bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterisation of Microbial Community Dynamics and Antibiotic Resistance Gene Dissemination in Malaysian Wastewater during the COVID-19 Pandemic
Authors: Shahid Umama , Li Hooi Suet , Yong Lim Shu , Mohd Aris Alijah , Chin Khor Bee , Ayub Qasim , Siew Tan Hock
Published: July 2024

Wastewater is a well-known hotspot for pathogens and spread of antibiotic resistance across species. Surveillance of wastewater microbial community can help draw clearer representation of actively culturing taxonomic groups and resistance-inducing mobile genetic elements before and after treatment. Studies have suggested that COVID-19 pandemic may also have caused increased dissemination of antibiotic-resistance genes (ARGs) and antibiotic-resistant bacteria in wastewater. Although immensely significant, no research has yet been performed on Malaysian wastewater microbial community and ARGs or their correlation with COVID-19 infections. This study utilised 16S metagenomics approach to characterise microbial community in Malaysian wastewater during high and low-case phases of pandemic. Among 20 most prevalent genera around Kuala Lumpur, Malaysia, those belonging to Bacteriodales, Bacillales, Actinomycetales and opportunistic pathogens-Arcobacters, Flavobacteria, and Campylobacterales, Neisseriales, were enriched during high-case periods of the COVID-19 pandemic. Copy number profiling of ARGs in water samples showed prevalence of elements conferring resistance to antibiotics like sulphonamides, cephalosporins, and colistin. High prevalence ofintI1and other ion-based transporters in samples highlight an extensive risk of horizontal gene transfer to previously susceptible species. Our study emphasises the importance of wastewater surveillance in understanding microbial community dynamics and ARG dissemination, particularly during public health crises like the COVID-19 pandemic.
Longitudinal Dynamics and Pluripotentiality of Polysymptomatic Clustering in Adolescent Mental Health
Authors: Kennedy Michelle F. , Schwenn Paul , Boyes Amanda , Mills Lia , Prince Taliah , Parker Marcella , Hermens Daniel F.
Published: July 2024

Background

Adolescence represents a sensitive developmental period characterised by an increased incidence of emerging mental health symptoms and formal diagnostic onset. These conditions can remain a significant burden throughout life. The Longitudinal Adolescent Brain Study (LABS) commenced in 2018 to track the onset and trajectory of mental health symptoms among general population participants. This research aims to identify polysymptomatic clusters of emerging mental health symptoms in adolescents and examine how these clusters vary by age and change over time, providing insights into the pluripotentiality of disorder development.

Methods

LABS participants aged 12-17 years (n=166) completed the Mini International Neuropsychiatric Interview (MINI Kid) approximately every 4 months, with up to 15 timepoints. Due to this high dimensional dataset, the data was first processed using a dimensionality reduction step (uniform manifold approximation and projection; UMAP). Following this, the data was clustered using Bayesian model averaging of k-means, gaussian mixture model and hierarchical clustering to identify distinct symptom clusters. Symptom clusters were described in terms of the original neuropsychiatric interview responses using separate XGBoost classifier models. Symptom cluster dynamics were analysed using Markov chain transition probability matrices and longitudinal analysis. To explore the relationship between symptom clusters and psychological distress and wellbeing, correlational analyses were conducted using scores from the Kessler Psychological Distress Scale (K10) and the COMPAS-W Wellbeing Scale.

Outcomes

Six symptom-based clusters (states) were identified: attention, anxiety, depression, manic episode - heritability, anhedonia, and well. Depression and anxiety clusters had the greatest pluripotentiality. Analysis of psychological distress and wellbeing demonstrated an inverse relationship between the states: those with greater psychological distress had more symptoms, conversely those with greater wellbeing had fewer symptoms.

Interpretations

Mapping polysymptomatic clusters of mental health symptoms and their pluripotential and transitory trajectories in adolescents enables more effective targeting of preventive interventions. This approach moves beyond categorical classifications to mitigate the progression of early symptoms into enduring psychiatric disorders.
Effects of Singing on Vascular Health in Older Adults with Coronary Artery Disease: A Randomized Trial
Authors: Bagherimohamadipour Mehri , Hammad Muhammad , Visotcky Alexis , Sparapani Rodney , Kulinski Jacquelyn
Published: July 2024

Background

The impact of singing on cardiovascular health has not been extensively studied. The aim of this study is to investigate the effect of singing on cardiovascular biomarkers in an aging population with coronary artery disease.

Methods

Participants had three study visits separated by 2-7 days, according to a randomized, single-blind, cross-over, controlled design: (1) a 30-minute period of coached singing from an in-person music therapist, (2) a 30-minute period of singing along to an instructional video and (3) a 30-minute rest (control). Primary outcomes included macrovascular endothelial function assessed by brachial artery flow-mediated dilation and microvascular function assessed by peripheral arterial tonometry (Framingham reactive hyperemia index; fRHI). Heart rate variability was a secondary outcome.

Results

Sixty-five subjects (mean age 67.7± 0.8, 40% women) completed the study. Compared to control, there was an increase in fRHI for the singing video intervention (estimate 0.54, SE 0.25, p=0.005) but not for the coaching intervention (estimate 0.11, SE 0.18, p=0.570). There was no change in macrovascular function with either intervention. The low frequency/high frequency (LF/HF) ratio increased by 2.80 (SE 1.03, p=0.008), and the LnHF power decreased by −0.90 ms2(SE 0.29, p=0.003) with the video (during to pre-change). When assessing post- to pre- change, the coaching intervention showed a significant change of −0.62 ms2(SE 0.29, p=0.036) in LnHF power.

Conclusions

Singing along to an instructional video for 30 minutes improved microvascular, but not macrovascular, endothelial function, in older patients with CAD. HRV changes with singing are similar to that of exercise.
Detection and segmentation of hyperdense middle cerebral artery sign on non-contrast CT using artificial intelligence
Authors: Kim Pyeong Eun , Ha Sue Young , Lee Myungjae , Kim Nakhoon , Kim Dongmin , Sunwoo Leonard , Ryu Wi-Sun , Kim Beom Joon
Published: July 2024

Background

The hyperdense artery sign (HAS) in patients with large vessel occlusion (LVO) is associated with outcomes after ischemic stroke. Considering the labor-intensive nature of manual segmentation of HAS, we developed and validated an automated HAS segmentation algorithm on non-contrast brain CT (NCCT) images using a multicenter dataset with independent annotations by two experts.

Methods

For the training dataset, we included patients with ischemic stroke undergoing concurrent NCCT and CT angiography between May 2011 and December 2022 from six stroke centers. The model was externally validated using a dataset from one stroke center. For the clinical validation dataset, a consecutive series of patients admitted within 24 hours of symptom onset were included between December 2020 and April 2023 from six stroke centers. The model was trained using a 2D U-Net algorithm with manual segmentation by two experts. We constructed models trained on datasets annotated individually by each expert, and an ensemble model using shuffled annotations from both experts. The performance of the models was compared using area under the receiver operating characteristics curve (AUROC), sensitivity, and specificity.

Results

A total of 673, 365, and 774 patients were included in the training, external validation, and clinical validation datasets, respectively, with mean (SD) ages of 68.8 (13.2), 67.6 (13.4), and 68.8 (13.6) years and male frequencies of 55.0%, 59.5%, and 57.6%. The ensemble model achieved higher AUROC and sensitivity compared to the models trained on annotations from a single expert in the external validation dataset. In the clinical validation dataset, the ensemble model exhibited an AUROC of 0.846 (95% CI, 0.819–0.871), sensitivity of 76.8% (65.1–86.1%), and specificity of 88.5% (85.9–90.8%). The predicted volume of the clot was significantly correlated with infarct volume on follow-up diffusion-weighted imaging (r=0.42; p<0.001).

Conclusion

Our algorithm promptly and accurately identifies clot signs, facilitating the screening of potential patients who may require intervention.
Cognitive Enhancement in Bipolar Disorder: A Double-Blind, Randomized Controlled Trial Utilizing a Novel DTI-Guided Multimodal Neuro-stimulation Protocol
Authors: Wang Minmin , Zhang Xiaomei , Zhou Hetong , Chen Qianfeng , Tong Qiqi , Han Qiai , Zhao Xudong , Wang Dandan , Lai Jianbo , He Hongjian , Zhang Shaomin , Hu Shaohua
Published: July 2024

Background

Traditional neuromodulation strategies for enhancing cognitive abilities in bipolar disorder (BD) patients have shown promise, yet there remains a need for novel intervention modalities to improve therapeutic outcomes.

Methods

This study introduces a novel multi-modal neuro-stimulaton (MNS) protocol using individualized DTI data to identify fiber tracts between the DLPFC and dACC. The highest structural connectivity point is selected as the individualized stimulation target, which is targeted using a combination of optimized tACS and robot-assisted navigated rTMS. A double-blind randomized controlled trial (Trial registration number:NCT05964777) was conducted to investigate the clinical efficacy of this innovative neuromodulation approach on cognitive abilities in BD patients. One hundred BD patients were randomly assigned to four groups: Group A (Active tACS-Active rTMS (MNS Protocol)), Group B (Sham tACS-Active rTMS), Group C (Active tACS-Sham rTMS), and Group D (Sham tACS-Sham rTMS). Participants underwent 15 sessions over three weeks. Cognitive assessments (THINC integrated tool) were conducted at baseline (Week 0), post-treatment (Week 3), and follow-up (Week 8).

Results

Sixty-six participants completed all 15 sessions. Group A (MNS Protocol) showed superior improvements in Spotter CRT, TMT, and DSST scores compared to other groups at Week 3, with sustained cognitive enhancement in Spotter CRT at Week 8 (P< 0.01). Only Group A exhibited significant activation in the left frontal region post-MNS intervention. The novel MNS protocol was well tolerated, with no significant side effects observed.

Conclusions

DTI-guided multimodal neuro-stimulation mode significantly improves cognitive impairments and is safe for BD patients.

Highlights

Using DTI-derived neural fiber density to determine the target sites for tACS and rTMS in patients with bipolar disorder.

Combining sequential tACS and rTMS to significantly improve cognitive function in the bipolar disorder patients.

Utilizing individually optimized tACS and robot-assisted navigated rTMS to achieve high-precision transcranial stimulation.
Utility of cellular imaging modality in subcellular spatial transcriptomic profiling of tumor tissues
Authors: Song Xiaofei , Yu Xiaoqing , Moran-Segura Carlos M , Grass G Daniel , Li Roger , Wang Xuefeng
Published: July 2024

Spatial transcriptomics (ST) technologies, like GeoMx Digital Spatial Profiler, are increasingly utilized to reveal the role of diverse tumor microenvironment components, particularly in relation to cancer progression, treatment response, and therapeutic resistance. However, in many ST studies, the spatial information obtained from immunofluorescence imaging is primarily used for identifying regions of interest, rather than as an integral part of downstream transcriptomic data interpretation. We developed ROICellTrack, a deep learning-based framework, to better integrate cellular imaging with spatial transcriptomic profiling. By examining 56 ROIs from urothelial carcinoma of the bladder (UCB) and upper tract urothelial carcinoma (UTUC), ROICellTrack accurately identified cancer-immune mixtures and associated cellular morphological features. This approach also revealed different sets of spatial clustering patterns and receptor-ligand interactions. Our findings underscore the importance of combining imaging and transcriptomics for comprehensive spatial omics analysis, offering potential new insights into within-sample heterogeneity and implications for targeted therapies and personalized medicine.
Disentangling shared genetic etiologies for kidney function and cardiovascular diseases
Authors: Qiao Jun , Yao Kaixin , Yuan Yujuan , Yang Xichen , Zhou Le , Long Yinqi , Chen Miaoran , Xie Wenjia , Yang Yixuan , Cao Yangpo , Pauklin Siim , Xu Jinguo , Yang Yining , Feng Yuliang
Published: July 2024

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with chronic kidney disease (CKD) identified as a significant risk factor. CKD is primarily monitored through the estimated glomerular filtration rate (eGFR), calculated using the CKD-EPI equation. Although epidemiological and clinical studies have consistently demonstrated strong associations between eGFR and CVDs, the genetic underpinnings of this relationship remain elusive. Recent genome-wide association studies (GWAS) have highlighted the polygenic nature of these conditions and identified several risk loci correlating with their cross-phenotypes. Nonetheless, the extent and pattern of their pleiotropic effects have yet to be fully elucidated. We analyzed the most comprehensive GWAS summary statistics, involving around 7.5 million individuals, to investigate the shared genetic architectures and the underlying mechanisms between eGFR and CVDs, focusing on single nucleotide polymorphisms (SNPs), genes, biological pathways, and proteins exhibiting pleiotropic effects. Our study identified 508 distinct genomic locations associated with pleiotropic effects across multiple traits, involving 379 unique genes, notablyL3MBTL3(6q23.1),MMP24(20q11.22), andABO(9q34.2). Additionally, pathways such as stem cell population maintenance and the glutathione metabolism pathway were pivotal in mediating the relationships between these traits. From the perspective of vertical pleiotropy, our findings suggest a causal relationship between eGFR and conditions such as atrial fibrillation and venous thromboembolism. These insights significantly enhance our understanding of the genetic links between eGFR and CVDs, potentially guiding the development of novel therapeutic strategies and improving the clinical management of these conditions.
Discussions about Goals of Care in the Emergency Department: a Qualitative Study of Emergency Physicians’ Opinions Using the Normalization Process Theory
Authors: Péloquin Fannie , Marmen Emile , Gélinas Véronique , Plaisance Ariane , Linteau Maude , Nolet Audrey , Germain Nathalie , Archambault Patrick
Published: July 2024

Purpose

We explored emergency department (ED) physicians’ opinions about the feasibility of leading goals of care discussions (GCD) in their daily practice.

Method

This qualitative study was based on the Normalization Process Theory (NPT). We conducted semi-structured interviews between April and May 2018 with a convenience sample of ten emergency physicians from one academic ED (Lévis, Canada) and aimed to reach data saturation. Using a mixed deductive and inductive thematic analysis, two authors codified the interviews under the four NPT constructs: coherence, cognitive participation, collective action, and reflexive monitoring. We calculated a kappa statistic to measure inter-rater agreement.

Results

We interviewed 10 emergency physicians. No new ideas emerged after the ninth interview and the inter-rater agreement was substantial. Fourteen themes were identified as factors influencing the feasibility of implementing GCD: (1) interpersonal communication, (2) efficiency of care, (3) anxiety generated by the discussion, (4) identification of an acute deterioration leading to the GCD, (5) meeting of the clinician, patient, and family, (6) importance of knowing the patient’s goals of care before medical handover, (7) lack of training, (8) availability of protocols, (9) heterogeneous prioritization for leading GCD, (10) need to take action before patients consult in the ED, (11) need to develop education programs, (12) need for legislation, (13) need to improve the ED environment and human resources, and (14) selective systematization of GCD for patients.

Conclusion

Goals of care discussions are possible and essential with selected ED patients. Physicians identified outstanding needs to normalize GCD in their practice: education for both themselves and patients on the concept of GCD, legislative action for the systematization of GCD for patients, and proactive documentation of patients’ preferences pre-ED. Patient, clinician and system-level policy-making efforts remain necessary to address these needs and ensure the normalization of GCD in emergency physicians’ daily practice as suggested by clinical guidelines.

Clinician’s capsule

What is known about the topic?

Goals of care discussions are important to provide care aligned with patients’ values and medical preferences.

What did this study ask?

According to emergency physicians, are goals of care discussions feasible in the emergency department?

What did this study find?

Goals of care discussions are essential and possible if patient, clinician and system-level policymaking structured efforts are deployed.

Why does this study matter to clinicians?

This study identified action items to improve the implementation and quality of goals of care discussions in the emergency department.
Using the Emergency Care Data Set for the epidemiological surveillance of Children and Young People aged less than 18 years: a case study of COVID-19 in England 2020-2023
Authors: Boateng Jacob , Oeser Clarissa , Seghezzo Giulia , Harman Katie , Dabrera Gavin , Webster Harriet , Hope Russell , Thelwall Simon , Lamagni Theresa
Published: July 2024

Background

The Emergency Care Data Set provides insight into emergency care activity in England, and combined with COVID-19 surveillance data, can provide new insights into acute COVID-19 infection.

Methods

This study identified individuals <18 years old who tested positive for SARS-CoV-2 between February 2020 and March 2023 and attended emergency care 1-14 days after a positive test. The study’s main objective was to explore ED attendance outcomes by demographic characteristics.

Results

There were significant differences (p < 0.05) across most of the characteristics of <18s admitted to hospital from emergency departments, and those who were discharged from ED. <18s in IMD decile 1 (14.9%) made up the highest proportion of admissions, with those in less deprived areas having a greater proportion of individuals discharged from ED. February to August 2020 (1.5%) and September 2022 to March 2023 (2.8%) saw the highest proportion of <18 cases attending ED, though the highest number of cases were seen between September 2021 and February 2022.

Conclusions

There is great value in the use of ECDS. It facilitates quick, regular insights into the health outcomes of key demographics, and provides a window into the health-seeking behaviours of individuals. Furthermore, outcomes of emergency care attendance can potentially inform assessments of infection severity across multiple demographics during outbreaks and pandemics.
A qualitative study of Benzodiazepine/Z-drug and Opioid co-use patterns and overdose risk
Authors: Family Hannah E. , Vojt Gabriele , Poulter Hannah , Bailey Chris P. , Abdala Sheikh Ana Paula , Cavallo Damiana , Karimi Sara , Booth Nick , Silva Peter Da , Aitken Louise , Stewart Samantha , Hickman Matthew , Henderson Graeme , Scott Jenny , Kesten Joanna M.
Published: July 2024

Background

Co-use of benzodiazepines and/or ‘z-drugs’ along with opioids is linked to the rise in drug related deaths (DRD) in the UK. Understanding patterns of co-use could inform harm reduction strategies for reducing DRDs. This study explored how people co-use, including dosages, timings, methods of administration, use of other substances and desired effects sought.

Methods

Forty-eight semi-structured interviews across Glasgow in Scotland (n=28), Bristol (n=10) and Teesside (n=10) in England with individuals who co-use illicit and/or prescribed opioids and benzodiazepines/z-drugs were conducted. Eighteen interviews were co-facilitated with qualitatively trained local peer researchers. Interviews were analysed using the Framework method.

Results

Six co-use patterns were generated: (1) co-use to aid sleep or come down, (2) curated co-use, opioid agonist therapy (OAT) only (3) morning and evening benzodiazepine doses with opioids throughout the day (4) co-use binges (5) co-use throughout the day, (6) benzodiazepine use throughout the day plus OAT. Patterns one to three reflected more controlled co-use with a focus on self-medicating to give confidence, manage anxiety, promote sleep and come-down from cocaine/ketamine. Patterns four to six involved greater poly-drug use, and less controlled co-use with a focus on seeking euphoria (“warm glow”, “gouching out”)or oblivion (to escape untreated mental health conditions and trauma). Patterns two, three, five and six involved daily co-use. People switched between patterns depending on available resources (e.g. finances) or changes to prescriptions (opioids or benzodiazepines). Near-fatal overdoses were reported by participants across all co-use patterns.

Patterns four to six were conceptualised as presenting greater overdose risk due to less controlled co- use and more extensive polydrug use.

Conclusions

The patterns identified provide opportunities for future harm reduction strategies, tailoring advice to patterns of use, updated prescribing guidance and policies, and the need for better access to mental health care, for people who co-use benzodiazepines and opioids to reduce DRDs.
Do smoking and alcohol behaviours influence risk of type 2 diabetes? A Mendelian randomisation study
Authors: Reed Zoe E. , Sallis Hannah M. , Richmond Rebecca C. , Attwood Angela S. , Lawlor Deborah A. , Munafò Marcus R.
Published: July 2024

Background

Previous studies suggest that smoking and higher alcohol consumption are both associated with greater risk of type 2 diabetes (T2D). However, studies examining whether these associations reflect causal relationships are limited and do not consider continuous glycaemic traits. The aim of the study was to determine whether there are causal effects of smoking and alcohol consumption on T2D risk and related glycaemic traits.

Methods and Findings

We conducted both two-sample and one-sample MR to examine the effects of lifetime smoking index (LSI) and alcoholic drinks per week on T2D and continuous traits (fasting glucose, fasting insulin and glycated haemoglobin, HbA1c). For two-sample MR we used results from genome-wide association studies (GWAS) of LSI (N=462,690), alcohol consumption (N=941,280), T2D (N= 148,726 cases and 965,732 controls) and continuous traits (N=149,289 to 209,605). We used inverse variance weighting (IVW) for our main analyses and conducted several sensitivity analyses to explore violation of MR assumptions. We compared two-sample MR to one-sample MR results for alcohol effects on T2D and HbA1c in UK Biobank (N=336,984). Only these analyses were conducted to avoid sample overlap and due to data availability. The main IVW two-sample MR results suggested possible causal effects of higher LSI on T2D risk (OR per 1SD higher LSI=1.42, 95% CI=1.22 to 1.64); however, sensitivity analyses did not consistently support this finding, and there was evidence of potential horizontal pleiotropy. There was no robust evidence that higher drinks per week influenced risk of T2D from our main IVW two-sample MR analyses (OR per 1 SD higher log-transformed drinks per week=1.04, 95% CI=0.40 to 2.65), despite evidence of causal effects on higher fasting glucose (difference in mean fasting glucose in mmol/l per 1SD higher log-transformed drinks per week=0.34, 95% CI=0.09 to 0.59). One-sample MR results suggested a possible causal effect of higher drinks per week on T2D risk (OR per 1 SD higher log-transformed drinks per week=1.71, 95% CI: 1.24 to 2.36), but in contrast, lower HbA1c levels (difference in mean SD of log transformed HbA1c (mol/mol) per 1 SD higher log-transformed drinks per week=-0.07, 95% CI: -0.11 to -0.02). Key limitations include limited generalisability of results due to analyses being conducted in European populations, and potential selection bias in UK Biobank influencing results.

Conclusion

Our results suggest effective public health interventions to prevent and/or reduce smoking and alcohol consumption are unlikely to reduce the prevalence of T2D.
High-sensitivity detection ofMycobacterium tuberculosisDNA in tongue swab samples
Authors: Olson Alaina M. , Wood Rachel C. , Weigel Kris M. , Yan Alexander J. , Lochner Katherine A. , Dragovich Rane B. , Luabeya Angelique K. , Yager Paul , Hatherill Mark , Cangelosi Gerard A.
Published: July 2024

Tongue swab (TS) sampling combined with qPCR to detectMycobacterium tuberculosis(MTB) DNA is a promising alternative to sputum testing for tuberculosis (TB) diagnosis. In prior studies, the sensitivity of tongue swabbing has usually been lower than sputum. In this study, we evaluated two strategies to improve sensitivity. In one, centrifugation was used to concentrate tongue dorsum bacteria from 2-mL suspensions eluted from high-capacity foam swab samples. The pellets were resuspended as 500-µL suspensions, and then mechanically lysed prior to dual-target qPCR to detect MTB insertion elements IS6110and IS1081. Fractionation experiments demonstrated that most of the MTB DNA signal in clinical swab samples (99.22% ± 1.46%) was present in the sedimentable fraction. When applied to archived foam swabs collected from 124 South Africans with presumptive TB, this strategy exhibited 83% sensitivity (71/86) and 100% specificity (38/38) relative to sputum MRS (microbiological reference standard; sputum culture and/or Xpert® Ultra). The second strategy used sequence- specific magnetic capture (SSMaC) to concentrate DNA released from MTB cells. This protocol was evaluated on archived Copan FLOQSwabs® flocked swab samples collected from 128 South African participants with presumptive TB. Material eluted into 500 µL buffer was mechanically lysed. The suspensions were digested by proteinase K, hybridized to biotinylated dual-target oligonucleotide probes, and then concentrated ∼20-fold using magnetic separation. Upon dual-target qPCR testing of concentrates, this strategy exhibited 90% sensitivity (83/92) and 97% specificity (35/36) relative to sputum MRS. These results point the way toward automatable, high-sensitivity methods for detecting MTB DNA in TS.

Importance

Improved testing for tuberculosis (TB) is needed. Using a more accessible sample type than sputum may enable the detection of more cases, but it is critical that alternative samples be tested appropriately. Here, we describe two new, highly accurate methods for testing tongue swabs for TB DNA.
Exploring the Application of Target Trial Emulation in Vaccine Evaluation: Scoping Review
Authors: Komura Toshiaki , Watanabe Miwa , Shioda Kayoko
Published: July 2024

Background: Target trial emulation (TTE) has gained popularity in evaluating treatments and health interventions. Its application to infectious disease outcomes requires careful consideration, as infectious disease transmission violates the assumption of no interference. We conducted a scoping review to understand how TTE approaches have been applied to vaccine evaluation. Methods: We conducted a systematic search of literature published in PubMed, Embase, and Web of Science until May 2024, using keywords related to TTE, infectious diseases, and vaccines. Three independent reviewers screened titles and abstracts for relevance. Full-text articles meeting inclusion criteria were further assessed for eligibility. Results: Our keyword-based search and citation search identified a total of 240 studies. Of these, 34 original research studies used TTE approaches to evaluate vaccines, predominantly published from 2022 to 2024. Most studies (n=32, 94%) were conducted in high-income countries. The majority (n=31, 91%) evaluated the effect of COVID-19 vaccines, with one study each evaluating influenza, mpox, and rotavirus vaccines. Nationwide healthcare databases were used in 17 studies (50%). Twenty-one studies (62%) conducted analysis among adults aged ≥18 years, while six studies (18%) focused on children <18 years. Most studies did not define which of the four effects of vaccination they evaluated (direct, indirect, total, or overall effect), and none incorporated interference in vaccine evaluation. Conclusions: Our review highlights the increasing popularity of TTE in vaccine evaluation following the COVID-19 pandemic. Further discussions are needed to establish TTE approaches to estimating four effects of vaccination, using large, routinely collected data.
A Methodological Evaluation of Meta-Analyses in tDCS - Motor Learning Research
Authors: Alsalti Taym , Hussey Ian , Elson Malte , Krause Robert , Pohl Steffi
Published: July 2024

With transcranial direct-current stimulation’s (tDCS) rising popularity both in motor learning research and as a commercial product, it is becoming increasingly important that the quality of evidence on its effectiveness be evaluated. Special attention should be paid to meta-analyses, as they usually have a large impact on research and clinical practice. The aim of this study was to evaluate the methodological quality of meta-analyses estimating the effect of tDCS on motor learning with respect to reproducibility as the main focus, and reporting quality and publication bias control as secondary aspects. The three meta-analyses we reviewed largely adhered to PRISMA reporting guidelines and reported the primary effect sizes and sampling variances / confidence intervals they calculated, enabling successful reproductions of pooled effect size estimates. However, akin to previous meta-research reviews with similar aims, we found the methods and results sections of the meta-analyses to be severely underreported, which compromises the ability to judge the soundness of the methodological procedure adopted as well as its reproducibility. While publication bias detection methods were applied, the approaches chosen do not allow for well informed decisions about the presence or extent of publication bias. These results reemphasise the need to transparently report methods in meta-analyses and to meticulously evaluate their quality before and after publication.
Epigenome-wide characterization reveals aberrant DNA methylation of host genes regulating CD4+ T cell HIV-1 reservoir size in women with HIV
Authors: Xu Ke , Zhang Xinyu , Asam Kesava , Quach Bryan C. , Page Grier P. , Konkle-Parker Deborah , Martinez Claudia , Lahiri Cecile D. , Topper Elizabeth T. , Cohen Mardge H. , Kassaye Seble G. , DeHovitz Jack , Kuniholm Mark H. , Archin Nancie M. , Valizadeh Amir , Tien Phyllis C. , Marconi Vincent C. , Hancock Dana B. , Johnson Eric Otto , Aouizerat Bradley E.
Published: July 2024

The underlying mechanism of the HIV-1 reservoir, a major barrier to an HIV cure, is largely unknown. The integration of HIV-1 DNA and immune defense mechanisms can disrupt the host epigenetic landscape, potentially silencing HIV-1 replication. Using bisulfite capture DNA methylation sequencing, we profiled approximately 3.2 million CpG sites in CD4+T cells isolated from the blood of 427 virally suppressed women with HIV. The average total CD4+T cell HIV-1 Reservoir (HRCD4) size was 1,409 copies per million cells. Most proviruses were defective with only a small proportion being intact. We found 245 differentially methylated positions (CpG sites) and 85 methylated regions associated with the total HRCD4size. Notably, 52% of significant methylation sites were in intronic regions. HRCD4-associated genes were involved in viral replication (e.g.,ISG15), HIV-1 latency (e.g.,MBD2), and cell growth and apoptosis (e.g.,IRF9). A subset of the identified genes with aberrant methylation was an established target of HIV-1 integration (e.g.,NFIA, SPPL3, DLEU2, ELMSAN1). Overall, HRCD4size was inversely associated with DNA methylation of interferon signaling genes and positively associated with methylation at established HIV-1 integration sites. HRCD4-associated genes were enriched in pathways including immune defense against the virus (i.e., interferon-α response and interferon-γ response), DNA binding transcription repression, and host-virus interaction such as Tau protein binding. Together, our results show that epigenomic alterations in CD4+T cells are associated with total HIV-1 reservoir size, offering new insights into HIV-1 latency and may provide potential molecular targets for future HIV-1 eradication strategies.
Proteomic Profiling Reveals Age-Related Changes in Transporter Proteins in the Human Blood-Brain Barrier
Authors: Zhou Xujia , Azimi Mina , Handin Niklas , Riselli Andrew , Vora Bianca , Chun Eden , Yee Sook Wah , Artursson Per , Giacomini Kathleen M
Published: July 2024

The Blood-Brain Barrier (BBB) is a crucial, selective barrier that regulates the entry of molecules including nutrients, environmental toxins, and therapeutic medications into the brain. This function relies heavily on brain endothelial cell proteins, particularly transporters and tight junction proteins. The BBB continues to develop postnatally, adapting its selective barrier function across different developmental phases, and alters with aging and disease. Here we present a global proteomics analysis focused on the ontogeny and aging of proteins in human brain microvessels (BMVs), predominantly composed of brain endothelial cells. Our proteomic profiling quantified 6,223 proteins and revealed possible age-related alteration in BBB permeability due to basement membrane component changes through the early developmental stage and age-dependent changes in transporter expression. Notable changes in expression levels were observed with development and age in nutrient transporters and transporters that play critical roles in drug disposition. This research 1) provides important information on the mechanisms that drive changes in the metabolic content of the brain with age and 2) enables the creation of physiologically based pharmacokinetic models for CNS drug distribution across different life stages.
Efficient internalization of poly(benzyl malate) and poly(ethylene glycol)-b-poly(benzyl malate) copolymer based nanoparticles by human hepatic HepaRG cells and macrophages : Impact of nanoparticle functionalization by GBVA10-9 peptide on cell uptake.
Authors: NAHAS Hanadi , SABA Saad , METLEJ Perla , RIBAULT Catherine , VENE Elise , LEPAREUR Nicolas , CAMMAS-MARION Sandrine , LOYER Pascal
Published: July 2024

In the past years, we have designed biodegradable poly(benzyl malate) (PMLABe73) homopolymer and amphiphilic poly(ethylene glycol)-b-PMLABe (PEG42-b-PMLABe73) copolymer and several modified (co)polymers to produce biocompatible polymeric nanoparticles (NPs) capable of targeting hepatic cells in vitro with the goal to develop applications in the treatment of liver diseases. The current study aimed at comparing the uptake of PMLABe73 PEG42-b-PMLABe73-based NPs in human hepatic HepaRG cells, primary macrophages and peripheral blood mononuclear cells (PBMC). The uptake of NPs prepared from PEG42-b-PMLABe73 was significantly lower than that of PMLABe73 in both hepatic cells and macrophages. In addition, the NPs uptake by HepaRG cells was inversely correlated to the density of PEG present on their surface. In contrast, the internalization of with PMLABe-based NPs by human macrophages was not affected by low PEG densities, only uptake of fully pegylated PEG42-b-PMLABe73based-NPs was significantly decreased. Herein, we also showed that PMLABe-based NPs did not strongly accumulated in PBMC, T lymphocytes and neutrophils while monocytes showed slightly higher uptake of these NPs. Moreover, we further demonstrated that PMLABe-derived NPs by did not trigger inflammasome activation and secretion of pro-inflammatory cytokines neither in macrophages nor HepaRG cells. Then, we demonstrated that peptide GBVA10-9 derived from George Baker (GB) Virus A, known to exhibit a good hepatotropism did not significantly affect the uptake of PMLABe73-based NPs in HepaRG cells and macrophages, when grafted onto these NPs. The present results demonstrate that PMLABe-derived NPs are very efficiently internalized in both macrophages and hepatocytes but not in PBMC and reinforce our previous reports regarding their biocompatibility.
Epithelial memory after respiratory viral infection results in long-lasting enhancement of antigen presentation
Authors: Janas Piotr P. , T’Jonck Wouter , Burgess Matthew O. , Chauché Caroline , Vermeren Matthieu , Lucas Christopher , Bain Calum , Illingworth Robert , Roberts Edward W. , McSorley Henry J. , Schwarze Jürgen
Published: July 2024

Background

Viral lower respiratory tract infections (LRTIs) can reduce severity of subsequent LRTIs but have also been linked to respiratory allergy development and exacerbation. Here, we show that viral LRTI can imprint lung epithelial cells (LECs), leading to long-term phenotypic and functional changes in their response to subsequent challenges.

Methods

Mice were infected via intranasal administration of respiratory syncytial virus (RSV). After 28 days, LECs were isolated using cold dispase digestion followed by magnetic-activated cell sorting. Epigenetic changes were assessed using CUT&RUN, while transcriptional changes were evaluated using NanoString and qPCR. Flow cytometry was employed to measure cell surface MHC levels, antigen uptake and processing rates, and OT-I proliferation.

Results

We identified epigenetic and transcriptomic changes in murine LECs 28 days post respiratory syncytial virus (RSV) infection after recovery in genes associated with major histocompatibility complexes (MHC). Lasting upregulation of MHC-I and MHC-II was further increased followingin vivoLPS stimulation. Importantly, MHC upregulation was associated with increased antigen uptake and processing, as well as increased antigen presentation to T cells.

Conclusions

Our data suggest that LRTI can induce long-term upregulation of antigen-presentation by LECs, thus facilitating local T cell responses to microbial antigens and allergens, potentially enhancing immunity or in susceptible hosts respiratory allergy.
Modelling molecular differences in the innate immune system responses of chickens and ducks to highly pathogenic avian influenza virus
Authors: Wood Tamsin , An Gary , Bryant Clare E. , Ferguson Brian J.
Published: July 2024

Highly pathogenic avian influenza virus (HPAIV) presents a global threat to chicken livestock; chickens infected by HPAIV tend to show severe symptoms and high mortality rates. In 2022, the largest recorded outbreak of HPAIV in Europe resulted in millions of chickens being culled in the UK alone to try to prevent further spread. Unlike chickens, mallard ducks show reduced symptom severity and lower mortality rates to HPAIV infection. Research into the immune system responses of these two species shows they differ in their molecular outputs: chickens produce a pro-inflammatory response; mallards produce an anti-viral response. These differences in immune responses are thought to be in part due to chickens missing pattern recognition receptor retinoic acid-inducible gene-I (RIG-I). This project aimed to model the innate immune systems of chickens and mallard ducks to an abstracted molecular level. A literature search was conducted, and the immune systems were modelled in NetLogo as an avian innate immune response agent-based model (AIIRABM). The AIIRABM enabled examination of the relative importance of molecular differences between the chicken and mallard duck innate immune systems and produced similar differences in chicken and mallard duck molecular outputs to those observedin vitroandin vivo. Simulation experiments with the AIIRABM supported the molecular difference RIG-I as key in causing the differences in the chicken and mallard duck innate immune responses to HPAIV. The AIIRABM will be used in further research on the chicken and mallard duck immune responses to HPAIV as the baseline in an iterative modelling cycle.
Reticulon dependent ER-phagy mediates adaptation to heat stress inC. elegans
Authors: Scarcelli Vincent , Serot Claudia , Pouget Alexandre , Largeau Céline , Sagot Audrey , El-Hachimi Kenza , Dupuy Denis , Culetto Emmanuel , Lefebvre Christophe , Legouis Renaud
Published: July 2024

The selective degradation of ER by autophagy, named ER-phagy, promotes the recovery of ER homeostasis after a stress. Depending on the ER stress, different types of ER-phagy involve various selective autophagy receptors. In this study, we report a macroER-phagy induced by the fragmentation of tubular ER in response to acute heat stress. We identified a novel ER-phagy receptor encoded by the reticulon long isoform RET-1d. RET-1d is mainly expressed in the nervous system and the epidermis and colocalize with the ubiquitin-like autophagy protein LGG-1/GABARAP during heat stress induced autophagy. Two LIR motifs in the long intrinsically disordered region of RET-1d mediate its interaction with LGG-1 protein. The specific depletion of RET-1d isoform resulted in a delay in autophagosome biogenesis and a decrease in the capacity of animals to adapt to heat stress. Our data revealed a RET-1d dependent ER-phagy mechanism that takes place in neurons and epidermis and participates to the adaptation ofC. elegansto heat stress.
Segmentation and Feature Extraction of Fingernail Plate and Lunula Based on Deep Learning
Authors: Fan Yu , You Mengxiang , Ge Jieyu , Zhai Guangtao , Wang Sijia
Published: July 2024

This paper proposes a novel deep learning method for accurate segmentation of the fingernail plate and lunula. To achieve this, we designed a new network structure called Nailnet, which segments the fingernail from images of the whole hand. The results show that Nailnet achieved an Intersection over Union (IoU) score of 0.9529 and an accuracy of 0.9725 for fingernail plate segmentation. For lunula segmentation, Nailnet achieved an IoU score of 0.7784 and an accuracy of 0.8846. Additionally, Nailnet successfully recognized the fingernail index, enabling the extraction of various fingernail phenotypes, including plate color, plate shape, lunula color, and lunula proportion.
Statistical learning beyond words in human neonates
Authors: Fló Ana , Benjamin Lucas , Palu Marie , Dehaene-Lambertz Ghislaine
Published: July 2024

Interest in statistical learning in developmental studies stems from the observation that 8-month-olds were able to extract words from a monotone speech stream solely using the transition probabilities (TP) between syllables (Saffran et al., 1996). A simple mechanism was thus part of the human infant’s toolbox for discovering regularities in language. Since this seminal study, observations on statistical learning capabilities have multiplied across domains and species, challenging the hypothesis of a dedicated mechanism for language acquisition. Here, we leverage the two dimensions conveyed by speech –speaker identity and phonemes– to examine (1) whether neonates can compute TPs on one dimension despite irrelevant variation on the other and (2) whether the linguistic dimension enjoys an advantage over the voice dimension. In two experiments, we exposed neonates to artificial speech streams constructed by concatenating syllables while recording EEG. The sequence had a statistical structure based either on the phonetic content, while the voices varied randomly (Experiment 1) or on voices with random phonetic content (Experiment 2). After familiarisation, neonates heard isolated duplets adhering, or not, to the structure they were familiarised with. In both experiments, we observed neural entrainment at the frequency of the regularity and distinct Event-Related Potentials (ERP) to correct and incorrect duplets, highlighting the universality of statistical learning mechanisms and suggesting it operates on virtually any dimension the input is factorised. However, only linguistic duplets elicited a specific ERP component, potentially an N400 precursor, suggesting a lexical stage triggered by phonetic regularities already at birth. These results show that, from birth, multiple input regularities can be processed in parallel and feed different higher-order networks.

HIGHLIGHTS

Human neonates are sensitive to regularities in speech, encompassing both phonetic content and voice dimension.

There is no observed advantage for statistical computations of linguistic content over voice content.

Both speech dimensions are processed in parallel by distinct networks.

Phonetic regularities evoked a specific ERP component in the post-learning phase, suggesting activations along the pathway to the lexicon.
Cdhr1a and pcdh15b link photoreceptor outer segments with inner segment calyceal processes revealing a potential mechanism for cone-rod dystrophy
Authors: Patel Meet K. , Piedade Warlen , Famulski Jakub K.
Published: July 2024

Cone rod dystrophy (CRD) is a macular degeneration disorder characterized by initial cone cell photoreceptor degeneration and subsequently of rod photoreceptors. Mutations in CDHR1, a photoreceptor specific cadherin have been found to be associated with the incidence of cone-rod dystrophy and recapitulated in mouse CDHR1 knockouts. However, the molecular function of CDHR1 remains unknown. CDHR1 has been shown to localize at the leading edge of murine rod nascent outer segment (OS) making junctions to an unknown partner in the inner segment. Using Structured Illumination Microscopy (SIM), we observed that the localization of zebrafish cdhr1a extends from basal nascent OS discs above the periciliary ridge of the inner segment to a considerable length along the OS, akin to calyceal process (CPs). When labeling the CPs using pcdh15b, a CP specific cadherin, we observed that cdhr1a at the leading edge of OS juxtaposes with pcdh15b in the CP. Similar localization patterns were detected in human, macaque, xenopus, ducks, and various rodent PRCs indicating conservation. Importantly, using immunoprecipitation and K652 cell aggregation assays we demonstrate that pcdh15b and cdhr1a can interact and potentially link the OS and CP. To analyze the consequences of OS-CP interactions in CRD, we established a zebrafishcdhr1amutant line (cdhr1afs*146) and analyzed CRD progression at high temporal resolution. Homozygouscdhr1afs*146mutants begin to exhibit minor cone OS morphology defects starting at 15 dpf (days post fertilization) and severe OS disruption and cell loss by 3 months. Rod OS defects were delayed until 3-6 months. Furthermore, we show that loss of cdhr1a function leads to disorganization and shortening of CPs coinciding with cone outer OS defects which is significantly exacerbated when combined with the loss of pcdh15b. In conclusion, we propose that cdhr1a and pcdh15b function to link cone OSs with CPs to maintain proper OS homeostasis thus revealing a potential novel mechanism for CRD.