bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunochemotherapy as induction treatment in Stage III (N2, N3) Non-small cell lung cancer
Authors: Deng Hongsheng , Liang Hengrui , Wang Wei , Li Jianfu , Xiong Shan , Cheng Bo , Li Caichen , Ai Qing , Chen Zhuxing , Wang Haixuan , Liang Wenhua , He Jianxing 
Published: June 2021

AbstractBackgroundTo increase locoregional and systemic tumor control, a portion of patients with stage III (N2, N3) non-small cell lung cancer (NSCLC) received pulmonary resection after immunochemotherapy in our center. Herein, we assessed the real-world downstage (T, N stage) effectiveness of immunochemotherapy as induction treatment and explored the proper cycle number for stage III (N2, N3) NSCLC.MethodsBiopsy confirmed stage III (N2, N3) NSCLC patients who underwent immunochemotherapy between January 1st, 2018, to August 30th, 2019, were identified. Tumor radiologic regression, lymph node down-staging, and pathological response information were collected.ResultsIn total, 16 patients with stage IIIA NSCLC, 30 with stage IIIB NSCLC, 9 with stage IIIC NSCLC (N2, N3 metastasis) were included. After immunochemotherapy, 25/55 (45.5%) patients achieved an objective response. Ultimately, 33/55 (60.0%) patients received lobectomy plus systemic lymphadenectomy, of whom 18/33 (54.5%) obtained major pathological response (MPR) of the primary lesion, and 24 (72.7%) had pathological-confirmed lymph node downstage (N2-3 to N0-1). Notably, four patients had MPR of the primary lesion but without lymph node downstage. At the time of data cutoff (December 30th, 2020), the median follow-up duration was 9.2 months (IQR 8.0-11.7), 24/33 (72.7%) of patients that had pulmonary resection were progression-free, with 30 of them alive. Binary logistics analysis showed that 3-4 induction cycles were favorably associated with MPR than 1-2 cycles (p = 0.017).ConclusionsImmunochemotherapy as induction treatment showed encouraging MPR and lymph nodes down-staging rates in stage III (N2, N3) NSCLC in this study. Prolonged (3-4) cycles of immunochemotherapy were recommended for a better pathological response.
Breadth of neutralising antibody responses to SARS-CoV-2 variants of concern is augmented by vaccination following prior infection: studies in UK healthcare workers and immunodeficient patients
Authors: Nadesalingam Angalee , Cantoni Diego , Wells David A , Aguinam Ernest T , Ferrari Matteo , Smith Peter , Chan Andrew , Carnell George , Ohlendorf Luis , Einhauser Sebastian , Wagner Ralf , Temperton Nigel , Castillo-Olivares Javier , Baxendale Helen , Heeney Jonathan L ,   the HICC consortium
Published: June 2021

AbstractApproximately 75% of the UK population has received only one dose of a 2-dose COVID-19 vaccine regime in the face of circulating SARS-CoV-2 Variants of Concern (VOCs). We aimed to determine the levels of vaccine-induced neutralising antibodies to SARS-CoV-2 variants B.1.1.7, B.1.351 and P.1. To do so, we undertook a single-centre cross-sectional study of health care workers (HCWs) and outpatients with immunodeficiencies (IDP) based at the same critical care tertiary NHS Trust, following a single dose of either BNT162b2 or AZD1222 vaccines. Data revealed low neutralising antibodies (nAbs) in IDPs, with only 5% and 3% showing detectable neutralisation of B.1.1.7 and B.1.351, respectively. In contrast, healthy HCWs without a prior SARS-CoV-2 infection demonstrated a wide range of nAb titres post-vaccination with responses significantly lower than HCWs with prior SARS-CoV-2 infection. Neutralisation of VOCs with the E484K mutation (B.1.351 and P.1) were consistently lower in HCWs in the absence of evidence of prior SARS-CoV-2 infection (p<0.001). Notably, in vaccinated HCWs with prior SARS-CoV-2 infection, there was a significant increase of neutralising titres post-vaccination to all variants, compared to their pre-vaccination neutralisation titres. This underscores the importance of vaccination to boost neutralising antibody breadth to VOCs, and also provides support for the hypothesis that repeated immunisations will boost protective immunity in individuals without prior SARS-CoV-2 exposure.
Subtle anomaly detection in MRI brain scans: Application to biomarkers extraction in patients withde novoParkinson’s disease
Authors: Muñoz-Ramírez Verónica , Kmetzsch Virgilio , Forbes Florence , Meoni Sara , Moro Elena , Dojat Michel 
Published: June 2021

AbstractWith the advent of recent deep learning techniques, computerized methods for automatic lesion segmentation have reached performances comparable to those of medical practitioners. However, little attention has been paid to the detection of subtle physiological changes caused by evolutive pathologies such as neurodegenerative diseases. In this work, we investigated the ability of deep learning models to detect anomalies in magnetic resonance imaging (MRI) brain scans of recently diagnosed and untreated (de novo) patients with Parkinson’s disease (PD). We evaluated two families of auto-encoders, fully convolutional and variational auto-encoders. The models were trained with diffusion tensor imaging (DTI) parameter maps of healthy controls. Then, reconstruction errors computed by the models in different brain regions allowed to classify controls and patients with ROC AUC up to 0.81. Moreover, the white matter and the subcortical structures, particularly the substantia nigra, were identified as the regions the most impacted by the disease, in accordance with the physio-pathology of PD. Our results suggest that deep learning-based anomaly detection models, even trained on a moderate number of images, are promising tools for extracting robust neuroimaging biomarkers of PD. Interestingly, such models can be seamlessly extended with additional quantitative MRI parameters and could provide new knowledge about the physio-pathology of neuro-degenerative diseases.
Small Area Estimation of Food Insecurity in the Eastern Indo-Gangetic Plain
Authors: Chandra Hukum , Guha Saurav , Desai Meghana , Pyne Saumyadipta 
Published: June 2021

ABSTRACTAchieving food security for all citizens is an important policy issue in India. While the existing data based on socio-economic surveys provide accurate estimates of food insecurity indicators at state and national level, due to small sample sizes, the surveys cannot be used directly to produce reliable estimates at the district or lower administrative levels. The availability of reliable and representative disaggregated measures of food insecurity is necessary for effective policy planning and monitoring, as food insecurity is often distributed unevenly within relatively small areas.This article explores a small area estimation (SAE) approach to derive reliable and representative estimates of food insecurity prevalence (FIP), gap (FIG), and severity (FIS) among people in different districts of the rural areas of the Eastern Indo-Gangetic Plain (EIGP) region by linking the latest round of available data from the Household Consumer Expenditure Survey collected by the National Sample Survey Office of India as well as the latest available Indian Population Census data. District-specific food insecurity indictors such as FIP, FIG, and FIS were estimated based on a recommended threshold of per capita caloric intake of 2400 kilocalories per day, as defined by the Ministry of Health and Family Welfare, Government of India. Spatial maps showing district level inequality in the distribution of the indicators of food insecurity among the population in EIGP region are also produced. Our disaggregated estimates can provide district-specific focused insights into food insecurity to policy-analysts and decision-makers, and could thereby prove to be useful and relevant to the U.N. Sustainable Development Goal Indicator 2.1.2.
ASSESSMENT OF PERFORMANCE AND IMPLEMENTATION CHARACTERISTICS OF RAPID POINT OF CARE SARS-CoV-2 ANTIGEN TESTING
Authors: Muthamia Eva , Mungai Samuel , Mungai Mary , Bandawe Gama , Qadri Firdausi , Kawser Zannat , Lockman Shahin , Ivers Louise C. , Walt David , Suliman Sara , Mwau Matilu , Gitaka Jesse 
Published: June 2021

AbstractBackgroundThe COVID-19 pandemic has resulted in a need for rapid identification of infectious cases. Testing barriers have prohibited adequate screening for SARS COV2, resulting in significant delays in treatment provision and commencement of outbreak control measures. This study aimed to generate evidence on the performance and implementation characteristics of the BD Veritor rapid antigen test as compared to the gold standard test for diagnosis of SARS COV2 in Kenya.MethodsThis was a field test performance evaluation in symptomatic and asymptomatic adults undergoing testing for SARS COV2. Recruited participants were classified as SARS-CoV2-positive based on the locally implemented gold standard reverse transcription polymerase chain reaction (RT-PCR) test performed on nasopharyngeal swabs. 272 antigen tests were performed with simultaneous gold standard testing, allowing us to estimate sensitivity, specificity, positive and negative predictive values for the BD Veritor rapid antigen test platform. Implementation characteristics were assessed using the Consolidated Framework for Implementation Research for feasibility, acceptability, turn-around time, and ease-of-use metrics.Results and DiscussionWe enrolled 97 PCR negative symptomatic and 128 PCR negative asymptomatic, and 28 PCR positive symptomatic and 19 PCR positive asymptomatic participants. Compared to the gold standard, the sensitivity of the BD Veritor antigen test was 94% (95% confidence interval [CI] 86.6 to 100.0) while the specificity was 98% (95% confidence interval [CI] 96 to 100). The sensitivity of BD Veritor antigen test was higher among symptomatic (100%) compared to asymptomatic (84%) participants, although this difference was not statistically significant. There was also a lack of association between cycle threshold value and sensitivity of BD Veritor test. The BD Veritor test had quick turnaround time and minimal resource requirements, and laboratory personnel conducting testing felt that it was easier to use than the gold standard RT-PCR.ConclusionThe BD Veritor rapid antigen test exhibited excellent sensitivity and specificity when used to detect SARS-CoV-2 infection among both symptomatic and asymptomatic individuals in varied population settings in Kenya. It was feasible to implement and easy to use, with rapid turnaround time.
Interpretable machine learning identifies paediatric Systemic Lupus Erythematosus subtypes based on gene expression data
Authors: Yones Sara A. , Annett Alva , Stoll Patricia , Diamanti Klev , Holmfeldt Linda , Barrenäs Carl Fredrik , Meadows Jennifer R. S. , Komorowski Jan 
Published: June 2021

ABSTRACTTranscriptomic analyses are commonly used to identify differentially expressed genes between patients and controls, or within individuals across disease courses. These methods, whilst effective, cannot encompass the combinatorial effects of genes driving disease. We applied rule-based machine learning (RBML) models and rule networks (RN) to an existing paediatric Systemic Lupus Erythematosus (SLE) blood expression dataset, with the goal of developing gene networks to separate low and high disease activity (DA1 and DA3). The resultant model had an 81% accuracy to distinguish between DA1 and DA3, with unsupervised hierarchical clustering revealing additional subgroups indicative of the immune axis involved or state of disease flare. These subgroups correlated with clinical variables, suggesting that the gene sets identified may further the understanding of gene networks that act in concert to drive disease progression. This included roles for genes i) induced by interferons (IFI35 and OTOF), ii) key to SLE cell types (KLRB1 encoding CD161), or iii) with roles in autophagy and NF-κB pathway responses (CKAP4). As demonstrated here, RBML approaches have the potential to reveal novel gene patterns from within a heterogeneous disease, facilitating patient clinical and therapeutic stratification.
An Alanine Aminotransferase is Required for Polysaccharide Regulation and Resistance of Aspergillus fumigatus Biofilms to Echinocandin Treatment
Authors: Kerkaert Joshua D. , Le Mauff François , Wucher Benjamin R. , Beattie Sarah R. , Vesely Elisa M. , Sheppard Donald C , Nadell Carey D. , Cramer Robert A. 
Published: June 2021

AbstractAlanine metabolism has been suggested as an adaptation strategy to oxygen limitation in organisms ranging from plants to mammals. Within the pulmonary infection microenvironment A. fumigatus forms biofilms with steep oxygen gradients defined by regions of oxygen limitation. A significant increase in alanine levels was observed in A. fumigatus cultured under oxygen limiting conditions. An alanine aminotransferase, AlaA, was observed to function in alanine catabolism and is required for several aspects of A. fumigatus biofilm physiology. Loss of alaA, or its catalytic activity, results in decreased adherence of biofilms through a defect in the maturation of the extracellular matrix polysaccharide galactosaminogalactan (GAG). Additionally, exposure of cell wall polysaccharides is also impacted by loss of alaA and loss of AlaA catalytic activity confers increased biofilm susceptibility to echinocandin treatment which is correlated with enhanced fungicidal activity. The increase in echinocandin susceptibility is specific to biofilms and chemical inhibition of alaA by the alanine aminotransferase inhibitor β-chloro-L-alanine is sufficient to sensitize A. fumigatus biofilms to echinocandin treatment. Finally, loss of alaA increases susceptibility of A. fumigatus to in vivo echinocandin treatment in a murine model of invasive pulmonary aspergillosis. Our results provide insight into the interplay of metabolism, biofilm formation, and antifungal drug resistance in A. fumigatus and describes a mechanism of increasing susceptibility of A. fumigatus biofilms to the echinocandin class of antifungal drugs.eLife DigestAspergillus fumigatus is a ubiquitous filamentous fungus that causes an array of diseases depending on the immune status of an individual, collectively termed aspergillosis. Antifungal therapy for invasive pulmonary aspergillosis (IPA) or chronic pulmonary aspergillosis (CPA) is limited and too often ineffective. This is in part due to A. fumigatus biofilm formation within the infection environment and the resulting emergent properties, particularly increased antifungal resistance. Thus, insights into biofilm formation and mechanisms driving increased antifungal drug resistance are critical for improving existing therapeutic strategies and development of novel antifungals. In this work, we describe an unexpected observation where alanine metabolism, via the alanine aminotransferase AlaA, is required for several aspects of A. fumigatus biofilm physiology including resistance of A. fumigatus biofilms to the echinocandin class of antifungal drugs. Importantly, we observed that chemical inhibition of alanine aminotransferases is sufficient to increase echinocandin susceptibility and that loss of alaA increases susceptibility to echinocandin treatment in a murine model of IPA.
Methanosarcina acetivorans simultaneously produces molybdenum, vanadium, and iron-only nitrogenases in response to fixed nitrogen and molybdenum depletion
Authors: Chanderban Melissa , Hill Christopher A. , Dhamad Ahmed E. , Lessner Daniel J. 
Published: June 2021

ABSTRACTAll nitrogen-fixing bacteria and archaea (diazotrophs) use molybdenum (Mo) nitrogenase to reduce dinitrogen (N2) to ammonia. Some diazotrophs also contain alternative nitrogenases that lack Mo: vanadium (V) and iron-only (Fe) nitrogenases. Among diazotrophs, the regulation and usage of the alternative nitrogenases in methanogens is largely unknown. Methanosarcina acetivorans contains nif, vnf, and anf gene clusters encoding putative Mo-, V-, and Fe-nitrogenases, respectively. This study investigated the effect of fixed nitrogen and Mo/V availability on nitrogenase expression and growth by M. acetivorans. The availability of Mo and V did not affect growth of M. acetivorans with fixed nitrogen but significantly affected growth with N2. M. acetivorans exhibited the fastest growth rate and highest cell yield during growth with N2 in medium containing Mo. Depletion of Mo (Fe-only condition) resulted in a significant decrease in growth rate and cell yield. The addition of V to Mo-depleted medium stimulated diazotrophic growth but was still less than growth in Mo-replete medium. qPCR analysis revealed transcription of the nif operon is only moderately affected by depletion of fixed nitrogen and Mo. However, vnf and anf transcription increased significantly when fixed nitrogen and Mo were depleted, with removal of Mo being the key factor. Immunoblot analysis revealed Mo-nitrogenase is produced when fixed nitrogen is depleted regardless of Mo availability, while V- and Fe-nitrogenases are produced only in the absence of fixed nitrogen and Mo. These results reveal that alternative nitrogenase production in M. acetivorans is tightly controlled and that all three nitrogenases can be simultaneously produced.IMPORTANCEMethanogens and closely related methanotrophs are the only archaea known or predicted to possess nitrogenase. As such, methanogens play critical roles in both the global biological nitrogen and carbon cycles. Moreover, methanogens are an ancient microbial lineage and nitrogenase likely originated in methanogens. An understanding of the usage and properties of nitrogenases in methanogens can provide new insight into the evolution of nitrogen fixation and aid in the development nitrogenase-based biotechnology. This study provides the first evidence that a methanogen can produce all three forms of nitrogenases, even simultaneously. Surprisingly, Mo-nitrogenase was produced in cells grown in the absence of Mo, indicating components of Mo-nitrogenase regulate or are needed to produce V- and Fe-nitrogenases in methanogens. The results provide a foundation to understanding the assembly, regulation, and activity of the alternative nitrogenases in methanogens.
Definitions matter: heterogeneity of COVID-19 disease severity criteria and incomplete reporting compromise meta-analysis
Authors: Guérin Philippe J. , McLean Alistair R.D. , Rashan Sumayyah , Lawal AbdulAzeez , Watson James A , Strub-Wourgaft Nathalie , White Nicholas J 
Published: June 2021

AbstractTherapeutic efficacy in COVID-19 is dependent upon disease stage and severity (treatment effect heterogeneity). Unfortunately, definitions of severity vary widely. This compromises the meta-analysis of randomised controlled trials (RCTs) and the therapeutic guidelines derived from them. The World Health Organisation ‘living’ guidelines for the treatment of COVID-19 are based on a network meta-analysis (NMA) of published RCTs. We reviewed the 81 studies included in the WHO COVID-19 living NMA and compared their severity classifications with the severity classifications employed by the international COVID-NMA initiative. The two were concordant in only 35% (24/68) of trials. Of the RCTs evaluated 69% (55/77) were considered by the WHO group to include patients with a range of severities (12 mild-moderate; 3 mild-severe; 18 mild-critical; 5 moderate-severe; 8 moderate-critical; 10 severe-critical), but the distribution of disease severities within these groups usually could not be determined, and data on the duration of illness and/or oxygen saturation values were often missing. Where severity classifications were clear there was substantial overlap in mortality across trials in different severity strata. This imprecision in severity assessment compromises the validity of some therapeutic recommendations; notably extrapolation of “lack of therapeutic benefit” shown in hospitalised severely ill patients on respiratory support to ambulant mildly ill patients is not warranted. Both harmonised unambiguous definitions of severity and individual patient data meta-analyses are needed to guide and improve therapeutic recommendations in COVID-19.
Clinical performance of two EUA-approved anti-COVID-19 IgG/IgM rapid lateral flow immunoassays using whole blood finger-sticks
Authors: Tagwerker Christian , Baig Irfan , Brunson Eric J. , Mundo Kristine , Dutra-Smith Davan , Carias-Marines Mary Jane , de Zoysa Ranulu Samanthi , Smith David J. 
Published: June 2021

AbstractSerological, or antibody, tests detect immunoglobulins produced by the hosts plasma B cells following exposure to foreign antigens. Venipuncture blood draws to collect human venous whole blood, plasma from anticoagulated blood (Li+ heparin, K2EDTA and sodium citrate), or serum are commonly utilized and require refrigerated temperatures during transport to the testing facility. Subsequent laboratory testing by enzyme-linked immunosorbent assays (ELISA) or chemiluminescence immunoassays (CLIA) can take an additional 2-5 hours. In the context of the COVID-19 pandemic, rapid diagnostic tests (RDT) to be used in point-of-care (POC) and remote settings have become essential during mandatory quarantine and isolation periods. RDTs allowed for more cost-effective testing using less collection materials with an immediate (5-10 minutes) test result. However, the majority of emerging RDTs receiving Emergency Use Authorization (EUA) approval by the Food and Drug Administration (FDA) for qualitative detection and differentiation of IgM and IgG antibodies to SARS-CoV-2 were only approved for use in human venous whole blood, plasma or serum. In this study we summarize performance characteristics of one RDT (COVID-19 IgG/IgM lateral flow immunoassay rapid cassette) to another by simultaneous application of whole blood finger-stick specimens (n = 32). The study was performed over 5 different days, with daily quality controls consisting of serum previously verified to be positive or negative by COVID-19 IgG/IgM ELISA testing.
Serial intervals observed in SARS-CoV-2 B.1.617.2 variant cases
Authors: Pung Rachael , Mak Tze Minn ,   CMMID COVID-19 working group, Kucharski Adam J , Lee Vernon J. 
Published: June 2021

AbstractRapid growth of the SARS-CoV-2 variant B.1.617.2 has been observed in many countries. The factors driving the recent rapid growth of COVID-19 cases could be attributed to shorten generation intervals or higher transmissibility (effective reproduction number, R), or both. Establishing the reasons for the observed rapid growth is key for outbreak control. In this study, we analysed the serial interval of household transmission pairs infected with SARS-CoV-2 B.1.617.2 variant and compared with those who were infected prior to the occurrence of the major global SARS-CoV-2 variants. After controlling for confounding factors, our findings suggest no significant changes in the serial intervals for SARS-CoV-2 cases infected with the B.1.617.2 variant. This, in turn, lends support for the hypothesis of a higher R in B.1.617.2 cases.