bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity of acetylcholine receptor autoantibody-mediated complement activity in patients with myasthenia gravis
Authors: Obaid Abeer H. , Zografou Chryssa , Vadysirisack Douangsone D. , Munro-Sheldon Bailey , Fichtner Miriam L. , Roy Bhaskar , Philbrick William M. , Bennett Jeffrey L. , Nowak Richard J. , O’Connor Kevin C. 
Published: October 2021

AbstractBackgroundAutoantibodies targeting the acetylcholine receptor (AChR), found in patients with myasthenia gravis (MG), mediate pathology through three mechanisms: complement-directed tissue damage, blocking of the acetylcholine binding site, and internalization of the AChR. Clinical assays, used to diagnose and monitor patients, measure only autoantibody binding. Consequently, they are limited in providing association with disease burden, understanding of mechanistic heterogeneity, and monitoring therapeutic response.ObjectiveDevelop a cell-based assay that measures AChR autoantibody-mediated complement membrane attack complex (MAC) formation.MethodsAn HEK293T cell line—modified using CRISPR/Cas9 genome editing to disrupt expression of the complement regulator genes (CD46, CD55 and CD59)—was used to measure AChR autoantibody-mediated MAC formation via flow cytometry.ResultsSerum samples (n=155) from 96 clinically confirmed AChR MG patients, representing a wide range of disease burden and autoantibody titer, were tested along with 32 healthy donor (HD) samples. AChR autoantibodies were detected in 139 of the 155 (89.7%) MG samples via a cell-based assay. Of the 139 AChR positive samples, autoantibody-mediated MAC formation was detected in 83 (59.7%), while MAC formation was undetectable in the HD group or AChR positive samples with low autoantibody levels. MAC formation was positively associated with autoantibody binding in most patient samples; ratios (MFI) of MAC formation to AChR autoantibody binding ranged between 0.27–48, with a median of 0.79 and interquartile range of 0.43 (0.58–1.1). However, the distribution of ratios was asymmetric and included extreme values; 16 samples were beyond the 10–90 percentile, with high-MAC to low-AChR autoantibody binding ratio or the reverse. Correlation between MAC formation and clinical disease scores suggested a modest positive association (rho=0.34, p=0.0023), which included a subset of outliers that did not follow this pattern. MAC formation did not associate with exposure to immunotherapy, thymectomy, or MG subtypes defined by age-of-onset.ConclusionsA novel assay for evaluating AChR autoantibody-mediated complement activity was developed. A subset of patients that lack association between MAC formation and autoantibody binding or disease burden was identified. The assay may provide a better understanding of the heterogeneous autoantibody molecular pathology and identify patients expected to benefit from complement inhibitor therapy.
Correlation between leukocyte phenotypes and prognosis of amyotrophic lateral sclerosis: a longitudinal cohort study
Authors: Cui Can , Ingre Caroline , Yin Li , Li Xia , Andersson John , Seitz Christina , Ruffin Nicolas , Pawitan Yudi , Piehl Fredrik , Fang Fang 
Published: October 2021

AbstractBackgroundImmune response changes have been reported in amyotrophic lateral sclerosis (ALS), but their clinical relevance remains undetermined. Therefore, we aim to evaluate the relationships between blood leukocyte subpopulations and prognosis of ALS.MethodsA longitudinal cohort of 288 ALS patients with up to 5 years of follow-up during 2015-2020 were recruited at the only tertiary referral center for ALS in Stockholm, Sweden. Routine differential leukocyte counts, and determination of lymphocyte subpopulations including an extended T cell panel with flow cytometry, collected at diagnosis and at regular intervals thereafter. The primary outcome was risk of death (alternatively use of invasive ventilation) after diagnosis of ALS. The secondary outcomes included repeatedly measured functional status - through Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) score and disease progression rate. Cox model was used to evaluate the associations between leukocytes and risk of death. Generalized estimating equation model (GEE) was used to assess the correlation between leukocytes and ALSFRS-R score and disease progression rate.ResultsThe counts of leukocytes, neutrophils and monocytes increased gradually over time since diagnosis and were negatively correlated with ALSFRS-R score, but not associated with risk of death or disease progression rate. Focusing on lymphocyte subpopulations, increasing counts of natural killer (NK) cells (HR=0.61, 95% CI= [0.42-0.88] per SD increase) and proportions of Th2-diffrentiated CD4+ central memory (CM) T cells (HR=0.64, 95% CI= [0.48-0.85] per SD increase) were correlated with a lower risk of death. Increasing proportions of CD4+ effector memory cells re-expressing CD45RA (EMRA) T cells (HR=1.39, 95% CI= [1.01-1.92] per SD increase) and CD8+ T cells (HR=1.38, 95% CI= [1.03-1.86] per SD increase) were associated with a higher risk of death. None of the lymphocyte subpopulations was correlated with ALSFRS-R score or disease progression rate.ConclusionOur findings suggest a dual role of immune responses in ALS prognosis, where neutrophils and monocytes primarily reflect functional status whereas NK cells and different T lymphocyte populations act as prognostic markers for survival. The findings also provide insights for cell-specific treatment for ALS.FundingThis work was supported by the European Research Council (ERC) Starting Grant (MegaALS, No. 802091), the Swedish Research Council (No. 2019-01088), Karolinska Institutet (Strategic Research Area in Epidemiology and Senior Researcher Award), and China Scholarship Council.
Paretic upper extremity strength at acute rehabilitation evaluation predicts motor function outcome after stroke
Authors: da Silva Mary Alice Saltão , Cook Christine , Stinear Cathy M , Wolf Steven L , Borich Michael R 
Published: October 2021

AbstractObjectiveThe primary objective of this study was to retrospectively assess current care practices to determine the routinely collected measures that are most predictive of paretic upper extremity (PUE) functional outcome post-stroke in patients undergoing acute inpatient rehabilitation (AR).MethodsWe conducted a longitudinal chart review of patients post-stroke who received care in the Emory University Hospital system for acute hospitalization, AR, and outpatient therapy in fiscal years 2016-2018. We identified eligible patients using previously established inclusion and exclusion criteria. We extracted demographics, stroke characteristics, and longitudinal documentation of post-stroke motor function from institutional electronic medical records. Serial assessments of PUE strength were estimated using available shoulder abduction and finger extension manual muscle test documentation (E-SAFE). Estimated Action Research Arm Test (E-ARAT) was used to quantify 3-month PUE functional outcome. Metric associations were explored through correlation and cluster analyses, Kruskal-Wallis tests, classification and regression tree (CART) analysis.ResultsThirty-four patients met study eligibility criteria. E-SAFE assessments performed closest to acute hospitalization day-3 (Acute E-SAFE) and upon AR admission (AR E-SAFE) were correlated with E-ARAT. Cluster analysis produced three distinct outcome groups and aligned closely to previous outcome categories. Outcome groups significantly differed in Acute E-SAFE and AR E-SAFE. Exploratory CART analysis selected AR E-SAFE to classify patient outcome with 70.6% accuracy.ConclusionsCurrent study findings reveal that: PUE E-SAFE, measured both acutely and at AR admission, is associated with PUE motor recovery outcome; categorizations of outcome are consistent with previous studies; and predictive models can identify recovery outcome category in patients undergoing AR.Impact StatementOur findings highlight the clinical utility of SAFE as an easy-to-acquire, readily implementable screening metric. Early, intentional use of SAFE in AR settings may improve clinical decision-making, enabling therapists to deliver precision-based interventions that serve to speed or enhance recovery outcome for patients post-stroke.
Comparison of MIS-C Related Myocarditis, Classic Viral Myocarditis, and COVID-19 Vaccine related Myocarditis in Children
Authors: Patel Trisha , Kelleman Michael , West Zachary , Peter Andrew , Dove Matthew , Butto Arene , Oster Matthew E. 
Published: October 2021

AbstractBackgroundAlthough rare, myocarditis in the pediatric population is a disease process that carries significant morbidity and mortality. Prior to the SARS-CoV-2 related (COVID-19) pandemic, enteroviruses were the most common cause of classic myocarditis. However, since 2020, myocarditis linked to multisystem inflammatory syndrome in children (MIS-C) is now common. In recent months, myocarditis related to COVID-19 vaccines has also been described. This study aims to compare these three different types of myocarditis with regards to clinical presentation, course, and outcomes.MethodsIn this retrospective cohort study, we included all patients <21 years of age hospitalized at our institution with classic viral myocarditis from 2015-2019, MIS-C myocarditis from 3/2020-2/2021 and COVID-19 vaccine-related myocarditis from 5/2021-6/2021. We compared demographics, initial symptomatology, treatment, laboratory data, and echocardiogram findings.ResultsOf 201 total participants, 43 patients had classic myocarditis, 149 had MIS-C myocarditis, and 9 had COVID-19 vaccine-related myocarditis. Peak troponin was highest in the classic myocarditis group, whereas the MIS-C myocarditis group had the highest recorded brain natriuretic peptide (BNP). There were significant differences in time to recovery of normal left ventricular ejection fraction (LVEF) for the three groups: nearly all patients with MIS-C myocarditis (n=139, 93%) and all patients with COVID-19 vaccine-related myocarditis (n=9, 100%) had normal LVEF at the time of discharge, but a lower proportion of the classic myocarditis group (n=30, 70%) had a normal LVEF at discharge (p<0.001). Three months post-discharge, 18 of 40 children (45%) in the classic myocarditis group still required heart failure treatment, whereas only one of the MIS-C myocarditis patients and none of the COVID-19 vaccine-associated myocarditis patients did.ConclusionsCompared to those with classic myocarditis, those with MIS-C myocarditis had more significant hematologic derangements and worse inflammation at presentation, but had better clinical outcomes, including rapid recovery of cardiac function. Patients with COVID-19 vaccine-related myocarditis had similar clinical presentation to patients with classic myocarditis, but their pattern of recovery was similar to those with MIS-C, with prompt resolution of symptoms and improvement of cardiac function. Long-term follow-up should focus on cardiac and non-cardiac consequences of myocarditis associated with COVID-19 illness and vaccination.
Burden of five healthcare associated infections in Australia
Authors: Lydeamore M. J. , Mitchell B.G. , Bucknall T. , Cheng A.C. , Russo P.L. , Stewardson A. J. 
Published: October 2021

AbstractHealthcare associated infections (HAIs) are associated with increased morbidity and mortality, but there are few data that quantify the burden of infection nationally in Australia. We used data from an Australian national point prevalence survey to estimate the burden of HAIs amongst adults in Australian public hospitals. The incidence based appropach, introduced by the ECDC Burden of Comunicable Diseases in Europe was used. We estimate that 170,574 HAIs occur in adults admitted to public hospitals in Australia annually, resulting in 7583 deaths. Hospital acquired pneumonia is the most frequent HAI, followed by surgical site infections, and urinary tract infections. We find that blood stream infections contribute a small percentage of HAIs, but contribute the highest number of deaths (3512), more than twice that of the second largest, while pneumonia has the highert impact on years lived with disability. This study is the first time the national burden of HAIs has been estimated for Australia from point prevalence data. The estimated burden is high, and highlights the need for continued investment in HAI prevention.
Effect of workplace infection control practices on workers’ psychological distress: a large-scale cohort study during the COVID-19 second state of emergency in Japan
Authors: Kodama Toyohiko , Ishimaru Tomohiro , Tateishi Seiichiro , Hino Ayako , Tsuji Mayumi , Ogami Akira , Nagata Tomohisa , Matsuda Shinya , Fujino Yoshihisa 
Published: October 2021

AbstractBackgroundThe COVID-19 pandemic has dramatically transformed the work environment and work practices worldwide. Long-term infection control practices may increase the psychological stress on workers, and conversely, inadequate infection control practices at the working place may increase the fear of infection. This study aimed to determine the relationship between infection control practices at the workplace and employee mental health during the COVID-19 pandemic in Japan.MethodsThis study was conducted in December 2020 and February 2021. The participants had undergone a preliminary survey, which revealed that they were in good mental health. Their psychological distress was investigated via a second survey, and the factors associated with distress were studied using a logistic model.ResultsThe results of the second survey indicated that 15.1% of participants demonstrated psychological distress. This was associated with leave-of-absence instructions, instructions for shortening business hours, and requests to avoid the workplace in case of any symptoms.ConclusionThe study found that while some infection control practices reduce workers’ distress, others worsen it. Employers need to consider infection control practices as well as the worsening mental health of employees following a decrease in income caused by such measures. Follow-up studies may be necessary to clarify the long-term effects on workers’ mental health.
Pan-cancer imaging of TERT expression using deuterium magnetic resonance spectroscopy-based assessment of pyruvate metabolism
Authors: Batsios Georgios , Taglang Céline , Tran Meryssa , Stevers Nicholas , Barger Carter , Gillespie Anne Marie , Ronen Sabrina M , Costello Joseph F , Viswanath Pavithra 
Published: October 2021

SUMMARYTelomerase reverse transcriptase (TERT) expression is indispensable for tumor immortality. Non-invasive methods of imaging TERT can, therefore, report on tumor proliferation and response to therapy. Here, we show that TERT expression is associated with elevated levels of the redox metabolite NADH in multiple cancers, including glioblastoma, oligodendroglioma, melanoma, neuroblastoma, and hepatocellular carcinoma. Mechanistically, TERT acts via the metabolic regulator FOXO1 to upregulate nicotinamide phosphoribosyl transferase, which is the key enzyme for NADH biosynthesis. Importantly, deuterium magnetic resonance spectroscopy (2H-MRS), which is a novel, clinically translatable metabolic imaging modality, can be leveraged for imaging TERT-linked NADH in preclinical tumor models in vivo. Since NADH is essential for pyruvate flux to lactate, 2H-MRS following administration of 2H-labeled pyruvate non-invasively visualizes TERT expression and reports on early response to therapy. Collectively, our study provides insights into the mechanisms of TERT-linked metabolic reprogramming and, importantly, establishes 2H-MRS as a pan-cancer strategy for imaging tumor immortality.
Fusion of quantitative susceptibility maps and T1-weighted images improve brain tissue contrast in primates
Authors: Dadarwal Rakshit , Ortiz-Rios Michael , Boretius Susann 
Published: October 2021

AbstractRecent progress in quantitative susceptibility mapping (QSM) has enabled the accurate delineation of submillimeter scale subcortical brain structures in humans. The simultaneous visualization of cortical, subcortical, and white matter structure remains, however, challenging, utilizing QSM data solely. Here we present TQ-SILiCON, a fusion method that enhances the contrast of cortical and subcortical structures and provides an excellent white matter delineation by combining QSM and conventional T1-weighted (T1w) images. In this study, we first applied QSM in the macaque monkey to map iron-rich subcortical structures. Implementing the same QSM acquisition and analysis methods allowed a similar accurate delineation of subcortical structures in humans. However, the QSM contrast of white and cortical gray matter was not sufficient for an appropriate segmentation. Applying automatic brain tissue segmentation to TQ-SILiCON images of the macaque improved the classification of subcortical brain structures as compared to the single T1 contrast by maintaining a good white to cortical gray matter contrast. Furthermore, we validated our dual-contrast fusion approach in humans and similarly demonstrated improvements in automated segmentation of cortical and subcortical structures. We believe the proposed contrast will facilitate translational studies in nonhuman primates to investigate the pathophysiology of neurodegenerative diseases that affect subcortical structures such as the basal ganglia in humans.HighlightsThe subcortical gray matter areas of macaque monkeys are reliably mapped by QSM, much as they are in humans.Combining T1w and QSM images improves the visualization and segmentation of white matter, cortical and subcortical structures in the macaque monkey.The proposed dual contrast TQ-SILiCON provides a similar image quality also in humans.TQ-SILiCON facilitates comparative and translational neuroscience studies investigating subcortical structures.
DiviSSR: Simple arithmetic for efficient identification of tandem repeats
Authors: Avvaru Akshay Kumar , Mishra Rakesh K , Sowpati Divya Tej 
Published: October 2021

SummaryNumerical or vector representations of DNA sequences have been applied for identification of specific sequence characteristics and patterns which are not evident in their character (A, C, G, T) representations. These transformations often reveal a mathematical structure to the sequences which can be captured efficiently using established mathematical methods. One such transformation, the 2-bit format, represents each nucleotide using only two bits instead of eight for efficient storage of genomic data. Here we describe a mathematical property that exists in the 2-bit representation of tandemly repeated DNA sequences. Our tool, DiviSSR (pronounced divisor), leverages this property and subsequent arithmetic to achieve ultrafast and accurate identification of tandem repeats. DiviSSR can process the entire human genome in ∼30s, and short sequence reads at a rate of >1 million reads/s on a single CPU thread. Our work also highlights the implications of using simple mathematical properties of DNA sequences for faster algorithms in genomics.AvailabilityDiviSSR can be installed directly using python pip. The source code and documentation of DiviSSR are available at https://github.com/avvaruakshay/divissr.git.
High fat diet exacerbates cognitive decline in mouse models of Alzheimer’s disease and mixed dementia in a sex-dependent manner
Authors: Gannon Olivia J. , Robison Lisa S. , Salinero Abigail E. , Abi-Ghanem Charly , Mansour Febronia , Tyagi Alvira , Brawley Rebekah , Ogg Jordan , Zuloaga Kristen L. 
Published: October 2021

AbstractApproximately 70% of Alzheimer’s disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3x more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD. Male and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet for 3 months prior to behavior assessment. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain. In females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, HF diet caused greater accumulation of amyloid beta in MxD females compared to MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis. In conclusion, high fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women.HighlightsCreated a mouse model of mixed dementia (MxD) with both AD + VCID pathology.HF diet caused greater metabolic impairment in AD and MxD females, compared to males.AD and MxD females showed a wider array of cognitive deficits, compared to males.Astrogliosis and Aβ pathology were more severe in AD/MxD females, compared to males.Metabolic impairment was more consistently associated with reductions in cognitive function in females.More severe glucose intolerance was associated with worse microgliosis in females only.