bluuebunny/crossref_metadata_2025 huggingface dataset:
Association ofBlastocystisand Gut Microbiota in Type 2 Diabetic Mellitus Patients and non-Diabetic Individuals
Authors: Mohd Shaari Nurul Saadah , Wan Sulaiman Wan Shahida , Omar Mohd Rahman , Umaisara Nadeeya’Ayn , Lee Ii Li , Anuar Tengku Shahrul , Abdullah Noradilah Samseh
Published: February 2024

The influence of anaerobic protozoanBlastocystison human gut health is not well understood. WhileBlastocystisspecies frequently inhabit the gut, their clinical importance and ecological function remain ambiguous. A study onBlastocystiswas carried out enrolling a total of 203 participants including T2DM patients and non-diabetic individuals to evaluate the prevalence ofBlastocystisand its association in gut microbiota.Blastocystissubtypes were identified by PCR and faecal microbiome was accessed by targeting V4 region of the bacterial 16S ribosomal gene. The prevalence ofBlastocystisin T2DM was 25.49% and 17.82% in non-diabetic individuals with the most prevalent subtype on total population was ST3, followed by ST1 and ST2. The composition of gut microbiota was significantly different betweenBlastocystis-positive andBlastocystis-negative individuals.Blastocystiscarriage was positively associated with higher alpha diversity in T2DM patients and non-diabetic individuals. Interestingly, at the phylum level, the T2DM group had an obvious increase of Bacteroidetes and a marked increase of Actinobacteria with the present ofBlastocystis. The findings suggested that the presence ofBlastocystiswas linked to increased diversity and richness in the gut bacterial composition, signifying at a potentially beneficial association betweenBlastocystisand the gut microbiota.

Author Summary

Type 2 Diabetes Mellitus Patients (T2DM), a prevalent global disease, affects a significant portion of the population across the world. Thus, there is need to better understanding onBlastocystisinfection among T2DM that could lead to the alteration toward gut health. We evaluated the association betweenBlastocystisand gut microbiota, where involving two groups; T2DM patients and non-Diabetic individuals. The research revealed a higherBlastocystisin T2DM patients compared to non-diabetic individuals, emphasizing on assumption toward its pathogenicity. However, amplicon-based sequencing of 16S rRNA genes indicates thatBlastocystiscarriers exhibit increased gut microbiota diversity. Our result suggested that,Blastocystishighlighted its potential role as a component of a balanced microbiota. Notably, optimal alteration in Actinobacteria and Bacteroidetes may contribute to the several gut health. Hence, the study could prompt for further exploration regarding ofBlastocystissubtypes and gut microbiota specifically in T2DM to propose for more precise assessment ofBlastocystisand gut microbial diversity.
The Burnout Syndrome among Dietitians in Arar, Saudi Arabia
Authors: Alqahtani Nasser , Albadareen Bushra , Mohammad-Mahmood Amna
Published: February 2024

This study identified and described the status of burnout experienced by Saudi dietitians in various settings. A questionnaire was sent to 160 members who were invited to participate via informal networks. The Copenhagen Burnout Inventory (CBI) scale was used to measure burnout status. The CBI comprises three subscales: personal burnoutPB(six items), work burnoutWB(seven items), and client-related burnoutCB(six items). Among the 160 participants in this study, 94 participants (58.75%) experienced burnout. most of the participants had moderate PB (n = 49, 30.6%), low WB (n = 58, 36.3%), and moderate CB (n = 73, 45.6%). These results suggest that the Saudi dietitians as a group perceive themselves to be moderately personal and client-related burnout, and to have a low level of work burnout. Further analysis also suggests that Saudi dietitians in nontraditional settings experience more burnout than those in healthcare clinical settings.
A deep-learning-based two-compartment predictive model (PKRNN-2CM) for vancomycin therapeutic drug monitoring
Authors: Mao Bingyu , Xie Ziqian , Nigo Masayuki , Rasmy Laila , Zhi Degui
Published: February 2024

Objective

Vancomycin is a widely used antibiotic that requires therapeutic drug monitoring (TDM) for optimized individual dosage. The deep learning-based model PKRNN-1CM has shown the advantage of leveraging time series electronic health record (EHR) data for individualized estimation of vancomycin pharmacokinetic (PK) parameters. While one-compartment (1CM) PK models are commonly used because of their simplicity and previous trough-based clinical practices for dose adjustment, the pre-deep learning literature suggests the superiority of two-compartment models (2CM). Motivated by this, we introduce a novel deep-learning-based approach, PKRNN-2CM, for vancomycin TDM.

Methods

PKRNN-2CM combines RNN-driven PK parameter estimation with a 2CM PK model to predict vancomycin concentration trajectories. Training on both simulated data and real-world EHR data allows for a comprehensive evaluation of its performance.

Results

Experiments based on simulated data highlight PKRNN-2CM’s superiority over the simpler 1CM model PKRNN-1CM (PKRNN-2CM RMSE=1.30, PKRNN-1CM RMSE=2.50). Application to real data showcases significant improvement over PKRNN-1CM (PKRNN-2CM RMSE=5.62, PKRNN-1CM RMSE=5.84, two-sample unpaired t-test p-value=0.01), with potential further gains expected with non-trough level measurements.

Conclusion

PKRNN-2CM is an important improvement in vancomycin TDM, demonstrating enhanced accuracy and performance compared to the PKRNN-1CM model. This deep learning model holds potential for future individualized vancomycin TDM optimization and broader application in diverse clinical scenarios.
A cluster-randomized trial of client and provider directed financial interventions to align incentives with appropriate case management in private medicine retailers: results of the TESTsmART Trial in Lagos, Nigeria
Authors: Visser T. , Laktabai J. , Kimachas E. , Kipkoech J. , Menya D. , Arthur D. , Zhou Y. , Chepkwony T. , Abel L. , Robie E. , Amunga M. , Ambani G. , Uhomoibhi P. , Ogbulafor N. , Oshinowo B. , Ogunsola O. , Woldeghebriel M. , Garber E. , Olaleye T. , Eze N. , Nwidae L. , Mudabai P. , Gallis J.A. , Fashanu C. , Saran I. , Woolsey A. , Turner E.L. , O’Meara W. Prudhomme
Published: February 2024

Malaria remains a major health priority in Nigeria. Among children with fever who seek care, less than a quarter gets tested for malaria, leading to inappropriate use of the recommended treatment for malaria; Artemether Combination Therapies (ACT). Here we test an innovative strategy to target ACT subsidies to clients seeking care in Nigeria’s private retail health sector who have a confirmed malaria diagnosis. We supported point-of-care malaria testing (mRDTs) in 48 Private Medicine Retailers (PMRs) in the city of Lagos, Nigeria and randomized them to two study arms; a control arm offering subsidized mRDT testing for USD $0.66, and an intervention arm where, in addition to access to subsidized testing as in the control arm, clients who received a positive mRDT at the PMR were eligible for a free (fully subsidized) first-line ACT and PMRs received USD $0.2 for every mRDT performed. Our primary outcome was the proportion of ACTs dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients who were tested at the PMR and adherence to diagnostic test results. Overall, 23% of clients chose to test at the PMR. Test results seemed to inform treatment decisions and resulted in enhanced targeting of ACTs to confirmed malaria cases with only 26% of test-negative clients purchasing an ACT compared to 58% of untested clients. However, the intervention did not offer further improvements, compared to the control arm, in testing rates or dispensing of ACTs to test-positive clients. We found that ACT subsidies were not passed on to clients testing positive in the intervention arm. We conclude that RDTs could reduce ACT overconsumption in Nigeria’s private retail health sector, but PMR-oriented incentive structures are difficult to implement and may need to be complemented with interventions targeting clients of PMRs to increase test uptake and adherence. Clinical Trials Registration Number:NCT04428307
Supporting carers: Study protocol of a meta-review of psychosocial interventions for carers of people with cancer
Authors: Nic Giolla Easpaig Bróna , Newman Bronwyn , Johnson Judith , Laidsaar-Powell Rebekah , Sansom-Daly Ursula M , Jones Lucy , Hofstätter Lukas , Robertson Eden G , Mears Stephen , Sattarshetty Kabir , Harrison Reema
Published: February 2024

Background

While there is a clear need for psychosocial interventions that promote cancer carer wellbeing, the corresponding evidence base is disparate, complex and difficult for end-users to navigate and interpret. Carers remain under-supported with a lack of dedicated, effective, evidence-based programs. We will conduct a meta-review to synthesise this evidence and determine the state of science in this field.

Objectives

This study aims to address the question of: “What psychosocial interventions are available to promote the wellbeing of carers for people with cancer?”

Methods

A meta-review will synthesise relevant reviews of psychosocial interventions that have been developed and/ or evaluated with carers for people with cancer. Four electronic databases (PsychInfo, Medline, CINAHL and Cochrane Database of Systematic Reviews) will be searched for reviews published between Jan 2013 and Dec 2023. A team-based approach will be taken to screening and assessment of the returned records against the eligibility criteria to determine inclusion. Included reviews will be critically appraised using JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses. Relevant data of study characteristics, carer and patient populations, intervention details and psychosocial outcomes will be extracted, synthesised and the findings will be presented in a narrative format. This study is registered with the International Prospective Register of Systematic Reviews (reference: CRD42023403219).

Results

It is anticipated that the study will be completed by April 2024.

Conclusion

Ensuring that carers have access to evidence-based programs which promote their wellbeing as they care for loved ones is critical. This meta-review will contribute to program development and translation efforts through providing a clear picture of the cancer carer intervention evidence-base, identifying notable strengths, weaknesses, and gaps across the literature. The findings are anticipated to offer future directions to advance research in the field.
Circulating long noncoding RNA PDE4DIPP6: A novel biomarker for improving the clinical management of acute coronary syndrome
Authors: Koch Pia F. , García-Hidalgo María C. , Labus Josephine , Biener Moritz , Thum Thomas , de Gonzalo-Calvo David , Bär Christian
Published: February 2024

Aim

Long noncoding RNAs (lncRNAs) have emerged as promising diagnostic biomarkers owing to their dynamic regulation in response to pathological conditions and their detection in clinically relevant samples. Here, we explored the utility of the cardiac expressed and plasma detectable lncRNA PDE4DIPP6 as a biomarker for acute coronary syndrome (ACS). The final goal was to improve the diagnostic efficacy of state-of-the-art tests, particularly the high-sensitivity cardiac troponin assay (hs-cTnT).

Methods

The study enrolled individuals presenting with suspected ACS at the emergency department (ED). LncRNA quantification was performed in plasma samples using RT-qPCR. Discriminatory performance was evaluated by calculating the Area Under the Curve (AUC). Reclassification metrics, including the Integrated Discrimination Improvement (IDI) and Net Reclassification Improvement (NRI) indexes, were employed to assess enhancements in diagnostic accuracy.

Results

The sample comprised 252 patients, 50.8% were diagnosed with ACS and 13.9% with Non-ST Segment Elevation Myocardial Infarction (NSTEMI). Elevated levels of PDE4DIPP6 were observed in ACS patients compared to non-ACS subjects. There was no significant correlation between lncRNA and hs-cTnT levels (rho=0.071), and no association between PDE4DIPP6 levels and potential confounding factors was observed. The inclusion of PDE4DIPP6 on top of troponin T significantly enhanced the discrimination and classification of ACS patients reflected in an improved AUC of 0.734, an IDI of 0.066 and NRI of 0.471. Similarly, elevated levels of the lncRNA were observed in NSTEMI patients compared to ACS patients without NSTEMI. Consistent with previous findings, the addition of PDE4DIPP6 to hs-cTnT improved the discrimination and classification of patients, evident in an increased AUC from 0.859 to 0.944, IDI of 0.237, and NRI of 0.658.

Conclusion

PDE4DIPP6 offers additional diagnostic insights beyond hs-cTnT, suggesting its potential to improve the clinical management of patients with ACS.
Patterns of Herbal Medicine Use in a General Outpatient Clinic in Nigeria- A Cross-sectional Study
Authors: Maiyegun Afisulahi Abiodun , Akangoziri Mark Divine , Grema Bukar Alhaji , Mutalub Yahkub Babatunde , Ibrahim Farida Buhari , Ibraheem AbdulRauf Segun
Published: February 2024

Background

Herbal medicine use remains an important part of primary care and the World Health Organization has mandated member countries to conduct research into this and other forms of traditional medicine. However, research into traditional medicine remains scanty, even in the developing where it is often a major health option.

Objective

to determine the prevalence, types and sources of herbal medicine used among the study population.

Methods

Three hundred and forty-one questionnaires were administered to adult patients attending the general outpatient clinic of a tertiary hospital in Northern Nigeria. The data was collected and analysed using EPI INFO version 7.2.5.0 software.

Results

The prevalence of herbal medicine use was 85.34%; the commonest herbs were moringa (59.8%), black seed (36.8%), and olive oil (34.4%); and the commonest source of the herbs were herbal practitioners and herbal medicine vendors (79.04%). Herbal medicine use was associated with religion (P= 0.0005) and residential area (P= 0.01). Only 18.12% of participants ever discussed herbal medicine use with their doctors.

Conclusion

herbal medicine use remains high even among patients attending outpatient clinics in tertiary hospitals in Nigeria. However, health workers are often not the source of herbal medicine and patients rarely disclose its use to them.
The crystal structure of the Shethna Protein II (FeSII) fromAzotobacter vinelandiisuggests a domain swap
Authors: Kabasakal Burak V. , Mcfarlane Ciaran R. , Cotton Charles A. R. , Schmidt Anna , Kung Andrea , Lieber Lucas , Murray James W.
Published: February 2024

TheAzotobacter vinelandiiFeSII protein forms an oxygen resistant complex with the nitrogenase MoFe and Fe proteins. FeSII is an adrenodoxin type ferredoxin, forming a dimer in solution. Previously, the crystal structure was solved (Schlesier et al., 2016), with 5 copies in the asymmetric unit. One copy is a normal adrenodoxin domain, forming a dimer with its crystallographic symmetry mate. The other four copies are in an “open” conformation with a loop flipped out exposing the 2Fe-2S cluster. The open and closed conformations were interpreted as oxidised and reduced, and the large conformational change in the open configuration allowed binding to nitrogenase. We have independently solved the structure of FeSII in the same crystal form. Our positioning of the atoms in the unit cell is similar to the earlier report. However, our interpretation of the structure is different. We interpret the “open” conformation as the product of a crystallization-induced domain swap. The 2Fe-2S cluster is not exposed to solvent, but in the crystal its interacting helix is replaced by the same helix residues from a crystal symmetry mate. The domain swap is complicated, as it is unusual in being in the middle of the protein rather than at a terminus, and it creates arrangements of molecules that can be interpreted in multiple ways. We caution that crystal structures should be interpreted in terms of the contents of the entire crystal rather than one asymmetric unit.
A constraint-based framework to reconstruct interaction networks in microbial communities
Authors: Oftadeh Omid , Sahin Asli , Vayena Evangelia , Hatzimanikatis Vassily
Published: February 2024

Microbial communities live in diverse habitats and significantly impact our health and the environment. However, the principles that govern their formation and evolution remain poorly understood. A crucial step in studying microbial communities is to identify the potential metabolic interactions between the community members, such as competition for nutrients or cross-feeding. Due to the size and complexity of the metabolic network of each organism, there may be a variety of connections between each pair of organisms, which poses a challenge to unraveling the metabolic interactions. Here, we present ReMIND, a computational framework to reconstruct the interaction networks in microbial communities based on the metabolic capabilities of individual organisms. We applied ReMIND to a well-studied uranium-reducing community and the honeybee gut microbiome. Our results provide new perspectives on the evolutionary forces that shape these ecosystems and the trade-off between metabolite exchange and biomass yield. By enumerating alternative interaction networks, we systematically identified the most likely metabolites to be exchanged and highlighted metabolites that could mediate competitive interactions. We envision that ReMIND will help characterize the metabolic capacity of individual members and elucidate metabolic interactions in diverse communities, thus holds the potential to guide many applications in precision medicine and synthetic ecology.
Somatic gene delivery for flexiblein vivomodeling of high-risk sarcoma
Authors: Imle Roland , Blösel Daniel , Kommoss Felix K.F. , Zhao Eric Stutheit , Autry Robert , Blume Christina , Lupar Dmitry , Schmitt Lukas , Winter Claudia , Wagner Lena , Placke Sara , von Eicke Malte , Hertwig Michael , Peterziel Heike , Oehme Ina , Scheuerman Sophia , Seitz Christian , Geyer Florian H. , Cidre-Aranaz Florencia , Grünewald Thomas G. P. , Vokuhl Christian , Chudasama Priya , Scholl Claudia , Schmidt Claudia , Günther Patrick , Sill Martin , Jones Kevin B. , Pfister Stefan M. , Banito Ana
Published: February 2024

A particular challenge hampering therapeutic advancements for high-risk sarcoma patients is the broad spectrum of molecularly distinct sarcoma entities and the corresponding lack of suitable model systems to recapitulate and study these diseases. To overcome this predicament, we developed a novel genetically-controlled, yet versatile mouse modeling platform allowing delivery of different genetic lesions by electroporation (EPO) of the thigh muscle wildtype mice. This optimized sarcoma EPO-GEMM (EPO-based genetically engineered mouse model) platform allowed the generation of ten biologically distinct sarcoma entities, including Synovial Sarcoma (SS), fusion-positive and fusion-negative Rhabdomyosarcoma (RMS), Alveolar Soft Part Sarcoma (ASPS), Undifferentiated Pleomorphic Sarcoma (UPS) and Infantile Fibrosarcoma (IFS). Comprehensive molecular profiling and cross-species analyses confirmed faithful recapitulation of the human disease, including the expression of relevant immunotherapy targets. Syngeneic allografting enabled reliable preservation and scalability of Sarcoma-EPO-GEMMs for treatment trials, such as B7-H3-directed CAR-T cell therapy in an immunocompetent background.
ViraLM: Empowering Virus Discovery through the Genome Foundation Model
Authors: Peng Cheng , Shang Jiayu , Guan Jiaojiao , Wang Donglin , Sun Yanni
Published: February 2024

Motivation

Viruses, with their ubiquitous presence and high diversity, play pivotal roles in ecological systems and have significant implications for public health. Accurately identifying these viruses in various ecosystems is essential for comprehending their variety and assessing their ecological influence. Metagenomic sequencing has become a major strategy to survey the viruses in various ecosystems. However, accurate and comprehensive virus detection in metagenomic data remains difficult. Limited reference sequences prevent alignment-based methods from identifying novel viruses. Machine learningbased tools are more promising in novel virus detection but often miss short viral contigs, which are abundant in typical metagenomic data. The inconsistency in virus search results produced by available tools further highlights the urgent need for a more robust tool for virus identification.

Results

In this work, we develop a Viral Language Model, named ViraLM, to identify novel viral contigs in metagenomic data. By employing the latest genome foundation model as the backbone and training on a rigorously constructed dataset, the model is able to distinguish viruses from other organisms based on the learned genomic characteristics. We thoroughly tested ViraLM on multiple datasets and the experimental results show that ViraLM outperforms available tools in different scenarios. In particular, ViraLM improves the F1-score on short contigs by 22%.

Availability

The source code of ViraLM is available via:https://github.com/ChengPENG-wolf/ViraLM.

Contact

yannisun@cityu.edu.hk
PHACTboost: A Phylogeny-aware Boosting Algorithm to Compute the Pathogenicity of Missense Mutations
Authors: Dereli Onur , Kuru Nurdan , Akkoyun Emrah , Bircan Aylin , Tastan Oznur , Adebali Ogün
Published: February 2024

Most algorithms that are used to predict the effects of variants rely on evolutionary conservation. However, a majority of such techniques compute evolutionary conservation by solely using the alignment of multiple sequences while overlooking the evolutionary context of substitution events. We had introduced PHACT, a scoring-based pathogenicity predictor for missense mutations that can leverage phylogenetic trees, in our previous study. By building on this foundation, we now propose PHACTboost, a gradient boosting tree-based classifier that combines PHACT scores with information from multiple sequence alignments, phylogenetic trees, and ancestral reconstruction. The results of comprehensive experiments on carefully constructed sets of variants demonstrated that PHACTboost can outperform 40 prevalent pathogenicity predictors reported in the dbNSFP, including conventional tools, meta-predictors, and deep learning-based approaches as well as state-of-the-art tools, AlphaMissense, EVE, and CPT-1. The superiority of PHACTboost over these methods was particularly evident in case of hard variants for which different pathogenicity predictors offered conflicting results. We provide predictions of 219 million missense variants over 20,191 proteins. PHACTboost can improve our understanding of genetic diseases and facilitate more accurate diagnoses.
In vivo targeted and deterministic single cell malignant transformation
Authors: Scerbo Pierluigi , Tisserand Benjamin , Delagrange Marine , Debare Heloise , Bensimon David , Ducos Bertrand
Published: February 2024

Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the ground state theory of cancer initiation through short-range dispersal of the first malignant cells preceding tumor growth.
Characteristics of vicarious touch reports in a general population
Authors: Smit Sophie , Crossley Matthew J. , Zopf Regine , Rich Anina N.
Published: February 2024

Vicarious touch refers to the phenomenon where individuals experience tactile sensations when observing another person being touched. This study explored vicarious touch reports in 422 undergraduate students using videos from the Validated Touch-Video Database (VTD), rated for hedonic qualities, arousal, and perceived threat levels. A surprisingly large majority (84%) of participants reported vicarious sensations such as touch, tingling, pressure, and pain, predominantly matching the location of touch to the hands observed in the videos. Contrary to previous studies, we found that vicarious touch was more prevalent in women than men. Additionally, while earlier research suggested a correlation between vicarious sensations and emotional empathy, our data did not support this relationship. The nature and intensity of reported sensations varied strongly with the emotional content of the videos: pleasant touches evoked ticklish or warm sensations, while unpleasant touches often resulted in pain or pressure. Participants often described their sensations as either pleasant or unpleasant, indicating that the affective qualities of observed touch were mirrored in their experiences. Arousal and threat ratings taken from the VTD for each video strongly correlated with the prevalence and intensity of vicarious touch measured here, with painful, highly arousing touches eliciting the strongest responses. Even touch involving non-human objects occasionally triggered similar vicarious sensations. Using a new clustering approach, we identified three distinct profiles of vicarious touch, each characterised by unique sensory experiences, variations in the localisation and intensity of sensations, and differences in responses to human versus object touch. Overall, our results challenge the traditional view that conscious vicarious touch experiences are a rare phenomenon and underscore the diversity of vicarious sensory perception.
Endogenous labeling empowers accurate detection of m6A from single long reads of direct RNA sequencing
Authors: Guo Wenbing , Ren Zhijun , Huang Xiang , He Jialiang , Zhang Jie , Wu Zehong , Guo Yang , Zhang Zijun , Cun Yixian , Wang Jinkai
Published: February 2024

Although plenty of machine learning models have been developed to detect m6A RNA modification sites using the electric current signals of ONT direct RNA sequencing (DRS) reads, the landscape of m6A on different RNA isoforms is still a mystery due to their limited capacity to distinguish the m6A on individual long reads and RNA isoforms. The primary challenge in training the model with single-read accuracy is the difficulty of obtaining the training data from individual DRS reads that comprehensively represent the m6A on endogenous RNAs. Here, we endogenously label the methylated m6A sites on single ONT DRS reads by APOBEC1-YTH induced C-to-U mutations, strategically positioned 10-100 nt away from the known m6A sites on the same reads. Adopting a semi-supervised leaning strategy, we obtain 700,438 reliable 5-mer single-read level m6A signals, providing a comprehensive representation of m6A on endogenous RNAs. Leveraging this dataset, we develop m6Aiso, a deep residual neural network model that not only accurately identifies and quantifies known m6A sites but also reveals unknown, subtly methylated m6A sites responsive to METTL3 depletion. Analyzing m6Aiso-determined m6A on single reads and isoforms uncovers distance-dependent linkages of m6A sites along single molecules, as well as differential methylation of identical m6A sites on different isoforms. Moreover, we find wide-spread functionally important dynamic changes of m6A sites on specific isoforms during epithelial-mesenchymal transition (EMT). The pivotal utilization of the endogenous labeling strategy empowers m6Aiso to achieve remarkable precision in pinpointing m6A on individual molecules, underscores its effectiveness in elucidating the intricate dynamics and complexities of m6A across RNA isoforms.
Outcrossing increases resistance against coevolving parasites
Authors: Slowinski Samuel P. , Gresham Jennifer D. , Penley McKenna J. , Lively Curtis M. , Morran Levi T.
Published: February 2024

Despite substantial costs, biparental sex is the dominant mode of reproduction across plant and animal taxa. The Red Queen hypothesis (RQH) posits that coevolutionary interactions with parasites can favor biparental sex in hosts, despite the costs. In support of the RQH, previous studies found that coevolutionary interactions with virulent bacterial parasites maintained high outcrossing rates in populations of the androdioecious nematode hostCaenorhabditis elegans. Here we test three non-mutually exclusive mechanisms that could explain how coevolving parasites maintain outcrossing rates inC. eleganshosts: 1) short-term parasite exposure induces plastic increases in the hosts’ propensity to outcross, 2) hosts evolve increased outcrossing propensity in response to selection imposed by coevolving parasites, and 3) outcrossed offspring incur less parasite-mediated fitness loss than selfed offspring, increasing host male frequencies and opportunities for outcrossing. We find no evidence that parasites cause plastic or evolved changes in host outcrossing propensity. However, parental outcrossing significantly increases survival of host offspring in the F2 generation when exposed to a coevolving parasite. Hence, coevolving parasites maintain outcrossing in host populations by selecting against selfed offspring, rather than by inducing changes in the propensity to outcross.
Identification, antimicrobial resistance and molecular detection of Shiga toxin-producingE. coli(STEC) isolated from raw milk of cattle in Chitwan, Nepal
Authors: Shrestha Sunita , Bhattarai Rebanta Kumar , Basnet Hom Bahadur , Luitel Himal , Bastola Sirjan
Published: February 2024

Shiga toxin-producingEscherichia coli(STEC) is one of the most common foodborne pathogens leading to gastroenteritis with symptoms of mild diarrhoea to the potential life-threatening haemolytic uremic syndrome. Serotype O157:H7 has been the most predominant type worldwide but there are an increasing number of outbreaks caused by non-O157:H7 STEC serotypes. This is the first study about STEC in milk used in Nepalese communities. A total of 267 raw milk samples were taken from different sites in Chitwan District, one of the major milk-producing districts of Nepal, using multi-stage sampling. The samples underwent microbiological and molecular analysis. The overall prevalence ofE. coliwas found to be 29.6% (79/267) in raw cattle milk.Z3276gene, a specific genetic marker ofE. coliO157:H7 was detected only in three isolates which also carriedstxgenes. The overall prevalence of STEC in raw cattle milk was 11.6% (31/267) whereas the prevalence of STEC amongE. coliisolates was 39.2% (31/79). The prevalence of O157:H7 STEC is 1.1% (3/267) and of non-O157:H7 STEC is 10.5% (28/267). Out of 12 antibiotics tested, the sensitivity of STEC to an antibiotic was highest with azithromycin, and levofloxacin, and the most resistant was with tetracycline, and doxycycline. The findings revealed that raw cattle milk was contaminated with STEC, posing a potential public health concern. The discovery of a greater occurrence ofstx2genes in this study highlights the possibility of more severe complications in humans. Molecular-based STEC surveillance is essential to minimize the risk of its transmission.
A “torn bag mechanism” of small extracellular vesicle release via limiting membrane rupture ofen blocreleased amphisomes (amphiectosomes)
Authors: Visnovitz Tamás , Lenzinger Dorina , Koncz Anna , Vizi Péter M , Bárkai Tünde , Vukman Krisztina V , Galinsoga Alicia , Németh Krisztina , Fletcher Kelsey , Komlósi Zsolt I , Cserép Csaba , Dénes Ádám , Lőrincz Péter , Valcz Gábor , Buzás Edit I
Published: February 2024

Recent studies showed an unexpected complexity of extracellular vesicle (EV) biogenesis pathways. We previously found evidence that human colorectal cancer cellsin vivorelease large multivesicular body-like structuresen bloc. Here, we tested whether this large extracellular vesicle type is unique to colorectal cancer cells. We found that all cell types we studied (including different cell lines and cells in their original tissue environment) released multivesicular large EVs (MV-lEVs). We also demonstrated that upon spontaneous rupture of the limiting membrane of the MV-lEVs, their intraluminal vesicles (ILVs) escaped to the extracellular environment by a ”torn bag mechanism”. We proved that the MV-lEVs were released by ectocytosis of amphisomes (hence, we termed them amphiectosomes). Both ILVs of amphiectosomes and small EVs separated from conditioned media were either exclusively CD63 or LC3B positive. According to our model, upon fusion of multivesicular bodies with autophagosomes, fragments of the autophagosomal inner membrane curl up to form LC3B positive ILVs of amphisomes, while CD63 positive small EVs are of multivesicular body origin. Our data suggest a novel common release mechanism for small EVs, distinct from the exocytosis of multivesicular bodies or amphisomes, as well as the small ectosome release pathway.
SingleM and Sandpiper: Robust microbial taxonomic profiles from metagenomic data
Authors: Woodcroft Ben J. , Aroney Samuel T. N. , Zhao Rossen , Cunningham Mitchell , Mitchell Joshua A. M. , Blackall Linda , Tyson Gene W.
Published: February 2024

Determining the taxonomy and relative abundance of microorganisms in metagenomic data is a foundational problem in microbial ecology. To address the limitations of existing approaches, we developed ‘SingleM’, which estimates community composition using conserved regions within universal marker genes. SingleM accurately profiles complex communities of known microbial species, and is the only tool that detects species without genomic representation, even those representing novel phyla. Given SingleM’s computational efficiency, we applied it to 248,559 publicly available metagenomes and show that the vast majority of samples from marine, freshwater, sediment and soil environments are dominated by novel species lacking genomic representation (median relative abundance 75.0%). SingleM also provides a way to identify metagenomes for the recovery of novel metagenome-assembled genomes from lineages of interest, and can incorporate user-recovered genomes into its reference database to improve profiling resolution. Quantifying the full diversity of Bacteria and Archaea in metagenomic data shows that microbial genome databases are far from saturated.
New Reference Values for Thyroid Volume by Ultrasound in German Children and Adolescents Under Iodine-Sufficient Conditions from a Population-Based Study
Authors: Hirtz Raphael , Thamm Roma , Kuhnert Ronny , Liesenkötter Klaus-Peter , Thamm Michael , Grasemann Corinna
Published: February 2024

Context

Reliable reference values for thyroid ultrasound measurements are essential to effectively guide individual diagnostics and direct health care measures at the population level, such as iodine fortification programs. However, the latest reference values for total thyroid volume (Tvol) provided by the WHO in 2004 only apply to the 6 to 12-year-old age group and are limited to countries with a long history of iodine sufficiency, which does not reflect the situation in most European countries, including Germany.

Objective

The present aims to derive up to date thyroid volume ultrasound reference values in German children and adolescents.

Design

Data from the baseline assessment of a nationwide study in German children and adolescents (KiGGS) conducted between 2003 and 2006 were used to determine sex-specific reference values for Tvol in thyroid-healthy participants aged 6 to 17 years by age and body surface area (BSA) according to the Lambda-Mu-Sigma (LMS) method.

Results

Data from 5559 participants were available for reference chart construction (girls: 2509 (45.1%)). On average, the 97th percentile is 33.4% and 28.5% higher than the corresponding WHO’s reference values for boys and girls, respectively. These findings are consistent with most other studies in German and European children and adolescents at a similar time of investigation. Notably, the sample used for this study was iodine-sufficient according to WHO criteria.

Conclusions

The reference values provided by the WHO are overly conservative for this population and could potentially apply to apply to other European countries with a similar history of iodine supply.
Magnetocardiography for the diagnosis of coronary artery disease: a systematic review and meta-analysis
Authors: Yang Miao , Sun Chenxi , Zhao Biying , Wu Bo , Xiang Jing , Xu Man , Wu Teng , Zhang Jianwei , Xu Wei , Guo Hong
Published: February 2024

Background

Globally, coronary heart disease (CHD) is a major public health issue because it significantly increases mortality and medical expenses. In the recent years, magnetocardiography (MCG) has shown its potential as a new tool for diagnosing CHD. However, the quantitative assessment of MCG currently used for CHD diagnosis are insufficient, preventing its full integration into routine clinical practice.

Methods

We searched PubMed (including MEDLINE), Embase, Web of Science, Cochrane Library, Scopus, China National Knowledge Infrastructure (CNKI), Wanfang Data, and ClinicalTrials.gov for studies published up to March 4, 2023. We systematically searched for studies that compare MCG (as the index test) with coronary angiography (as the standard reference) for diagnosing CHD in suspected population. Three authors assessed the quality of the included studies independently using the QUADAS-2 tool. We calculated the pooled value of the sensitivity and specificity of MCG using the bivariate model. To investigate clinical and methodological factors that might contribute to the statistical heterogeneity, we used meta-regression and subgroup analysis. This systematic review and meta-analysis has been conformed to PRISMA guidelines and registered with PROSPERO (number CRD42022332272).

Results

By searching, we found 174 studies, 18 of them included 2,571 subjects from 6 countries and regions and met the inclusion criteria. The combined values for sensitivity and specificity are 86% (95% CI: 80-91) and 79% (95% CI: 71-86), respectively. The summary receiver operating characteristic (SROC) curve’s area under the curve was 0.90. We found significant statistical heterogeneity between studies (for sensitivity, I2=94.22% (95% CI: 92.48-95.96), Q=294.11,P<0.01; for specificity, I2=88.98% (95% CI: 84.95-93.01), Q=154.26,P<0.01.

Conclusion

Given its high sensitivity, MCG has a high value for diagnosing CHD, especially in primary screening. Further investigation is required to examine additional factors that may affect the performance of MCG considering the limited clinical trials and sample size.
Trends and Adverse Outcomes of Xylazine Misuse: A Digital Surveillance Study
Authors: Bhagavathula Akshaya Srikanth , Aldhaleei Wafa A. , Kim Seongjin
Published: February 2024

Background

Xylazine is an animal tranquilizer without approved medical use in humans that is increasingly being misused as an adulterant in illicit drugs. This study aimed to characterize national trends and adverse outcomes associated with the emerging misuse of xylazine using digital surveillance data.

Methods

We examined online search trends and social media discussions related to xylazine misuse in the U.S. from 2019-2023 using Google Searches data and conducted Joinpoint regression to assess trends. We also examined social media attention using Almetric attention score and analyzed reports on xylazine in the FDA Adverse Event Reporting System (FAERS) through September 2023 using logistic regression.

Results

Our analysis revealed an overall increasing trend in online searches for “xylazine” nationally, with an average monthly percentage change of 4.6% (95% CI: 3.9–5.1,Ptrend<0.001), indicating growing awareness. On social media, mentions of xylazine rose exponentially starting in late 2021. Analysis of the FAERS data identified 94 reports of adverse events related to xylazine, most of which involved men (70.2%), with a mean age of 36.5 ± 14.3 years. Alarmingly, these xylazine-linked adverse events had an 87.2% fatality rate, which increased over 40-fold with concurrent fentanyl use (reported OR: 40.5, 95% CI: 4.0–407.4,P=0.002).

Conclusions

These findings underscore the urgent need for greater public health awareness, harm reduction strategies, and enhanced surveillance targeting the worsening xylazine addiction and overdose crisis.
Efgartigimod efficacy and safety in refractory Myasthenia Gravis - UK’s first real-world experience
Authors: Dionísio J Moniz , Ambrose P , Burke G , Farrugia M , Garcia-Reitboeck P , Hewamadduma C , Hill M , Howard RS , Jacob S , Kullmann DM , Leite MI , Miller J , Pinto A , Pritchard J , Riswick T , Sathasivam S , Thambarigjah N , Viegas S , Norwood F , Spillane J
Published: February 2024

Background

We report our experience of patients with generalised MG (gMG) treated with Efgartigimod, an FcN antagonist, under the Early Access to Medicine Scheme (EAMS) in the UK.

Methods

Data from all UK patients treated with Efgartigimod under the EAMS June 22-July 23 were collected retrospectively. Efgartigimod was administered as per the ADAPT protocol (consisting of a treatment cycle of 4 infusions at weekly intervals with further cycles given according to clinical need).

Results

48 patients with AChR antibody-positive gMG were treated in 12 centres. Most (75%) were female and most had a disease duration of over 10 years. The average MG-ADL score at baseline was 11.2. Most (72.9%) patients had undergone thymectomy. 77.0% were taking prednisolone at baseline. All patients had utilized non-steroidal immunosuppressant treatments, the average number tried was 2.6 (range 1-6). 51% had received Rituximab. 54.2% of patients required regular IVIg/PLEX.

75% of patients had a mean reduction in the MG-ADL of ≥2 points in the first cycle and this remained stable throughout the study. The mean intracycle reduction in the MG-ADL score in the 1st, 2nd, 3rd and 4th cycles were -4.6, -3.9, -3.4 and -4.2 respectively. Side effects were generally mild though one patient stopped treatment due to severe hypokalemia. No rescue treatments were required. At the end of the study, 96% of patients remained on Efgartigimod.

Conclusion

Efgartigimod is a safe and effective treatment for patients with refractory, treatment-resistant gMG.
Intraocular pressure, primary open-angle glaucoma and the risk of retinal vein occlusion: a Mendelian randomization mediation analysis
Authors: Katsimpris Andreas , Baumeister Sebastian-Edgar , Voulgari Nafsika , Baurecht Hansjörg , Kandarakis Stylianos , Nolde Michael
Published: February 2024

Background

The etiological connection between intraocular pressure (IOP) and the risk of retinal vein occlusion (RVO) remains elusive, particularly regarding whether this risk emanates from the direct influence of elevated intraocular pressure (IOP), irrespective of the presence of primary open-angle glaucoma (POAG), or if it arises as a consequence of the sequelae of POAG. Therefore, we conducted a Mendelian Randomization (MR) mediation analysis to elucidate the mediating role of POAG in the association between IOP and RVO.

Methods

We identified 47 single-nucleotide polymorphisms (SNPs) associated with IOP (P-value < 5×10-8) leveraging data from a genome-wide association study (GWAS) (N = 97,653) obtained from the UK Biobank and 50 SNPs associated with POAG (P-value < 5×10-8) from a GWAS meta-analysis (16,677 cases and 199,580 controls). We related these SNPs with RVO using a GWAS of 775 RVO cases and 376,502 controls from FinnGen. By utilizing univariable and multivariable MR analyses we calculated the total effect of IOP on RVO and estimated the degree to which POAG mediates this association.

Results

MR analyses showed that higher IOP is associated with higher RVO risk (odds ratio of RVO per 1 mmHg increase in IOP: 1.53; 95% confidence interval: 1.04 to 2.26; p-value = 0.03). Moreover, our MR mediation analysis suggested that 91.6% of the total effect of IOP on RVO risk was mediated through POAG. The primary results were consistent with estimates of pleiotropy-robust MR methods.

Conclusion

Our findings suggest that higher IOP increases the risk of RVO and that the majority of this effect is mediated through POAG.
Improved Complexity Stratification in Congenital Heart Disease; the Impact of Including Procedural Data on Accuracy and Reliability
Authors: Chami Jason , Nicholson Calum , Baker David , Cordina Rachael , Strange Geoff , Celermajer David S.
Published: February 2024

Introduction

In order to manage a class of diseases as broad as congenital heart disease (CHD), multiple “manually generated” classification systems defining CHDs as mild, moderate and severe have been developed and used to good effect. As databases have grown, however, such “manual” complexity scoring has become infeasible. Though past attempts have been made to determine CHD complexity algorithmically using a list of diagnoses alone, missing data and lack of procedural information have been significant limitations.

Methods

We built an algorithm that can stratify the complexity of patients with CHD by integrating their diagnoses with a list of their previous procedures. Specific procedures which address a missing diagnosis or imply a certain operative status were used to supplement the diagnosis list. To verify this algorithm, CHD specialists manually checked the classification of 100 children and 100 adults across four hospitals in Australia.

Results

Our algorithm was 99.5% accurate in the manually checked cohort (100% in children and 99% in adults), and was able to automatically classify more than 90% of a cohort of over 24,000 CHD patients, including 92.5% of children (vs 84.4% without procedures, p < 0.0001) and 91.1% of adults (vs 70.4% without procedures; p < 0.0001).

Conclusions

CHD complexity scoring is significantly improved by access to procedural history and can be automatically calculated with high accuracy.
The DBD-α4 helix of EWSR1::FLI1 is required for GGAA microsatellite binding that underlies genome regulation in Ewing sarcoma
Authors: Bayanjargal Ariunaa , Taslim Cenny , Showpnil Iftekhar A. , Selich-Anderson Julia , Crow Jesse C. , Lessnick Stephen L. , Theisen Emily R.
Published: February 2024

Ewing sarcoma is the second most common bone cancer in children and young adults. In 85% of patients, a translocation between chromosomes 11 and 22 results in a potent fusion oncoprotein, EWSR1::FLI1. EWSR1::FLI1 is the only genetic alteration in an otherwise unaltered genome of Ewing sarcoma tumors. The EWSR1 portion of the protein is an intrinsically disordered domain involved in transcriptional regulation by EWSR1::FLI1. The FLI portion of the fusion contains a DNA binding domain shown to bind core GGAA motifs and GGAA repeats. A small alpha-helix in the DNA binding domain of FLI1, DBD-α4 helix, is critical for the transcription function of EWSR1::FLI1. In this study, we aimed to understand the mechanism by which the DBD-α4 helix promotes transcription, and therefore oncogenic transformation. We utilized a multi-omics approach to assess chromatin organization, active chromatin marks, genome binding, and gene expression in cells expressing EWSR1::FLI1 constructs with and without the DBD-α4 helix. Our studies revealed DBD-α4 helix is crucial for cooperative binding of EWSR1::FLI1 at GGAA microsatellites. This binding underlies many aspects of genome regulation by EWSR1::FLI1 such as formation of TADs, chromatin loops, enhancers and productive transcription hubs.