bluuebunny/crossref_metadata_2025_split huggingface dataset:
Artificial Contrast
Authors: Haase Robert , Pinetz Thomas , Kobler Erich , Paech Daniel , Effland Alexander , Radbruch Alexander , Deike-Hofmann Katerina 
Published: February 2023

AbstractDeep learning approaches are playing an ever-increasing role throughout diagnostic medicine, especially in neuroradiology, to solve a wide range of problems such as segmentation, synthesis of missing sequences, and image quality improvement. Of particular interest is their application in the reduction of gadolinium-based contrast agents, the administration of which has been under cautious reevaluation in recent years because of concerns about gadolinium deposition and its unclear long-term consequences. A growing number of studies are investigating the reduction (low-dose approach) or even complete substitution (zero-dose approach) of gadolinium-based contrast agents in diverse patient populations using a variety of deep learning methods. This work aims to highlight selected research and discusses the advantages and limitations of recent deep learning approaches, the challenges of assessing its output, and the progress toward clinical applicability distinguishing between the low-dose and zero-dose approach.
A unique cytotoxic CD4+T cells signature defines critical COVID-19
Authors: Baird Sarah , Ashley Caroline L. , Marsh-Wakefield Felix , Alca Sibel , Ashhurst Thomas M. , Ferguson Angela L. , Lukeman Hannah , Counoupas Claudio , Post Jeffrey J. , Konecny Pamela , Bartlett Adam , Martinello Marianne , Bull Rowena A. , Lloyd Andrew , Grey Alice , Hutchings Owen , Palendira Umaimainthan , Britton Warwick J. , Steain Megan , Triccas James A. 
Published: February 2023

AbstractBackground and objectivesSARS-CoV-2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T cell response to the resolution or progression of disease is still unclear. Optimal protective immunity may require activation of distinct immune pathways. As such, defining the contribution of individual T cell subsets to disease outcome is imperative to inform the development of next-generation COVID-19 vaccines. To address this, we performed immunophenotyping of T cell responses in unvaccinated individuals, representing the full spectrum of COVID-19 clinical presentation.MethodsSpectral cytometry was performed on peripheral blood mononuclear cell samples from patients with PCR-confirmed SARS-CoV-2 infection. Computational and manual analyses were used to identify T cell populations associated with distinct disease states through unbiased clustering, principal component analysis and discriminant analysis.ResultsCritical SARS-CoV-2 infection was characterised by an increase in activated and cytotoxic CD4+(CTL) cells of a T follicular helper (TFH) or effector memory re-expressing CD45RA (TEMRA) phenotype. These CD4+CTLs were largely absent in those with less severe disease. In contrast, those with asymptomatic or mild disease were associated with high proportions of naïve T cells and reduced expression of activation markers.ConclusionHighly activated and cytotoxic CD4+T cell responses may contribute to cell-mediated host tissue damage and progression of COVID-19. Potential for induction of these detrimental T cell responses should be considered when developing and implementing effective COVID-19 control strategies.
Relationship between Serum Leptin, Lipid Metabolism, HbA1c, and Renal Function in Individuals with Type 2 Diabetes Mellitus and Obesity and in Individuals with Type 2 Diabetes Mellitus without Obesity
Authors: Akinjinmi A. A. , Amballi A.A. , Opeyemi Abdulrahman Abdulbasit , Nicholas Aderinto , Ayokunle Adeniyi Akinbobola , Akindele I. A. , Muili AbdulBasit Opeyemi 
Published: February 2023

ABSTRACTBackgroundType 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterised by hyperglycaemia, impaired lipid metabolism, and insulin resistance. In addition to the traditional risk factors, recent studies have suggested that adipose tissue-derived hormones such as Leptin play a crucial role in the pathogenesis of T2DM and its related complications. However, the exact mechanism underlying the relationship between serum leptin levels and these comorbidities remains unclear.Methods and MaterialsThe study included 222 individuals, with 74 having T2DM and obesity, and 74 having T2DM without obesity and 74 control group. Serum levels of leptin, total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and HbA1c were measured, and the glomerular filtration rate (GFR) was used as a measure of renal function.ResultsSerum leptin levels were significantly higher in individuals with T2DM and obesity compared to those without obesity (p<0.05). Additionally, total cholesterol, triglycerides, and LDL were significantly higher in individuals with T2DM and obesity compared to those without obesity (p<0.05). Serum leptin levels were positively correlated with total cholesterol, triglycerides, and LDL (p<0.05) and negatively correlated with HDL (p<0.01). The GFR was not significant when both groups were compared.ConclusionObesity has a negative impact on lipid profile and glycemic control in type 2 diabetes patients and highlights the significance of considering the effect of obesity on the relationship between leptin and lipid profile in diabetic patients. These findings suggest that targeting obesity and leptin levels may be an effective strategy for improving lipid profile and glycemic control in type 2 diabetes.
ANALYSIS OF RIFAMPICIN INDETERMINATE RESULTS USING SHEWHART CONTROL CHARTS: IMPLICATIONS FOR PATIENTS AND TUBERCULOSIS CONTROL PROGRAMMES
Authors: Abaate Taagbara Jolly , Alali Aloni Adolphus 
Published: February 2023

AbstractBackgroundAntimicrobial resistance is a growing global public health concern, and multidrug-resistant tuberculosis is responsible for roughly one-quarter of all antimicrobial-resistant infection-related deaths worldwide. GeneXpert is a rapid, automated molecular test that detects multi-drug-resistant tuberculosis using rifampicin as a predictor. It was recommended by the World Health Organization (WHO) in 2010 for national tuberculosis programs in developing countries; however, it has limitations. Indeterminate results for Mycobacterium tuberculosis indicate that the test was unable to determine whether the bacteria were resistant to rifampicin. This study used Shewhart Control Chart, which has action limits, to investigate the causes of indeterminate results.MethodsThe control limits on the Shewhart chart are central, upper, and lower. GeneXpert indeterminate results obtained between January 2017 and December 2020 in a tertiary hospital in a low and middle-income country were plotted. Points above the upper control limit were used to determine whether or not the process was under control.ResultThe proportion of GeneXpert results that were indeterminate varied, with 58% exceeding the upper limit. Only 42% were within the control limit, in comparison.The majority of the laboratory results revealed an out-of-control signal by displaying points outside the control limits or non-random patterns of points known as special-cause variation, according to this study.ConclusionsGeneXpert indeterminate results have an impact on patient management by preventing accurate diagnosis and delaying the start of anti-tuberculosis medication. Machine malfunctions, insufficient bacterial load, poor quality samples, operator errors, or faulty laboratory materials could all be to blame. Regular equipment checks by laboratory personnel, program sponsors, or leadership will be extremely beneficial in achieving the desired results and initiating appropriate treatment. Statistical process control is widely used in hospital performance monitoring and improvement, and it is becoming more popular in public health surveillance.
In Vivo CRISPR Gene Editing in Patients with Herpes Stromal Keratitis
Authors: Wei Anji , Yin Di , Zhai Zimeng , Ling Sikai , Le Huangying , Tian Lijia , Xu Jianjiang , Paludan Soren R , Cai Yujia , Hong Jiaxu 
Published: February 2023

AbstractIn vivo CRISPR gene therapy holds large clinical potential, but the safety and efficacy remain largely unknown. Here, we injected a single dose of HSV-1-targeting CRISPR formulation in the cornea of three patients with severe refractory herpes stromal keratitis (HSK) during corneal transplantation. Our study is an investigated initiated, open-label, single-arm, non-randomized interventional trial at a single center (NCT04560790). We found neither detectable CRISPR-induced off-target cleavages by GUIDE-seq nor systemic adverse events for 18 months on average in all three patients. The HSV-1 remained undetectable during the study. Our preliminary clinical results suggest that in vivo gene editing targeting the HSV-1 genome holds acceptable safety as a potential therapy for HSK.One-Sentence SummaryOur study is the first in vivo CRISPR therapy for treating infectious disease and the first virus-like particle (VLP)-delivered gene therapy, reporting clinical follow-up to 21 months in HSK patients without seeing virus relapse, HSK recurrence, and CRISPR-associated side effects.
Machine Diagnosis of Chronic Obstructive Pulmonary Disease using a Novel Fast-Response Capnometer
Authors: Talker Leeran , Neville Daniel , Wiffen Laura , Selim Ahmed B , Haines Matthew , Carter Julian C , Broomfield Henry , Lim Rui Hen , Lambert Gabriel ,   BRS study team, Weiss Scott T , Hayward Gail , Brown Thomas , Chauhan Anoop , Patel Ameera X 
Published: February 2023

AbstractBackgroundAlthough currently most widely used in mechanical ventilation and cardiopulmonary resuscitation, features of the carbon dioxide waveform produced through capnometry have been shown to correlate with V/Q mismatch, dead space volume, type of breathing pattern, and small airway obstruction. This study applied feature engineering and machine learning techniques to capnography data collected by the N-Tidal™ device across four clinical studies to build a classifier that could distinguish CO2recordings (capnograms) of patients with COPD from those without COPD.MethodsCapnography data from four longitudinal observational studies (CBRS, GBRS, CBRS2 and ABRS) was analysed from 295 patients, generating a total of 88,186 capnograms. CO2sensor data was processed using Cambridge Respiratory Innovations’ regulated cloud platform, performing real-time geometric analysis on CO2waveforms to generate 82 physiologic features per capnogram. These features were used to train machine learning classifiers to discriminate COPD from ‘non-COPD’ (a group that included healthy participants and those with other cardiorespiratory conditions); model performance was validated on independent test sets.ResultsThe best machine learning model (XGBoost) performance provided a class-balanced AUROC of 0·968 ± 0·017 and a positive predictive value (PPV) of 0·911 ± 0·028 for a diagnosis of COPD. The waveform features that are most important for driving classification are related to the alpha angle and expiratory plateau regions. These features correlated with spirometry readings, supporting their proposed properties as markers of COPD.ConclusionThe N-Tidal device can be used to accurately diagnose COPD in near-real-time, lending support to future use in a clinical setting.FundingNIHR (i4i grant), Innovate UK, SBRI Healthcare and Pfizer OpenAir.
Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes
Authors:   Epi25 Collaborative, Chen Siwei , Neale Benjamin M , Berkovic Samuel F 
Published: February 2023

AbstractIdentifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.
DNA damage signaling inDrosophilamacrophages modulates systemic cytokine levels in response to oxidative stress
Authors: Hersperger Fabian , Meyring Tim , Weber Pia , Chhatbar Chintan , Monaco Gianni , Dionne Marc S. , Paeschke Katrin , Prinz Marco , Groß Olaf , Classen Anne-Kathrin , Kierdorf Katrin 
Published: February 2023

SummaryEnvironmental factors, infection, or injury can cause oxidative stress in diverse tissues and loss of tissue homeostasis. Effective stress response cascades, conserved from invertebrates to mammals, ensure reestablishment of homeostasis and tissue repair. Hemocytes, theDrosophilablood-like cells, rapidly respond to oxidative stress by immune activation. However, the precise signals how they sense oxidative stress and integrate these signals to modulate and balance the response to oxidative stress in the adult fly are ill-defined. Furthermore, hemocyte diversification was not explored yet on oxidative stress. Here, we employed high throughput single nuclei RNA-sequencing to explore hemocytes and other cell types, such as fat body, during oxidative stress in the adult fly. We identified distinct cellular responder states in plasmatocytes, theDrosophilamacrophages, associated with immune response and metabolic activation upon oxidative stress. We further define oxidative stress-induced DNA damage signaling as a key sensor and a rate-limiting step in immune-activated plasmatocytes controlling JNK-mediated release of the pro-inflammatory cytokineunpaired-3. We subsequently tested the role of this specific immune activated cell stage during oxidative stress and found that inhibition of DNA damage signaling in plasmatocytes, as well as JNK or upd3 overactivation, result in a higher susceptibility to oxidative stress. Our findings uncover that a balanced composition and response of hemocyte subclusters is essential for the survival of adultDrosophilaon oxidative stress by regulating systemic cytokine levels and cross-talk to other organs, such as the fat body, to control energy mobilization.
Seizure Semiology and Response to Treatment in a Pediatric Cohort withSCN2AVariants: A Parent Report
Authors: O’Connor John B. , Kirschenblatt Emily B. , Laux Linda , Berg Anne T. , Misra Sunita N. , Millichap John J. 
Published: February 2023

ABSTRACTWe examined seizure semiology and response to medications in 28 children (9 female, 19 male) with likely pathogenic and pathogenicSCN2A-related epilepsy. Parents reported seizure onset, seizure semiology, genetic variants, therapies used for seizures, and response to treatment. 27 children experienced defined seizures and 1 reported no seizure history. The most common initial seizures were focal or hemi-convulsions (n=8). Tonic seizures were the most common reported seizure type while febrile and atonic or drop seizures were the least common. Most patients experienced multiple seizures daily or were entirely seizure-free, with no difference based on age at seizure onset. The proportion of effective trials of the 8 most commonly reported medications ranged from 4 of 26 trials (levetiracetam) to 5 of 10 trials (valproic acid). Phenytoin was the most commonly reported effective treatment (N=4). Topiramate was reported to be the most effective treatment in combination with another treatment (N=6). We found a wide phenotypic spectrum ofSCN2A-related disorders and a possible correlation between genotype and seizure onset, semiology, and treatment response. Gain-of-function mutations in early-onsetSCN2Aepilepsies responded well to sodium channel blockers. Further exploration ofSCN2Apathogenic variants are needed to identify mediation mechanisms of action inSCN2A-related epilepsy.
Disseminating sleep education to graduate psychology programs online: A knowledge translation study to improve the management of insomnia
Authors: Meaklim Hailey , Meltzer Lisa J. , Rehm Imogen C. , Junge Moira F. , Monfries Melissa , Kennedy Gerard A. , Bucks Romola S. , Graco Marnie , Jackson Melinda L. 
Published: February 2023

AbstractStudy objectivesDespite the negative impact of poor sleep on mental health, evidence-based insomnia management guidelines have not been translated into routine mental healthcare. Here, we evaluate a state-wide knowledge translation effort to disseminate sleep and insomnia education to graduate psychology programs online using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) evaluation framework.MethodsUsing a non-randomized waitlist control design, graduate psychology students attended a validated six-hour online sleep education workshop delivered as part of their graduate psychology program in Victoria, Australia. Sleep knowledge, attitudes, and practice assessments were conducted pre- and post-program, with long-term feedback collected at 12 months.ResultsSeven out of ten graduate psychology programs adopted the workshop (adoption rate = 70%). The workshop reached 313 graduate students, with a research participation rate of 81%. The workshop was effective at improving students’ sleep knowledge and self-efficacy to manage sleep disturbances using Cognitive Behavioral Therapy for Insomnia (CBT-I), compared to the waitlist control with medium-to-large effect sizes (allp<.001). Implementation feedback was positive, with 96% of students rating the workshop as very good-to-excellent. Twelve-month maintenance data demonstrated that 83% of students had used the sleep knowledge/skills learned in the workshop in their clinical practice. However, more practical training is required to achieve CBT-I competency.ConclusionOnline sleep education workshops can be scaled to deliver cost-effective foundational sleep training to graduate psychology students. This workshop will accelerate the translation of insomnia management guidelines into psychology practice to improve sleep and mental health outcomes nationwide.
Structural basis of histone H2A lysine 119 deubiquitination by Polycomb Repressive Deubiquitinase BAP1/ASXL1
Authors: Thomas Jonathan F. , Valencia-Sánchez Marco Igor , Tamburri Simone , Gloor Susan L. , Rustichelli Samantha , Godínez-López Victoria , De Ioannes Pablo , Lee Rachel , Abini-Agbomson Stephen , Gretarsson Kristjan , Burg Jonathan M. , Hickman Allison R. , Sun Lu , Gopinath Saarang , Taylor Hailey , Meiners Matthew J. , Cheek Marcus A. , Rice William , Nudler Evgeny , Lu Chao , Keogh Michael-Christopher , Pasini Diego , Armache Karim-Jean 
Published: February 2023

AbstractThe maintenance of gene expression patterns during metazoan development is achieved by the actions of Polycomb group (PcG) complexes. An essential modification marking silenced genes is monoubiquitination of histone H2A lysine 119 (H2AK119Ub) deposited by the E3 ubiquitin ligase activity of the non-canonical Polycomb Repressive Complex 1. The Polycomb Repressive Deubiquitinase (PR-DUB) complex cleaves monoubiquitin from histone H2A lysine 119 (H2AK119Ub) to restrict focal H2AK119Ub at Polycomb target sites and to protect active genes from aberrant silencing. BAP1 and ASXL1, subunits that form active PR-DUB, are among the most frequently mutated epigenetic factors in human cancers, underscoring their biological importance. How PR-DUB achieves specificity for H2AK119Ub to regulate Polycomb silencing is unknown, and the mechanisms of most of the mutations in BAP1 and ASXL1 found in cancer have not been established. Here we determine a cryo-EM structure of human BAP1 bound to the ASXL1 DEUBAD domain in complex with a H2AK119Ub nucleosome. Our structural, biochemical, and cellular data reveal the molecular interactions of BAP1 and ASXL1 with histones and DNA that are critical for remodeling the nucleosome and thus establishing specificity for H2AK119Ub. These results further provide a molecular explanation for how >50 mutations in BAP1 and ASXL1 found in cancer can dysregulate H2AK119Ub deubiquitination, providing new insight into understanding cancer etiology.One Sentence SummaryWe reveal the molecular mechanism of nucleosomal H2AK119Ub deubiquitination by human BAP1/ASXL1.
Cortical interneurons: fit for function and fit to function? Evidence from development and evolution
Authors: Keijser Joram , Sprekeler Henning 
Published: February 2023

AbstractCortical inhibitory interneurons form a broad spectrum of subtypes. This diversity suggests a division of labour, in which each cell type supports a distinct function. In the present era of optimisation-based algorithms, it is tempting to speculate that these functions were the evolutionary or developmental driving force for the spectrum of interneurons we see in the mature mammalian brain. In this study, we evaluated this hypothesis using the two most common interneuron types, parvalbumin (PV) and somatostatin (SST) expressing cells, as examples. PV and SST interneurons control the activity in the cell bodies and the apical dendrites of excitatory pyramidal cells, respectively, due to a combination of anatomical and synaptic properties. But was this compartment-specific inhibition indeed the function for which PV and SST cells originally evolved? Does the compartmental structure of pyramidal cells shape the diversification of PV and SST interneurons over development? To address these questions, we reviewed and reanalysed publicly available data on the development and evolution of PV and SST interneurons on one hand, and pyramidal cell morphology on the other. These data speak against the idea that the compartment structure of pyramidal cells drove the diversification into PV and SST interneurons. In particular, pyramidal cells mature late, while interneurons are likely committed to a particular fate (PV vs. SST) during early development. Moreover, comparative anatomy and single cell RNA-sequencing data indicate that PV and SST cells, but not the compartment structure of pyramidal cells, existed in the last common ancestor of mammals and reptiles. Specifically, turtle and songbird SST cells also express theElfn1andCbln4genes that are thought to play a role in compartment-specific inhibition in mammals. PV and SST cells therefore evolved and developed the properties that allow them to provide compartment-specific inhibition before there was selective pressure for this function. This suggest that interneuron diversity originally resulted from a different evolutionary driving force and was only later co-opted for the compartment-specific inhibition it seems to serve in mammals today. Future experiments could further test this idea using our computational reconstruction of ancestral Elfn1 protein sequences.