaluations. In this paper, we propose a longitudinal, explanatory approach to implementation fidelity through a realist evaluation lens. We apply this approach to a mixed-method assessment of implementation fidelity to an electronic decision support system intervention to improve the quality of antenatal care in Nepal.

Methods

The tablet-based electronic decision support system was implemented in 19 primary care facilities in Nepal. As part of the project’s process evaluation, we used four data sources – monitoring visit checklists and fieldnotes, software backend data, and longitudinal case studies in four facilities – to examine three components of fidelity: use at the point of care, use for all antenatal visits, and quality of data entry. Quantitative data were analysed descriptively. Qualitative data were analysed thematically using template analysis to examine descriptive findings across the three fidelity components and later to develop and reflect on the causal mechanisms. Findings were synthesised, drawing on Normalization Process Theory, to understand the processes driving the different patterns of fidelity observed.

Results

Fidelity to point-of-care use declined over time with healthcare providers often entering data after antenatal visits had ended because providers understood the intervention as primarily about recordkeeping rather than decision support. Even in facilities with higher fidelity to point-of-care use, software decision-support prompts were largely ignored. Low antenatal client caseloads and the suggestion by fieldworkers to practice back-entering data from previous antenatal visits undermined understanding of the intervention’s purpose for decision support.

Conclusions

Our assessment explains how and why patterns of implementation fidelity occurred, yielding more nuanced understanding of the project evaluation’s null result that moves beyond intervention vs implementation failure. Our findings demonstrate the importance of discussing intervention theory in terms fieldworkers and participants understand so as not to undermine fidelity.
Genome-wide association meta-analysis of age at onset of walking
Authors: Gui Anna , Hollowell Anja , Wigdor Emilie M. , Morgan Morgan J. , Hannigan Laurie J. , Corfield Elizabeth C. , Odintsova Veronika , Hottenga Jouke-Jan , Wong Andrew , Pool René , Cullen Harriet , Wilson Siân , Warrier Varun , Eilertsen Espen M. , Andreassen Ole A. , Middeldorp Christel M. , Pourcain Beate St , Bartels Meike , Boomsma Dorret I. , Hartman Catharina A. , Robinson Elise B. , Arichi Tomoki , Edwards David , Johnson Mark H. , Dudbridge Frank , Sanders Stephan J. , Havdahl Alexandra , Ronald Angelica
Published: May 2024

Onset of walking is a developmental milestone with wide individual differences and high heritability in humans. In this genome-wide association study meta-analysis of age at onset of walking (N=70,560 European-ancestry infants), SNP-based heritability was 24.13% (SE=1.16%) with ∼11.9K variants accounting for about 90% of it, suggesting high polygenicity. We identified 11 independent genome-wide significant loci, including a “double hit” haplotype in which both decreased expression ofRBL2and a potentially deleterious missense variant inRBL2are associated with delayed walking. Age at onset of walking (in months) was negatively genetically correlated with ADHD and BMI, and positively genetically correlated with intelligence, educational attainment, and adult brain gyrification. The polygenic score showed out-of-sample prediction of 3-5.6%, confirmed to be largely due to direct effects in sib-pair analyses, and was associated with volume of neonatal brain structures involved in motor control. This offers new biological insights of clinical relevance into neurodevelopment.
Diverging functional connectivity timescales: Capturing distinct aspects of cognitive performance in early psychosis
Authors: Hirsch Fabian , Bumanglag Ângelo , Zhang Yifei , Wohlschlaeger Afra
Published: May 2024

Background

Psychosis spectrum disorders (PSDs) are marked by cognitive impairments, the neurobiological correlates of which remain poorly understood. Here, we investigate the entropy of time-varying functional connectivity (TVFC) patterns from resting-state fMRI (rfMRI) as potential biomarker for cognitive performance in PSDs. By combining our results with multimodal reference data, we hope to generate new insights into the mechanisms underlying cognitive dysfunction in PSDs. We hypothesized that low-entropy TVFC patterns (LEN) would be more behaviorally informative than high-entropy TVFC patterns (HEN), especially for tasks that require extensive integration across diverse cognitive subdomains.

Methods

rfMRI and behavioral data from 97 patients in the early phases of psychosis and 53 controls were analyzed. Positron-Emission Tomography (PET) and magnetoencephalography (MEG) data were taken from a public repository (Hansen et al., 2022). Multivariate analyses were conducted to examine relationships between TVFC patterns at multiple spatial scales and cognitive performance in patients.

Results

Compared to HEN, LEN explained significantly more cognitive variance on average in PSD patients, driven by superior encoding of information on psychometrically more integrated tasks. HEN better captured information in specific subdomains of executive functioning. Nodal HEN-LEN transitions were spatially aligned with neurobiological gradients reflecting monoaminergic transporter densities and MEG beta power. Exploratory analyses revealed a close statistical relationship between LEN and positive PSD symptoms.

Conclusion

Our entropy-based analysis of TVFC patterns dissociates distinct aspects of cognition in PSDs. By linking topographies of neurotransmission and oscillatory dynamics with cognitive performance, it enhances our understanding of the mechanisms underlying cognitive deficits in PSDs.

CRediT Authorship Contribution Statement

Fabian Hirsch:Conceptualization, Methodology, Software, Formal analysis, Writing - Original Draft, Writing - Review & Editing, Visualization;Ângelo Bumanglag:Methodology, Software, Formal analysis, Writing - Review & Editing;Yifei Zhang:Methodology, Software, Formal analysis, Writing - Review & Editing;Afra Wohlschlaeger:Methodology, Writing - Review & Editing, Supervision, Project administration
Automated Identification of Thrombectomy Amenable Vessel Occlusion on Computed Tomography Angiography using Deep Learning
Authors: Han Jung Hoon , Lee Hoyeon , Park Gi-Hoon , Hong Hotak , Kim Dongmin , Kim Jae Guk , Kim Joon-Tae , Sunwoo Leonard , Kim Chi Kyung , Ryu Wi-Sun
Published: May 2024

Objectives

Recent advancements have extended the treatment window for large vessel occlusion in acute ischemic stroke, prompting a shift in the standard of care for patients presenting within 6 to 24 hours. We developed and externally validated an automated deep learning algorithm for detecting thrombectomy amenable vessel occlusion (TAVO) in computed tomography angiography (CTA).

Methods

The algorithm was trained on 2,045 acute ischemic stroke patients who underwent CTA, and validation was conducted using two external datasets comprising 64 (external 1) and 313 (external 2) patients with ischemic stroke. TAVO was defined as occlusion in the intracranial internal carotid artery (ICA), or M1/M2 segment of the middle cerebral artery (MCA). Utilizing U-Net for vessel segmentation and EfficientNetV2 for TAVO prediction, the algorithm’s diagnostic performance was assessed using the area under the receiver operating characteristics curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Results

The mean age in the training and validation dataset was 68.7±12.6; 56.3% were men, and 18.0% had TAVO. The algorithm achieved AUC of 0.950 (95% CI, 0.915–0.971) in the internal test. For the external datasets 1 and 2, the AUCs were 0.970 (0.897–0.997) and 0.971 (0.924–0.990), respectively. Notably, the algorithm demonstrated robust sensitivity and specificity (approximately 0.95) for intracranial ICA or M1-MCA occlusion, but a slight reduction in performance for isolated M2-MCA occlusion.

Conclusion

This validated algorithm has potential applications in identifying TAVO and could aid less-experienced clinicians, potentially expediting the treatment process for eligible patients.
Circulating microRNAs are related to cognitive domains in the general population
Authors: Melas Konstantinos , Talevi Valentina , Etteldorf Rika , Estrada Santiago , Krüger Dennis M. , Pena Tonatiuh , Aziz N. Ahmad , Fischer André , Breteler Monique M.B.
Published: May 2024

INTRODUCTION

Circulating microRNAs have been suggested as candidates for detecting and preventing subclinical cognitive dysfunction. However, replication of previous findings and identification of novel microRNAs associated with cognitive domains, including their relation to brain structure and the pathways they regulate, are still lacking.

METHODS

We examined circulating microRNAs and microRNAco-expressionclusters in relation to cognitive domains, structural MRI measures, and target gene expression in 2869 participants of a population-based cohort.

RESULTS

Five previously identified and 10 novel microRNAs were associated with cognitive domains. Importantly, seven of these microRNAs were also associated with cortical thickness and two with hippocampal volume. Functional genomics analysis showed that the identified microRNAs regulated genes in pathways like neurogenesis, axon guidance, and synapse assembly.

DISCUSSION

We identified microRNAs associated with cognitive domains, brain regions, and neuronal processes affected by aging and neurodegeneration, making them promising candidate blood-based biomarkers or therapeutic targets of subclinical cognitive dysfunction.
Automated Neuroprognostication via Machine Learning in Neonates with Hypoxic-Ischemic Encephalopathy
Authors: Lewis John D. , Miran Atiyeh A. , Stoopler Michelle , Branson Helen M. , Danguecan Ashley , Raghu Krishna , Ly Linh G. , Cizmeci Mehmet N. , Kalish Brian T.
Published: May 2024

Objectives

Neonatal hypoxic-ischemic encephalopathy is a serious neurologic condition associated with death or neurodevelopmental impairments. Magnetic resonance imaging (MRI) is routinely used for neuroprognostication, but there is substantial subjectivity and uncertainty about neurodevelopmental outcome prediction. We sought to develop an objective and automated approach for the analysis of newborn brain MRI to improve the accuracy of prognostication.

Methods

We created an anatomical MRI template from a sample of 286 infants treated with therapeutic hypothermia, and labeled the deep gray-matter structures. We extracted quantitative information, including shape-related information, and information represented by complex patterns (radiomic measures), from each of these structures in all infants. We then trained an elastic net model to use either only these measures, only the infants’ clinical data, or both, to predict neurodevelopmental outcomes, as measured by the Bayley Scales of Infant and Toddler Development at 18 months of age.

Results

Amongst those infants who survived and for whom Bayley scores were available for cognitive, language, and motor outcomes, we found sets of MRI-based measures that could predict their Bayley scores with correlations that were more than twice the correlations based on only the clinical data, and explained more than four times the variance in the observed scores; predictions based on the combination of the clinical and MRI-based measures were similar or marginally better.

Interpretation

Our findings show that machine learning models using MRI-based measures can predict neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy across all neurodevelopmental domains and across the full spectrum of outcomes.
Rapid spread of the SARS-CoV-2 Omicron XDR lineage derived from recombination between XBB and BA.2.86 subvariants circulating in Brazil in late 2023
Authors: Arantes Ighor , Ito Kimihito , Gomes Marcelo , de Carvalho Felipe Cotrim , de Almeida Walquiria Aparecida Ferreira , Khouri Ricardo , Miyajima Fabio , Wallau Gabriel Luz , Naveca Felipe Gomes , Pereira Elisa Cavalcante ,   COVID-19 Fiocruz Genomic Surveillance Network, Siqueira Marilda Mendonça , Resende Paola Cristina , Bello Gonzalo
Published: May 2024

Recombination plays a crucial role in the evolution of SARS-CoV-2. The Omicron XBB* recombinant lineages are a noteworthy example, as they have been the dominant SARS-CoV-2 variant worldwide in the first half of 2023. Since November 2023, a new recombinant lineage between Omicron subvariants XBB and BA.2.86, designated XDR, has been detected mainly in Brazil. In this study, we reconstructed the spatiotemporal dynamics and estimated the absolute and relative transmissibility of the XDR lineage. The XDR lineage displayed a recombination breakpoint in the ORF1a coding region, and the most closely related sequences to the 5’ and 3’ ends of the recombinant correspond to JD.1.1 and JN.1.1 lineages, respectively. The first XDR sequences were detected in November 2023 in the Northeastern Brazilian region, and their prevalence rapidly surged from <1% to 25% by February 2024. The Bayesian phylogeographic analysis supports that the XDR lineage likely emerged in the Northeastern Brazilian region around late October 2023 and rapidly disseminated within and outside Brazilian borders from mid-November onwards. The median effective reproductive number of the XDR lineage in Brazil during the initial expansion phase was estimated to be around 1.5. In contrast, the average relative instantaneous reproduction numbers of XDR and JN* lineages were estimated to be 1.37 and 1.29 higher than that of co-circulating XBB* lineages. In summary, these findings support that the recombinant lineage XDR arose in the Northeastern Brazilian region in October 2023, shortly after the first detection of JN.1 sequences in the country. In Brazil, the XDR lineage exhibited a higher transmissibility level than its parental XBB.* lineages and is spreading at a rate similar to or slightly faster than the JN.1* lineages.
Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology
Authors: Park Seungmee , Noblett Nathaniel , Pitts Lauren , Colavita Antonio , Wehman Ann M. , Jin Yishi , Chisholm Andrew D.
Published: May 2024

Mature neurons maintain their distinctive morphology for extended periods in adult life. Compared to developmental neurite outgrowth, axon guidance, and target selection, relatively little is known of mechanisms that maintain mature neuron morphology. Loss of function inC. elegansDIP-2, a member of the conserved lipid metabolic regulator Dip2 family, results in progressive overgrowth of neurites in adults. We find thatdip-2mutants display specific genetic interactions withsax-2, theC. elegansortholog of Drosophila Furry and mammalian FRY. Combined loss of DIP-2 and SAX-2 results in severe disruption of neuronal morphology maintenance accompanied by increased release of neuronal extracellular vesicles (EVs). By screening for suppressors ofdip-2 sax-2double mutant defects we identified gain-of-function (gf) mutations in the conserved Dopey family protein PAD-1 and its associated phospholipid flippase TAT-5/ATP9A. Indip-2 sax-2double mutants carrying eitherpad-1(gf)ortat-5(gf)mutation, EV release is reduced and neuronal morphology across multiple neuron types is restored to largely normal. PAD-1(gf) acts cell autonomously in neurons. The domain containingpad-1(gf) is essential for PAD-1 function, and PAD-1(gf) protein displays increased association with the plasma membrane and inhibits EV release. Our findings uncover a novel functional network of DIP-2, SAX-2, PAD-1, and TAT-5 that maintains morphology of neurons and other types of cells, shedding light on the mechanistic basis of neurological disorders involving human orthologs of these genes.
Interresponse time and run length shaping by discrete-trial percentile schedule incorporating fixed consecutive number procedure
Authors: Orihara Tomotaka , Tanno Takayuki
Published: May 2024

The effect of incorporating a fixed consecutive number (FCN) procedure in interresponse time (IRT) shaping using a discrete-trial percentile schedule was examined. Eight pigeons were used. On each trial, pigeons were required to peck the IRT start key and then the IRT end key. Reinforcers were presented according to the percentile schedule based on the time interval (IRT) or the cumulative response count to the IRT start key during those two key pecks. Multiple responses to the IRT start key were allowed only in the condition incorporating the FCN procedure. Results showed that incorporating the FCN procedure improved the success of IRT shaping from 1/8 to 7/8 of the pigeons. The procedure developed in this study provides an ideal baseline for studying response shaping with IRT as the dependent variable.
E-cadherin tunes tissue mechanical behavior before and during morphogenetic tissue flows
Authors: Wang Xun , Cupo Christian M. , Ostvar Sassan , Countryman Andrew D. , Kasza Karen E.
Published: May 2024

Adhesion between epithelial cells enables the remarkable mechanical behavior of epithelial tissues during morphogenesis. However, it remains unclear how cell-cell adhesion influences mechanics in static as well as in dynamically flowing epithelial tissues. Here, we systematically modulate E-cadherin-mediated adhesion in theDrosophilaembryo and study the effects on the mechanical behavior of the germband epithelium before and during dramatic tissue remodeling and flow associated with body axis elongation. Before axis elongation, we find that increasing E-cadherin levels produces tissue comprising more elongated cells and predicted to be more fluid-like, providing reduced resistance to tissue flow. During axis elongation, we find that the dominant effect of E-cadherin is tuning the speed at which cells proceed through rearrangement events, revealing potential roles for E-cadherin in generating friction between cells. Before and during axis elongation, E-cadherin levels influence patterns of actomyosin-dependent forces, supporting the notion that E-cadherin tunes tissue mechanics in part through effects on actomyosin. Taken together, these findings reveal dual—and sometimes opposing—roles for E-cadherin-mediated adhesion in controlling tissue structure and dynamicsin vivothat result in unexpected relationships between adhesion and flow.
Fast-spiking interneuron detonation drives high-fidelity inhibition in the olfactory bulb
Authors: Burton Shawn D. , Malyshko Christina M. , Urban Nathaniel N.
Published: May 2024

Inhibitory circuits in the mammalian olfactory bulb (OB) dynamically reformat olfactory information as it propagates from peripheral receptors to downstream cortex. To gain mechanistic insight into how specific OB interneuron types support this sensory processing, we examine unitary synaptic interactions between excitatory mitral and tufted cells (MTCs), the OB projection cells, and a conserved population of anaxonic external plexiform layer interneurons (EPL-INs) using pair and quartet whole-cell recordings in acute mouse brain slices. Physiological, morphological, neurochemical, and synaptic analyses divide EPL-INs into distinct subtypes and reveal that parvalbumin-expressing fast-spiking EPL-INs (FSIs) perisomatically innervate MTCs with release-competent dendrites and synaptically detonate to mediate fast, short-latency recurrent and lateral inhibition. Sparse MTC synchronization supralinearly increases this high-fidelity inhibition, while sensory afferent activation combined with single-cell silencing reveals that individual FSIs account for a substantial fraction of total network-driven MTC lateral inhibition. OB output is thus powerfully shaped by detonation-driven high-fidelity perisomatic inhibition.
Development of Retinotopic Feedback: Layer 6 Pyramids to Lateral Geniculate Principal Cells
Authors: Levy William B. , Baxter Robert A.
Published: May 2024

The development of many feedforward pathways in the brain, from sensory inputs to neocortex, have been studied and modeled extensively, but the development of feedback connections, which tend to occur after the development of feedforward pathways, have received less attention. The abundance of feedback connections within neocortex and between neocortex and thalamus suggests that understanding feedback connections is crucial to understanding connectivity and signal processing in the brain. It is well known that many neural layers are arranged topologically with respect to sensory input, and many neural models impose a symmetry of connections between layers, commonly referred to as reciprocal connectivity. Here, we are concerned with how such reciprocal, feedback connections develop so that the topology of the sensory input is preserved. We focus on feedback connections from layer 6 of visual area V1 to primary neurons in the Lateral Geniculate Nucleus (LGN). The proposed model is based on the hypothesis that feedback connections from V1-L6 to LGN use voltage-activated T-channels to appropriately establish and modify synapses in spite of unavoidable temporal delays. We also hypothesize that developmental spindling relates to synaptogenesis and memory consolidation.
The microbiome shapes immunity in a sex-specific manner in mouse models of Alzheimer’s disease
Authors: Bostick John W. , Connerly T. Jaymie , Thron Taren , Needham Brittany D. , de Castro Fonseca Matheus , Kaddurah-Daouk Rima , Knight Rob , Mazmanian Sarkis K.
Published: May 2024

INTRODUCTION: Preclinical studies reveal that the microbiome broadly affects immune responses and deposition and/or clearance of amyloid-beta (Aβ) in mouse models of Alzheimer’s disease (AD). Whether the microbiome shapes central and peripheral immune profiles in AD models remains unknown.

METHODS: We examined adaptive immune responses in two mouse models containing AD- related genetic predispositions (3xTg and 5xFAD) in the presence or absence of the microbiome.

RESULTS: T and B cells were altered in brain-associated and systemic immune tissues between genetic models and wildtype mice, with earlier signs of immune activity in females. Systemic immune responses were modulated by the microbiome and differed by sex. Further, the absence of a microbiome in germ-free mice resulted in reduced cognitive deficits, primarily in females.

DISCUSSION: These data reveal sexual dimorphism in early signs of immune activity and microbiome effects, and highlight an interesting interaction between sex and the microbiome in mouse models of AD.
Epidermal Collagen Reduction Drives Selective Aspects of Aging in Sensory Neurons
Authors: Krishna Meera M. , Waghmare Swapnil G. , Franitza Ariel L. , Maccoux Emily C. , Lezi E
Published: May 2024

Despite advances in understanding molecular and cellular changes in the aging nervous system, the upstream drivers of these changes remain poorly defined. Here, we investigate the roles of non-neural tissues in neuronal aging, using the cutaneous PVD polymodal sensory neuron inCaenorhabditis elegansas a model. We demonstrate that during normal aging, PVD neurons progressively develop excessive dendritic branching, functionally correlated with age-related proprioceptive deficits. Our study reveals that decreased collagen expression, a common age-related phenomenon across species, triggers this process. Specifically, loss-of-function indpy-5orcol-120, genes encoding cuticular collagens secreted to the epidermal apical surface, induces early-onset excessive dendritic branching and proprioceptive deficits. Adulthood-specific overexpression ofdpy-5orcol-120mitigates excessive branching in aged animals without extending lifespan, highlighting the specific role of these collagens in promoting neuronal healthspan. Notably, collagen reduction specifically drives excessive branching in select sensory neuron subclasses but does not contribute to dendritic beading, another aging-associated neurodegenerative phenotype distinctively associated with a different mechanosensitive dysfunction. Lastly, we identify thatrig-3, an Immunoglobulin Superfamily member expressed in interneurons, acts upstream of collagen genes to maintain PVD dendritic homeostasis during aging, with downstream requirement ofdaf-16/FOXO. These findings reveal that age-related collagen reduction cues neuronal aging independently of collagen’s traditional structural support function, potentially involving bi-directional communication processes between neurons and non-neuronal cells. Our study also offers new insights into understanding selective neuron vulnerability in aging, emphasizing the importance of multi-tissue strategies to address the complexities of neuronal aging.
Transcriptional Signatures Associated with the Survival ofEscherichia coliBiofilm During Treatment with Plasma-Activated Water
Authors: Vyas Heema Kumari Nilesh , Hoque M. Mozammel , Xia Binbin , Alam David , Cullen Patrick J. , Rice Scott A. , Mai-Prochnow Anne
Published: May 2024

Biofilm formation on surfaces, tools and equipment can damage their quality and lead to high repair or replacement costs. Plasma-activated water (PAW), a new technology, has shown promise in killing biofilm and non-biofilm bacteria due to its mix of reactive oxygen and nitrogen species (RONS), and in particular superoxide. However, the specific genetic mechanisms behind PAW’s effectiveness, especially against biofilms, are not yet fully understood. Here, we examined the stress responses ofEscherichia colibiofilms when exposed to sub-lethal PAW treatment with and without superoxide (by adding the scavenger Tiron to remove it). A 40% variation in gene expression was observed for PAW treated biofilms when compared to PAW-Tiron and controls. Specifically, PAW treatment resulted in 478 upregulated genes (> 1.5 log2FC) and 186 downregulated genes (< −1.5 log2FC) compared to the control. Pathway enrichment and biological process enrichment analysis revealed significant upregulation of sulfur metabolism, ATP-binding cassette transporter genes, amino acid metabolic/biosynthesis pathways, hypochlorite response systems and oxidative phosphorylation for biofilms treated with PAW compared to control. Knockout mutants of significantly upregulated genes associated with these pathwaystrxC(4.23-fold),cysP(1.58-fold) andnuoM(1.74-fold) were compared to the wild-type (WT) for their biofilm viability and intracellular RONS accumulation. Relative to PAW-treated WT,ΔtrxCandΔnuoMknockout mutants displayed significantly reduced biofilm viability (P ≤ 0.05) confirming their role in PAW-mediated response. Interestingly,ΔtrxCbiofilms had the highest intracellular ROS accumulation, as revealed by DCFDA staining after PAW treatment. This study gives a detailed insight into howE. colibiofilms respond to oxidative stress induced by PAW. It highlights the significance of superoxide in PAW’s bactericidal effects. Overall, our findings shed light on the specific genes and pathways that helpE. colibiofilms survive and respond to PAW treatment, offering a new understanding of plasma technology and its anti-biofilm mechanisms.
STECode: an automated virulence barcode generator to aid clinical and public health risk assessment of Shiga toxin-producingEscherichia coli
Authors: Sim Eby M. , Fong Winkie , Suster Carl , Agius Jessica E. , Chandra Shona , Suliman Basel , Wang Qinning , Ngo Christine , Finemore Connor , Chen Sharon C-A. , Basile Kerri , Sintchenko Vitali
Published: May 2024

Shiga Toxin (Stx) producingEscherichia coli(STEC) is a subset of pathogenicE. colithat can produce two types of Stx, Stx1 and Stx2, which can be further subtyped into four and 15 subtypes respectively. Not all subtypes, however, are equal in virulence potential, and the risk of severe disease including haemolytic uraemic syndrome has been linked to certain Stx2 subtypes e.g. Stx2a, Stx2d, highlighting the importance to surveystxsubtypes. Previously, we developed a STEC virulence barcode to capture pertinent information on virulence genes to infer pathogenic potential. However, the process required multiple manual curation steps to determine the barcode. Here we introduce STECode, a bioinformatic tool to automate the STEC virulence barcode generation from sequencing reads or genomic assemblies. The development, and validation of STECode is described using a set of publicly available completed STEC genomes, along with their corresponding short reads. STECode was applied to interrogate the virulence landscape and molecular epidemiology of human STEC isolated during the period of the international border closures related to COVID-19 in the state of New South Wales, Australia.

Impact statement

Whole genome sequencing has been used to great effect in the genomic surveillance of STEC for public health purposes via the tracking of outbreaks. With STECode, we present a method to generate a STEC virulence barcode which captures pertinent subtyping information, useful for genomic inference of pathogenic potential. A key blind spot generated in short-read sequencing is the inability to detect the presence of multiple, isogenicstxcopies in STEC. STECode mitigates this by inferring and reporting on the possibility of this occurrence. We envisage that this tool will value-add current genomic surveillance workflows through the ability to infer pathogenic potential.
Factors affecting contact tracing for the early detection of Leprosy cases: A qualitative study in Ho, Volta Region, Ghana
Authors: Ahiabu Araba Aseye , Tabong Philip Teg-Neefah
Published: May 2024

Introduction

Despite Ghana being at the elimination phase of Leprosy, new cases of Leprosy are recorded in the country annually. These cases are usually detected in the advanced stages when Grade 2 disabilities (G2D) have set in. The WHO regards high G2D rates as an indication that measures need to be taken especially with regard to early detection. Late detection of cases raises concern about the spread of the infection. Contact tracing of index cases of Leprosy is therefore key in containing the spread. If the current situation is left unattended, Ghana faces the challenge of retrogressing in its fight against Leprosy. The general objective is to explore the factors affecting contact tracing for early case detection of Leprosy.

Methods

This study employed a qualitative research methodology. Specifically, the study adopted the phenomenology study design. Maximum variation purposive sampling technique was used for people affected by Leprosy who were either on treatment at the Ho Polyclinic or had completed treatment, health workers of the Polyclinic and community members at Ho, in the Volta Region of Ghana. Data was collected using in-depth interviews and focus group discussions among selected participants. All IDIs and FGDs were audio-recorded and transcribed verbatim. The data was coded using NVivO version 14 and analysed thematically.

Results

The results of this study showed that a majority of the community members and people affected by Leprosy perceived that Leprosy is caused by supernatural forces and hence the disease is not transmissible. Factors such as the stigma associated with the disease, reliance on divine forms of healing, use of herbs and poor symptom recognition hinder early detection. The study also revealed gaps in contact tracing efforts such as the inadequacy of funds for contact tracing as well as the reluctance of some contacts to be involved in the process.

Conclusion

The study concluded that both community and health system factors affect early detection of Leprosy cases in Ho. This has the potential to undermine Ghana’s quest to eliminate Leprosy. There is a need to increase awareness of the importance of contact tracing for early detection of Leprosy.
Child diarrhea in Cambodia: A descriptive analysis of temporal and geospatial trends and logistic regression-based examination of factors associated with diarrhea in children under five years
Authors: Um Samnang , Phan Channnarong , Sakha Sok , Dany Leng
Published: May 2024

Diarrhea is a global public health problem that is the third leading cause of death in under five years, with an estimated 1.7 billion cases in 2023 and 1.8 million deaths from diarrhea diseases every year. To better understand child diarrhea in Cambodia, we examined descriptively temporal and geospatial trends of diarrhea and used multivariate logistic regression to analyze its association with individual and household characteristics and diarrhea among children aged 0-59 months using data from the Cambodia Demographic and Health Survey for 2005 to 2022. The prevalence of diarrhea among children aged 0–59 months decreased from 19.7% in 2005 to 6.2% in 2022. The highest prevalence of childhood diarrhea in Kampong Cham (30.1%), in Mondul Kiri/Ratanak Kiri (24.6%), Battambang/Pailin (20.9%), and Mondul Kiri/Ratanak Kiri (12.9%) for 2005, 2010, 2014 and 2022. After adjusting for other variables, factors independently associated with childhood diarrhea included mothers aged 25-34 years (adjusted odds ratio (AOR) = 0.68; 95% CI: 0.48–0.96), 35-49 years (AOR = 0.60; 95% CI: 0.42–0.87), completed higher education (AOR = 0.61; 95% CI: 0.41–0.91), and employed (AOR = 0.79; 95% CI: 0.72– 0.96). Children were less likely to have diarrhea if they were older than 36 months, richest household (AOR = 0.69; 95% CI: 0.55–0.86), coastal region (AOR = 0.53; 95% CI: 0.41–0.69), born to smoker mothers (AOR = 1.61; 95% CI: 1.25–2.08), had barrier access to healthcare services (AOR = 1.20; 95% CI: 1.07–1.35), or children aged 6–23 months. Diarrhea remains highly prevalent among children in Cambodia. Public health interventions and policies to alleviate diarrhea should be prioritized to address these factors across geographical.
A 3D approach to understanding heterogeneity in early developing autisms
Authors: Mandelli Veronica , Severino Ines , Eyler Lisa , Pierce Karen , Courchesne Eric , Lombardo Michael V.
Published: May 2024

Phenotypic heterogeneity in early language, intellectual, motor, and adaptive functioning (LIMA) features are amongst the most striking features that distinguish different types of autistic individuals. Yet the current diagnostic criteria uses a single label of autism and implicitly emphasizes what individuals have in common as core social-communicative and restricted repetitive behavior difficulties. Subtype labels based on the non-core LIMA features may help to more meaningfully distinguish types of autisms with differing developmental paths and differential underlying biology. Using relatively large (n=615) publicly available data from early developing (24-68 months) standardized clinical tests tapping LIMA features, we show that stability-based relative cluster validation analysis can identify two robust and replicable clusters in the autism population with high levels of generalization accuracy (98%). These clusters can be described as Type I versus Type II autisms differentiated by relatively high versus low scores on LIMA features. These two types of autisms are also distinguished by different developmental trajectories over the first decade of life. Finally, these two types of autisms reveal striking differences in functional and structural neuroimaging phenotypes and their relationships with gene expression. This work emphasizes the potential importance of stratifying autism by a Type I versus Type II distinction focused on LIMA features and which may be of high prognostic and biological significance.
The association betweenToxoplasma gondiiinfection and asthma in the United States: A cross-sectional survey analysis
Authors: Anholt Heather
Published: May 2024

The hygiene hypothesis proposes that declining exposure to microbial influences early in life is implicated in the rising trend of allergy and asthma in high-income societies. Approximately 8% of Americans have been diagnosed with asthma, representing 25 million people, and understanding how the human microbiome affects asthma could help guide exposure recommendations or microbe-based therapeutics.Toxoplasma gondiiis a common gastro-intestinal microorganism that may modulate immune function. We used a cross-sectional study design to examine a public database of U.S. residents aged 6 to 80 years or older from the 2012-2014 survey cycles of the American National Health and Nutrition Examination Survey (NHANES) to construct an ordinal logistic regression model of the relationship betweenT. gondiiinfection and asthma. There was no significant relationship detected betweenT. gondiiinfection and asthma when the model was adjusted for key demographic factors.
Oncogenic human papillomavirus and anal microbiota in men who have sex with men and are living with HIV in Northern Taiwan
Authors: Cheng Shu-Hsing , Yang Yu-Chen , Chen Cheng-Pin , Hsieh Hui-Ting , Lin Yi-Chun , Cheng Chien-Yu , Liao Kuo-Sheng , Chu Fang-Yeh , Liu Yun-Ru
Published: May 2024

Few studies have demonstrated the interplay between human immunodeficiency virus (HIV), anal human papillomavirus (HPV), and anal microbiota, especially in persons living with HIV who are men who have sex with men. We therefore explored these interrelationships in a cohort of persons living with HIV, mainly comprising men who have sex with men. HPV genotyping using a commercial genotyping kit and ThinPrep cytology interpreted by Bethesda systems were performed on samples from 291 patients. Samples were characterized by high-throughput sequencing of dual-index barcoded 16s rRNA (V3–4). Bacterial diversity was diminished in individuals living with HIV with CD4+ T cells <500 cells/µL and anal cytology yielding atypical squamous cells of undetermined significance or higher grades (ASCUS+) with detectable HPV 16/18 compared with those with CD4+ T cells ≥500 cells/µL with ASCUS+ and HPV 16/18 and those with normal anal cytology or inflammation without HPV 16/18. Enterobacteriaceae, Ruminococcus, and Bacilli were significantly abundant in persons living with HIV with CD4+ T cells <500 cells/µL with ASCUS+ and HPV 16/18. Bacterial diversity, composition, and homogeneity of dispersion were different in individuals living with HIV with low CD4+ T cells with ASCUS+ and HPV 16/18. These patients should be followed up for the development of anal precancerous lesions.
Assessing the impact of Covid-19 on Nurturing Care in Nairobi Slums: Findings from 5 rounds of cross-sectional telephone surveys
Authors: Hughes Robert C , Onyango Silas , Langat Nelson , Muendo Ruth , Juel Rachel , Kimani-Murage Elizabeth , Hill Zelee , Kirkwood Betty , Bhopal Sunil S , Kitsao-Wekulo Patricia
Published: May 2024

Introduction

This study investigates the multifaceted impacts of the Covid-19 pandemic on early childhood in three of Nairobi’s informal settlements or slums. Focusing on the first five years of life, a critical period for human capital development, we analyse how Nurturing Care across five domains (Health, Nutrition, Responsive Caring, Early Learning, Security and Safety) was influenced by the pandemic and the mitigation measures that were implemented.

Methods

Using a longitudinal design, we conducted five rounds of cross-sectional surveys (with between 578 and 774 respondents in each) over 13 months, correlating with different phases of the pandemic and varying levels of Covid-19 restrictions.

Results

Our findings reveal significant disruptions in healthcare services, particularly pronounced in early rounds with missed vaccinations (reported by 1 in 5 parents of infants) and therapeutic healthcare seeking (missed by up to 21% of families). The study also highlights persistent food and nutrition insecurity, with a large majority of families struggling to feed their children (up to 72% in Round 1) due to financial constraints. Economic shocks were near-universal, with widespread losses in income and employment reported; 99.7% of respondents reporting earning less since the start of the pandemic. The use of paid childcare initially plummeted but showed a resurgence over time (up to 21% usage by Round 5) as the pandemic and control measures evolved. Young children were commonly left alone in all rounds, but especially earlier in the pandemic; 24% in Round 1, and at least 13% in all rounds, underscoring the enduring challenges in providing consistent nurturing care in these settings. Very few (less than 2%) of study participants reported direct experience of Covid-19 in their family in any round.

Conclusion

Despite adaptations over time and the decrease in reported disruptions, the prolonged economic shock was associated with multiple adverse effects Nurturing Care. The study’s longitudinal scope provides insights into the dynamic nature of ensuring young children in slums thrive during crises, highlighting the need for tailored interventions and policies that address the compounded vulnerabilities of young children in these communities.
Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Non-structural Proteins Inhibitors
Authors: Lu Xiaojie , Hu Hangchen , Mei Lianghe , Wang Xudong , Xiong Liwei , Zhu Ying , Liu Sixiu , Zhao Wenfeng , Mengnisa Seydimemet , Li Linjie , Lin Xian , Liu Jiaxiang , Wang Xuan , Duan Zhiqiang , Lu Weiwei , Suo Yanrui , Wu Xinyuan , Cui Mengqing , Yue Jinfeng , Xu Yechun
Published: May 2024

The global coronavirus disease 2019 (COVID-19) pandemic persists, with the ongoing mutation of the virus. Consequently, the development of inhibitors with diverse binding modes and mechanisms of action, along with the elucidation of novel binding sites is of paramount importance. The 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) are two validated cysteine proteases that cleave the viral polyprotein and are essential for viral replication. In this study, we utilized covalent DNA-Encoded libraries (CoDELs) workflow to identify two series of triazine-based covalent inhibitors targeting 3CLpro and PLpro. Molecular docking facilitated the identification of optimization pathways, further refined through medicinal chemistry efforts, leading to the development of the non-peptide 3CLpro inhibitor LU9, which exhibited an IC50 value of 0.34 μM, and crystal structure of LU10 revealed a unique binding mode within the active site. Additionally, the X-ray cocrystal structure of SARS-CoV-2 PLpro with XD5 uncovered a previously unexplored binding site, adjacent to the catalytic pocket, providing an opportunity for further development of PLpro inhibitors. Overall, these novel compounds serve as valuable chemical probes for target validation and represent promising drug candidates for the continued development of SARS-CoV-2 antivirals.
Depletion of m6A-RNA inEscherichia colireduces the infectious potential of T5 bacteriophage
Authors: Saikia Bibakhya , Riquelme-Barrios Sebastian , Carell Thomas , Brameyer Sophie , Jung Kirsten
Published: May 2024

N6-methyladenosine (m6A) is the most abundant internal modification of mRNA in eukaryotes that plays, among other mechanisms, an essential role in virus replication. However, the understanding of m6A RNA modification in prokaryotes, especially in relation to phage replication, is limited. To address this knowledge gap, we investigated the effects of m6A RNA modification on phage replication in two model organisms:Vibrio campbelliiBAA-1116 (previouslyV. harveyiBB120) andEscherichia coliMG1655. An m6A-RNA depletedV. campbelliimutant (ΔrlmFΔrlmJ) did not differ from the wild type in the induction of lysogenic phages or in susceptibility to the lytic Virtus phage. In contrast, the infection potential of the T5 phage, but not that of other T phages or the lambda phage, was reduced in an m6A-RNA depletedE. colimutant (ΔrlmFΔrlmJ) compared to the wild type. This was shown by a lower efficiency of plaquing and a higher percentage of surviving cells. There were no differences in T5 phage adsorption rate, but the mutant exhibited a 5 min delay in the rise period during the one-step growth curve. This is the first report demonstrating thatE. colicells with lower m6A RNA levels have a higher chance of surviving T5 phage infection.

Importance

The importance of RNA modifications has been thoroughly studied in the context of eukaryotic viral infections. However, their role in bacterial hosts during phage infections is largely unexplored. Our research delves into this gap by investigating the effect of host m6A-RNA modifications during phage infection. We found that anE. colimutant depleted of m6A-RNA is more resistant to T5 infection than the wild type. This finding emphasizes the need to further investigate how RNA modifications affect the fine-tuned regulation of individual bacterial survival in the presence of phages to ensure population survival.
Patterning effects of FGF17 and cAMP on generation of dopaminergic progenitors for cell replacement therapy in Parkinson’s disease
Authors: Nygaard Amalie Holm , Schörling Alrik L. , Abay-Nørgaard Zehra , Hänninen Erno , Li Yuan , Santoja Adrian , Rathore Gaurav Singh , Salvador Alison , Rusimbi Charlotte , Zhang Yu , Kirkeby Agnete
Published: May 2024

Cell replacement therapies using human pluripotent stem cell-derived ventral midbrain (VM) dopaminergic (DA) progenitors are currently in clinical trials for treatment of Parkinson’s disease (PD). Recapitulating developmental patterning cues, such as fibroblast growth factor 8 (FGF8), secreted at the midbrain-hindbrain boundary (MHB), is critical for thein vitroproduction of authentic VM DA progenitors. Here, we explore the application of alternative MHB-secreted FGF-family members, FGF17 and FGF18, for VM DA pro-genitor patterning. We show that while FGF17 and FGF18 both recapitulate VM DA progenitor patterning events, FGF17 induced expression of key VM DA progenitor markers at higher levels than FGF8 and transplanted FGF17-patterned progenitors fully reversed motor deficits in a rat PD model. Early activation of the cAMP pathway mimicked FGF17-induced patterning, although strong cAMP activation came at the expense of EN1 expression. In summary, we identified FGF17 as a promising candidate for more robust VM DA progenitor patterning, with the potential to improve cell products for treatment of PD.

Summary statement

In this article we find that FGF17 induces high expression of key dopamine progenitor markers and that these cells can provide functional rescue in a rat model of Parkinson’s disease.