bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal change in mitochondrial heteroplasmy exhibits positive selection for deleterious variants
Authors: Kuiper Lieke M. , Shi Wen , Verlouw Joost , Hong Yun Soo , Arp Pascal , Puiu Daniela , Broer Linda , Xie Jiaqi , Newcomb Charles , Rich Stephen S. , Taylor Kent D. , Rotter Jerome I. , Bader Joel S. , Guallar Eliseo , van Meurs Joyce B.J. , Arking Dan E. 
Published: March 2024

AbstractA common feature of human aging is the acquisition of somatic mutations, and mitochondria are particularly prone to mutation due to their inefficient DNA repair and close proximity to reactive oxygen species, leading to a state of mitochondrial DNA heteroplasmy1,2. Cross-sectional studies have demonstrated that detection of heteroplasmy increases with participant age3, a phenomenon that has been attributed to genetic drift4–7. In this first large-scale longitudinal study, we measured heteroplasmy in two prospective cohorts (combined n=1405) at two timepoints (mean time between visits, 8.6 years), demonstrating that deleterious heteroplasmies were more likely to increase in variant allele fraction (VAF). We further demonstrated that increase in VAF was associated with increased risk of overall mortality. These results challenge the claim that somatic mtDNA mutations arise mainly due to genetic drift, instead demonstrating positive selection for predicted deleterious mutations at the cellular level, despite an negative impact on overall mortality.
Educational interventions to combat burnout: Are General Practitioners interested? A Qualitative Study
Authors: Williams Darius 
Published: March 2024

AbstractBackgroundRising burnout in General Practitioners has been noted as a major issue worldwide that is contributing to many leaving the profession earlier than anticipated or reducing their hours of clinical work. Educational interventions as part of continuing professional development (CPD) have been shown to be effective in reducing burnout and improving overall wellbeing amongst GPs. There is no published evidence available describing attitudes of GPs toward such CPD-based burnout interventions. The objective of this study is to assess GPs’ perspectives and opinions towards educational CPD-based interventions aimed at improving burnout in the GP population.MethodsA qualitative research approach using grounded theory methods was used. Participants were interviewed 1 to 1 via video call. Video files of the interviews were recorded and auto-transcription software used to generate a text file which was checked for accuracy of transcription. Transcripts underwent grounded thematic analysis with emergent themes synthesised and combined to develop a targeted analysis concordant with the objectives of the study. The study received ethical approval from the Swansea University Medicine, Health and Life Science Ethics Approval Board.Results5 participants were interviewed – all were GPs listed on the GMC GP register and currently engaged in the Wales GP appraisal process. Two participants had prior experience of CPD resources focused on burnout. Participants universally noted positive sentiment towards an educational-based CPD intervention focused at reducing burnout and noted their preferences in how such an intervention might be designed. Several important perceived barriers were highlighted that would need to be considered in the design of any future interventions.DiscussionAttitudes of participants suggest an educational-based CPD intervention would be well received, and further research is needed to assess the efficacy and cost-effectiveness of such an intervention in this population.
Strengthening implementation of integrated care for small and nutritionally at-risk infants under six months: pre-trial feasibility study
Authors: McGrath Marie , Girma Shimelis , Berhane Melkamu , Abera Mubarek , Hailu Endashaw , Bathorp Hatty , Grijalva-Eternod Carlos , Woldie Mirkuzie , Abdissa Alemseged , Girma Tsinuel , Kerac Marko , Smythe Tracey 
Published: March 2024

AbstractAn integrated care pathway to manage small and nutritionally at-risk infants under 6 months (u6m) and their mothers (MAMI Care Pathway) is consistent with 2023 WHO malnutrition guidelines and is being tested in a randomised controlled trial (RCT) in Ethiopia. To optimize trial implementation, we investigated contextual fit with key local stakeholders. We used scenario-based interviews with 17 health workers and four district managers to explore perceived feasibility. Eighteen policymakers were also surveyed to explore policy coherence, demand, acceptability, evidence needs, opportunities and risks. The Bowen feasibility framework and an access to healthcare framework were adapted and applied. Health workers perceived the MAMI Care Pathway as feasible to implement with support to access services and provide care. The approach is acceptable, given consistency with national policies, local protocols and potential to improve routine care quality. Demand for more comprehensive, preventive and person-centred outpatient care was driven by concerns about unmet, hidden and costly care burden for health services and families. Inpatient care for all severe wasting treatment is inaccessible and unacceptable. Support for routine and expanded components, especially maternal mental health, is needed for successful implementation. Wider contextual factors may affect implementation fidelity and strength. Policymakers cautiously welcomed the approach, which resonates with national commitments, policies and plans but need evidence on how it can work within varied, complex contexts without further system overstretch. A responsive, pragmatic RCT will generate the most useful evidence for policymakers. Findings have informed trial preparation and implementation, including a realist evaluation to contextualise outcomes.
Strengthening access to and confidence in COVID-19 vaccines among equity-deserving populations across Canada: An exploratory qualitative study
Authors: Bashir Kainat , Ouedraogo Mariame O. , Dharma Christoffer , Sobers Mercedes , Atukorale Vajini , Mauer-Vakil Dane , Ataullahjan Anushka , Fadel Shaza A. , Allin Sara 
Published: March 2024

ABSTRACTIntroductionThere is a need to reflect on the COVID-19 vaccine distribution across Canada and the extent to which they considered equity-deserving populations. This paper examined and compared strategies implemented by six Canadian provinces to increase access and promote the uptake of COVID-19 vaccines among selected priority populations. We also explored the factors that impacted the implementation of these strategies.MethodsIn six provinces (Alberta, British Columbia, Manitoba, Nova Scotia, Ontario, and Quebec), we conducted an environmental scan of provincial rollout documents and media sources reporting vaccine distribution among selected priority populations: First Nations, Inuit, and Metis; Black communities; essential workers; people experiencing homelessness; and people with disabilities. We subsequently interviewed 39 key informants to validate the environmental scan results, identify additional strategies to increase COVID-19 vaccine uptake, and uncover perceptions of the facilitators and challenges that influenced the strategies’ implementation.ResultsThrough the environmental scans and key informant interviews, we identified that provincial health authorities employed a panoply of strategies to overcome geographic, financial, and attitudinal barriers to COVID-19 vaccines experienced by the priority populations. Most provinces implemented walk-in, mobile, and pop-up vaccination clinics, mobilized public and private health workforce, and designed multilingual communication materials. Facilitators in implementing COVID-19 vaccination strategies included fostering inter-governmental cooperation, harmonizing communication efforts, leveraging existing relationships and networks, and ensuring representation and leadership of community partners. Challenges to implementing COVID-19 vaccination strategies included uncoordinated communication efforts, inadequate distribution of vaccines to areas with the greatest need, mistrust in the government and healthcare system, vaccine hesitancy, and lack of cultural competence by vaccine providers.ConclusionsThis study highlights the divide between well-intentioned strategies and interventions and the reality of on-the-ground implementation. The findings offer valuable insights and can inform the implementation of strategies to distribute vaccines equitably in future large-scale vaccination efforts in Canada and globally.
Supporting Respiratory Epithelia and Lowering Inflammation to Effectively Treat Common Cold Symptoms: A Randomized Controlled Trial
Authors: Pugach Pavel , Sadeghi-Latefi Nazlie 
Published: March 2024

ABSTRACTCommon cold viruses are leading triggers of asthma attacks, causing nearly two million hospitalizations per year and productivity losses approaching $40B. They also increase susceptibility to bacterial infections driving antibiotic use. Post-market clinical studies have questioned the efficacy of most over the counter (OTC) cough and cold ingredients against placebo in treating various symptoms. To our knowledge, only aspirin significantly improved overall illness severity compared to placebo and that was by about 25-30%. In this double-blind randomized placebo-controlled trial involving 157 participants, we sought to determine whether a throat spray containing a mucosal immune complex (MIC) (comprised of lysozyme, lactoferrin, and aloe) can increase the hereto reported efficacy of aspirin at reducing common cold symptoms. Previously published reports showed that the MIC can protect respiratory epithelia and lower inflammatory cytokines. Participants self-administered treatments (throat sprays every hour and tablets every four hours) and completed surveys at home over two days. Treatments included MIC spray mixed with 6mg aspirin + placebo tablet (Treatment 1), MIC spray + placebo tablet (Treatment 2), MIC spray + 325 mg aspirin tablet (Treatment 3). Participants included adult volunteers ages 21-66 (average 44), 54% female, 46% male, 46% African American, 8% Asian, 39% Caucasian, and 7% Hispanic, having common cold symptoms lasting less than two days. The main outcome measures included Sore Throat Pain Intensity (STPIS) 0-100 at 36 hours (primary endpoint) and Modified Jackson Score (MJS), a combination of eight cold symptoms (secondary endpoint).Both primary and secondary endpoints were met. Sore throat pain as measured by STPIS decreased 68-75% by 36 hours depending on treatment. Other symptoms such as nasal discharge, congestion, sneezing, cough, sore throat, and malaise as measured by MJS decreased 38-68% depending on treatment. In repeated measure within group analysis observing the same participants over multiple time points; STPIS mean change from baseline to 36 hours was as follows: Placebo (-7.84 (-14%) [95% CI -14.20 to -1.47]; p<0.0001), Treatment 1 (-42.41 (-75%)[95% CI -48.30 to -36.52]; p<0.0001), Treatment 2 (-38.60 (-68%)[95% CI -46.64 to -31.56]; p<0.0001), and Treatment 3 (-44.19 (-79%) [95% CI -52.11to -36.27]; p<0.0001). In repeated measure within group analysis all treatments significantly reduced cold symptom severity (MJS) from Days 1-2. Results were as follows: Treatment 1 (-2.26 (-38%) [95% CI -3.04 --1.47] p<0.0001), Treatment 2 (-3.81 (-53%) [95% CI -4.82 - -2.80] p<0.0001), Treatment 3 (-4.49 (-69%) [95% CI -5.62- -3.57]; p<0.0001).As a result of this study, we conclude that supporting upper respiratory epithelia and reducing COX-mediated inflammation may be used to effectively treat common cold symptoms.Trial registrationClinicalTrials.govIdentifier:NCT06106880Posted 30/10/2023
In-silico functional analyses identifyTMPRSS15-mediated intestinal absorption of lithium as a modulator of lithium response in bipolar disorder
Authors: Stacey David , Suppiah Vijayaprakash , Benyamin Beben , Lee S Hong , Hyppönen Elina 
Published: March 2024

AbstractBackgroundThe therapeutic response to lithium in patients with bipolar disorder is highly variable and has a polygenic basis. Genome-wide association studies investigating lithium response have identified several relevant loci, though the precise mechanisms driving these associations are poorly understood. We aimed to prioritise the most likely effector gene and determine the mechanisms underlying an intergenic lithium response locus on chromosome 21 identified by the International Consortium of Lithium Genetics (ConLi+Gen).MethodsWe conducted in-silico functional analyses by integrating and synthesising information from several publicly available functional genetic datasets and databases including the Genotype-Tissue Expression (GTEx) project and HaploReg.ResultsThe findings from this study highlightedTMPRSS15as the most likely effector gene at the ConLi+Gen lithium response locus.TMPRSS15encodes enterokinase, a gastrointestinal enzyme responsible for converting trypsinogen into trypsin and thus aiding digestion. Convergent findings from gene-based lookups in human and mouse databases as well as co-expression network analyses of small intestinal RNA-seq data (GTEx) implicatedTMPRSS15in the regulation of intestinal nutrient absorption, including ions like sodium and potassium, which may extend to lithium.LimitationsAlthough the findings from this study indicated thatTMPRSS15was the most likely effector gene at the ConLi+Gen lithium response locus, the evidence was circumstantial. Thus, the conclusions from this study need to be validated in appropriately designed wet-lab studies.ConclusionsThe findings from this study are consistent with a model wherebyTMPRSS15impacts the efficacy of lithium treatment in patients with bipolar disorder by modulating intestinal lithium absorption.
Carbohydrate-active enzymes fromAkkermansia muciniphilabreakdown mucin O-glycans to completion
Authors: Bakshani Cassie R. , Ojuri Taiwo O. , Pilgaard Bo , Holck Jesper , McInnes Ross , Kozak Radoslaw P , Zakhour Maria , Çakaj Sara , Kerouedan Manon , Newton Emily , Bolam David N. , Crouch Lucy I. 
Published: March 2024

AbstractAkkermansia muciniphilais a human microbial symbiont residing in the mucosal layer of the large intestine. Its main carbon source is the highly heterogeneous mucin glycoprotein andA. muciniphilauses an array of Carbohydrate-active enzymes and sulfatases to access this complex energy source. Here we describe the biochemical characterisation of fifty-four glycoside hydrolases, eleven sulfatases, and one polysaccharide lyase fromA. muciniphilato provide a holistic understanding of the carbohydrate-degrading activities. The results provide an extensive insight into the sequence of O-glycan degradation and howA. muciniphilacan access this structurally variable substrate. One of the most outstanding elements of this work was the demonstration that these enzymes can act synergistically to degrade the O-glycans on the mucin polypeptide to completion, down to the core GalNAc. Additionally, human breast milk oligosaccharide, ganglioside, and globoside glycan structures were included in the study to understand the full degradative capability ofA. muciniphila.
Dual-view jointly learning improves personalized drug synergy prediction
Authors: Li Xueliang , shen Bihan , Feng Fangyoumin , Li Kunshi , Li Hong 
Published: March 2024

AbstractBackgroundAccurate and robust estimation of the synergistic drug combination is important for precision medicine. Although some computational methods have been developed, some predictions are still unreliable especially for the cross-dataset predictions, due to the complex mechanism of drug combinations and heterogeneity of cancer samples.MethodsWe have proposed JointSyn that utilizes dual-view jointly learning to predict sample-specific effects of drug combination from drug and cell features. JointSyn capture the drug synergy related features from two views. One view is the embedding of drug combination on cancer cell lines, and the other view is the combination of two drugs’ embeddings on cancer cell lines. Finally, the prediction net uses the features learned from the two views to predict the drug synergy of the drug combination on the cell line. In addition, we used the fine-tuning method to improve the JointSyn’s performance on the unseen subset within a dataset or cross dataset.ResultsJointSyn outperforms existing state-of-the-art methods in predictive accuracy and robustness across various benchmarks. Each view of JointSyn captures drug synergy-related characteristics and make complementary contributes to the final accurate prediction of drug combination. Moreover, JointSyn with fine-tuning improves its generalization ability to predict a novel drug combination or cancer sample only using a small number of experimental measurements. We also used JointSyn to generate an estimated atlas of drug synergy for pan-cancer and explored the differential pattern among cancers.ConclusionsThese results demonstrate the potential of JointSyn to predict drug synergy, supporting the development of personalized combinatorial therapies. The source code is available on GitHub athttps://github.com/LiHongCSBLab/JointSyn.
Nematocida displodereMechanosensitive Ion Channel of Small Conductance 2 assembles into a unique 6-channel super-structurein vitro
Authors: Berg Alexandra , Berntsson Ronnie P-A , Barandun Jonas 
Published: March 2024

AbstractMechanosensitive ion channels play an essential role in reacting to environmental signals and sustaining cell integrity by facilitating ion flux across membranes. For obligate intracellular pathogens like microsporidia, adapting to changes in host environment is crucial for survival and propagation. Despite representing a eukaryote of extreme genome reduction, microsporidia have expanded the gene family of mechanosensitive ion channels of small conductance (mscS) through repeated gene duplication and horizontal gene transfer. All microsporidian genomes that are characterized to-date containmscSgenes of both eukaryotic and bacterial origin, and have at least 5 differentmscScopies. Here, we investigated the cryo-electron microscopy structure of the bacterially derived mechanosensitive ion channel of small conductance 2 (MscS2) fromNematocida displodere, an intracellular pathogen ofCaenorhabditis elegans. MscS2 is the most compact MscS known, and assembles into a unique superstructurein vitrowith six heptameric MscS2 channels oligomerizing through their transmembrane domains. Individual MscS2 channels are oriented in a heterogeneous manner to one another, resembling an asymmetric, flexible six-way cross joint. Finally, we show that, despite the extreme compaction, microsporidian MscS2 still forms a heptameric membrane channel, conserving the most important structural features of bacterial MscS.
Is tourist accommodation homogeneous? An analysis of the adults-only category through a three-step approach
Authors: Mellinas Juan Pedro , Bulchand-Gidumal Jacques , Alarcón-del-Amo María-del-Carmen 
Published: March 2024

Purpose
This paper aims to classify tourist accommodation using data from Booking.com and TripAdvisor and analyse the extent to which the different segments identified differ in terms of being adults-only.

Design/methodology/approach
In total, 1,535 properties located in nine Spanish sun and beach destinations were examined using a latent class cluster analysis (LCCA). The bias-adjusted three-step approach was used to investigate the differences between belonging to adults-only accommodation or not among the identified clusters.

Findings
Results show that adults-only accommodation tends to belong to the cluster with higher online ratings. In small Spanish islands, adults-only hotels account for a large share (more than 25%) of hotels.

Research limitations/implications
It was not possible to analyse whether the higher rating was due to the accommodation being better or due to the tourists being more satisfied with their stay.

Practical implications
In urban destinations, the model is not widely used. However, in coastal destinations, it is becoming more than a novelty or a new trend.

Social implications
In small Spanish islands, people traveling with children are becoming a minority. Families may feel discriminated against and express dissatisfaction with this situation in the future.

Originality/value
This study covers the gap in the academic literature on this growing hotel segment.
Supply chain sustainability, risk and transformational tension: a systems perspective
Authors: Göçer Aysu , Brockhaus Sebastian , Fawcett Stanley E. , Vural Ceren Altuntas , Knemeyer A. Michael 
Published: March 2024

PurposeSustainability continues to be put forth as a strategic priority. However, sustainability efforts are often deemphasized for short-term profitability. This study explores the nuances in managerial decision-making related to adopting sustainability initiatives within food supply chains in an emerging economy. We identify a complex interaction between sustainability efforts and risk mitigation. We derive a model to explain conflicting company goals, managerial decisions and system design.Design/methodology/approachWe followed an exploratory research design with an inductive approach. We analyzed data from semi-structured interviews with 29 companies representing different tiers in Turkish food supply chains. We refined and validated the interview findings through a focus group with nine senior managers. We conducted open, focused and theoretical coding in an iterative and reflective manner to analyze the data and derive our results.FindingsFrom the data, three themes emerged, indicating that managers are pursuing different, often conflicting, goals concerning value creation, risk management and sustainability performance. Managers identified and commented on new risks brought on by sustainability initiatives. These sustainability-induced risks were seen as a threat to operational performance, a driver of increased costs and a negative impact on product quality and delivery performance. Trade-offs across operating, sustainability and risk management systems create transformational tension that confounds the sustainability adoption decision-making process.Originality/valueThe data from the study was contrasted with a theoretical framework derived from systems theory, goal-setting theory of motivation and the theory of planned behavior. We identified four distinct decision paths that managers pursue. Increased awareness of transformational tension and how it influences managerial decision-making can enhance strategic sustainability system design and initiative success.