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This study evaluates the efficacy and safety of plasmapheresis without plasma transfusion tandem with chemotherapy in treating multiple myeloma (MM).This retrospective study involves seventy-two patients, newly diagnosed with multiple myeloma, divided into two groups; one with plasmapheresis without plasma transfusion tandem with the chemotherapy group (Trial group), while the second was chemotherapy group (Control group). The levels of Plasma Globulin, β2-microglobulin, Creatinine, Vascular endothelial growth factor (VEGF), and IL-6 were monitored after plasmapheresis, at initial diagnosis, and after four chemotherapy courses. Overall response rate of groups after four courses of chemotherapy was analyzed, and the adverse events were recorded.The baseline data showed that sixty-seven percent of patients were at the ISS III stage and showed more severe renal insufficiency in the Trial group. The Plasma Globulin, β2-microglobulin, VEGF and IL-6 levels were significantly different between the two groups during the initial diagnosis. After three times plasmapheresis, Plasma Globulin, β2-microglobulin, VEGF, and IL-6 were significantly reduced in the plasmapheresis group. The Creatinine levels were also lowered, but the differences were not statistically significant. After four courses of chemotherapy, the levels of VEGF and IL-6 in the two groups were significantly reduced than the initial diagnosis; the differences were statistically considerable. No adverse events were found in the trial group as compared to the control group.Plasmapheresis reduces Globulin, β2-microglobulin, serum VEGF and IL-6 levels in MM, improves renal functions, and releases some patients from dialysis dependence.

At present, GATA binding protein 3 (GATA-3) is the most frequently used diagnostic immunohistochemical (IHC) marker for breast carcinoma (BC). However, it is not specific and has very low sensitivity for triple-negative BC (TNBC). SRY-box transcription factor 10 (SOX-10) and trichorhinophalangeal syndrome type 1 (TRPS-1) have been suggested for inclusion in the diagnostic workup of TNBC. TRPS-1 has not been established in cytology specimens as a diagnostic IHC marker for metastatic BC (MBC). Hence, in the present study we evaluated the utility of TRPS-1 in diagnosing MBC in cytology specimens.MBC cases diagnosed on cytology specimens from January to October 2020 were included in the present study. Only cases with hormonal status available and ≥20 tumor cells on cell blocks were included in the study. The cell blocks were assessed for TRPS-1, GATA-3, and SOX-10 IHC marker positivity (intensity and percentage of tumor cells). The results were correlated with the specimen type (fine needle aspiration [FNA] versus body fluid) and various BC prognostic subgroups.We analyzed 61 cases, including 33 body fluid and 28 FNA (13 lymph node, 10 bone, 2 liver, 2 soft tissue, and 1 lung) specimens. TRPS-1 had 97.2% positivity in ER/PR+ (estrogen receptor/progesterone receptor-positive) MBC compared with GATA-3, which had 100% positivity in the same group. TRPS-1 showed high positivity in 35 of 37 cases (94.6%) and intermediate positivity in 1 (2.6%) and was negative/low positive in 1 case (2.7%). In contrast, GATA-3 showed high positivity for all 37 cases (100%). SOX-10 showed positivity in only 1 of 37 cases (2.7%), with intermediate positivity. In the HER2+ (human epidermal growth factor receptor 2-positive) group, TRPS-1 showed high positivity in 5 of 7 cases (71.4%), intermediate positivity in 1 case (14.3%), and negativity in 1 case (14.3%). However, GATA-3 showed high positivity in 6 of 7 cases (85.7%) and negative/low positivity in 1 case (14.3%). SOX-10 was negative in all 7 cases. In TNBC, TRPS-1 showed high positivity in 16 of 17 cases (94%) and intermediate positivity in 1 (5.9%), and GATA-3 showed high positivity in 9 (53%), intermediate positivity in 2 (11.8%), and low positive/negative in 6 of the 17 cases (35.3%). TRPS-1 expression was significantly higher than GATA-3 expression for the number of positive cases (P = 0.07), mean percentage of positive tumor cells (P = 0.005), and intensity of reactivity (P = 0.005). SOX-10 expression was present in only 5 of 17 cases (29%), with a mean percentage of positivity in the tumor cells of 26.5% and intensity of 0.8. No differences were found in the IHC results between the different specimen types (FNA versus fluid) in any group.TRPS-1 is a highly sensitive new diagnostic IHC marker for breast carcinoma, with a similar positivity rate in ER/PR+ and HER2+ BC compared with GATA-3 and a higher positivity rate than GATA-3 and SOX-10 in TNBC in cytology specimens. In particular, when only a few clusters of tumor cells are present on the cell block, TRPS-1 can be highly useful, because its mean percentage of positive tumor cells and intensity are higher than those of other IHC markers.

The most important consideration in determining treatment strategies for undifferentiated early gastric cancer (UEGC) is the risk of lymph node metastasis (LNM). Therefore, identifying a potential biomarker that predicts LNM is quite useful in determining treatment.To develop a machine learning (ML)-based integral procedure to construct the LNM gray-level co-occurrence matrix (GLCM) prediction model.We retrospectively selected 526 cases of UEGC confirmed through pathological examination after radical gastrectomy without endoscopic treatment in four tertiary hospitals between January 2015 to December 2021. We extracted GLCM-based features from grayscale images and applied ML to the classification of candidate predictive variables. The robustness and clinical utility of each model were evaluated based on the following factors: Receiver operating characteristic curve (ROC), decision curve analysis, and clinical impact curve.GLCM-based feature extraction significantly correlated with LNM. The top 7 GLCM-based factors included inertia value 0° (IV_0), inertia value 45° (IV_45), inverse gap 0° (IG_0), inverse gap 45° (IG_45), inverse gap full angle (IG_all), Haralick 30° (Haralick_30), Haralick full angle (Haralick_all), and Entropy. The areas under the ROC curve (AUCs) of the random forest classifier (RFC) model, support vector machine, eXtreme gradient boosting, artificial neural network, and decision tree ranged from 0.805 [95% confidence interval (CI): 0.258-1.352] to 0.925 (95%CI: 0.378-1.472) in the training set and from 0.794 (95%CI: 0.237-1.351) to 0.912 (95%CI: 0.355-1.469) in the testing set, respectively. The RFC (training set: AUC: 0.925, 95%CI: 0.378-1.472; testing set: AUC: 0.912, 95%CI: 0.355-1.469) model that incorporates Entropy, Haralick_all, Haralick_30, IG_all, IG_45, IG_0, and IV_45 had the highest predictive accuracy.The evaluation results indicate that the method of selecting radiological and textural features becomes more effective in the LNM discrimination against UEGC patients. Additionally, the ML-based prediction model developed using the RFC can be used to derive treatment options and identify LNM, which can hence improve clinical outcomes.

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

A young man presented to the emergency department with seizures and recurrent episodes of polymorphic ventricular tachycardia (PMVT)/torsades de pointes (TdP) requiring cardioversion and administration of intravenous magnesium. A battery of tests performed to identify a cause for his arrhythmias and seizures were all normal. A revisit of history with family revealed he had consumed over 100 tablets/day of loperamide for the past 1 year. A prolonged QT interval on his ECG raised concerns for long QT syndrome (LQTS) (congenital or acquired). Our patient was suspected to have loperamide-induced cardiotoxicity. TdP is a specific PMVT that occurs with a prolonged QT interval and is usually drug-induced. Less frequently, congenital LQTS may be implicated. With supportive care, including mechanical ventilation, vasopressors and temporary transvenous overdrive pacing, our patient recovered completely. We describe the importance of a systematic and time-sensitive approach to diagnosing critical illness. Loperamide overdose may cause QT prolongation, life-threatening arrhythmias/cardiogenic shock, or cardiac arrest. Seizures/epilepsy may also be a manifestation in young patients. There is a substantial need to revisit the safety of over-the-counter medications and increasing awareness of manifestations of drug overdose.

Human cognition is influenced by the way the nervous system processes information and is linked to this mechanical explanation of the human body’s cognitive function. Accuracy is the key emphasis in neuroscience which may be enhanced by utilising new hardware, mathematical, statistical, and computational methodologies. Feature extraction and feature selection also play a crucial function in gaining improved accuracy since the proper characteristics can identify brain states efficiently. However, both feature extraction and selection procedures are dependent on mathematical and statistical techniques which implies that mathematical and statistical techniques have a direct or indirect influence on prediction accuracy. The forthcoming challenges of the brain-computer interface necessitate a thorough critical understanding of the complicated structure and uncertain behavior of the brain. It is impossible to upgrade hardware periodically, and thus, an option is necessary to collect maximum information from the brain against varied actions. The mathematical and statistical combination could be the ideal answer for neuroscientists which can be utilised for feature extraction, feature selection, and classification. That is why in this research a statistical technique is offered together with specialised feature extraction and selection methods to increase the accuracy. A score fusion function is changed utilising an enhanced cumulants-driven likelihood ratio test employing multivariate pattern analysis. Functional MRI data were acquired from 12 patients versus a visual test that comprises of pictures from five distinct categories. After cleaning the data, feature extraction and selection were done using mathematical approaches, and lastly, the best match of the projected class was established using the likelihood ratio test. To validate the suggested approach, it is compared with the current methods reported in recent research.

Aurora kinases (Aurora A, B, and C) are a family of serine/threonine kinases that play critical roles during mitotic initiation and progression. Aurora A and B kinases are ubiquitously expressed, and their overexpression and/or amplification in many cancers have been associated with poor prognosis. Several inhibitors that target Aurora kinases A, B, or both have been developed during the past decade with efficacy in different in vitro and in vivo models for a variety of cancers. Recent studies have also identified Aurora A as a synthetic lethal target for different tumor suppressors, including RB1, SMARCA4, and ARID1A, which signifies the need for Aurora-A-selective inhibitors. Here, we report the screening of a small library of quinones (nine naphthoquinones, one orthoquinone, and one anthraquinone) in a biochemical assay for Aurora A kinase that resulted in the identification of several quinones as inhibitors. IC

To reducing the risk of venous thromboembolic (VTE) events and subsequent mortality in covid-19 patients is still a matter of research. This systematic review and meta-analysis serve the purpose of comparing the mortality associated with the intensity of anticoagulation in patients admitted with covid-19.A total of 7120 patients were recruited in 11 studies comparing using prophylactic anticoagulants against therapeutic anticoagulants.Our study showed that using prophylactic anticoagulants was associated with a 42% reduction in mortality compared to therapeutic anticoagulants (OR 0.58 (95% CI:0.676-0.499),Our meta-analysis favors using prophylactic anticoagulation in covid-19 patients reduces all-cause mortality in comparison to therapeutic anticoagulation however the impact on mortality when compared with no anticoagulation was not significant.PROSPERO Number: CRD42021257320.

TNFα and NF-kB contribute in activation of pro-inflammatory signaling pathways and complications of coronary artery diseases (CAD). Current study highlights novel properties of Au (15 ± 2 nm), ZnO (77 ± 45 nm) and MgO (11 ± 4 nm) nanoparticles (NPs) as possible anti-inflammatory agents with greater efficacy and lower toxicity. Decrease in TNFα and NF-kB levels in Single Vessel Disease (SVD), Double Vessel Disease (DVD) and Triple-Vessel coronary artery disease (TVD) macrophage and lymphocyte cultures at varying concentrations of NPs has been studied to find an effective therapeutic concentration (ETC). Au and MgO NPs exhibits 5 µg/ml ETC compared to 1 µg/ml ZnO in all three CAD categories with negligible toxicity. ZnO remains most statistically significant (p 0.001) in SVD and TVD cultures whereas MgO shows efficacy in DVD and TVD cultures with more than 50% reduction in TNFα and NF-kB levels at their respective ETCs. Au NPs exhibit prominent effect in DVD cultures. The mRNA expression results support the down-regulation of TNFα and NF-kB after NPs exposure in respective cultures. Findings of this prospective observational cohort study suggest use of NPs as an alternate anti-inflammatory agent in coronary artery and other diseases.

Sub endothelial infarcts leads to non-ST-elevation acute coronary syndrome. Proinflammatory cytokines are raised in serum, the severity of which is a poor prognostic sign. Vitamin D deficiency is prevalent among patients of ACS. Vitamin D has immunomodulatory roles having effects on various aspects of inflammation. A total of 40 patients were divided into experimental (n=20) and control (n=20) groups. Experimental group was given single dose of vitamin D 200,000 IU. They were assessed for baseline C-reactive protein, interleukin-6, tumor necrosis factor-α levels by using sandwich ELISA technique. Four months after intervention resampling was done for the same parameters. Findings were expressed as mean±SD. Independent sample t-test was used to compare effect of vitamin D intervention between control group and intervention group. p-value of ≤0.05 was considered to be significant. The serum C-reactive protein showed significant reduction (p=0.028*) after intervention with vitamin D. Serum interleukin-6 (p=0.848), tumor necrosis factor-α (p=0.20) were decreased non-significantly in experimental as compared to the control group. It was concluded that a single large dose of vitamin D was able to reduce the C-reactive protein in non-ST-elevation acute coronary syndrome patients while non-significant reductions in interleukin-6 and tumor necrosis factor-α were observed.

On the translational front, integrative genomic approaches have spurred the identification of diverse mechanisms of drug resistance, tumor heterogeneity, metastasis and emerging preclinical targets. Recent breakthroughs in oncogenic cell signaling pathways have forged new links and multi-disciplinary researchers have unraveled different facets of signaling landscapes. Natural product research has witnessed breakneck developments mainly in the context of the ever-expanding list of bioactive components having significantly pharmacological properties. Genistein has gradually gained appreciation because of its multifaceted roles in the prevention and inhibition of carcinogenesis and metastasis. More importantly, the entry of genistein into various phases of clinical trials substantiates the medicinal and pharmacological significance of genistein in cancer chemoprevention. In this review, we have attempted to summarize how genistein regulated different oncogenic pathways in carcinogenesis and metastasis. Furthermore, genistein-mediated regulation of non-coding RNAs is also an interesting feature that has been included in this review to realistically analyze how genistein-mediated control of miRNAs, lncRNAs and circRNAs influence carcinogenesis. In the later sections, we have provided a summary of clinical trials related to genistein for cancer prevention/inhibition. However, apart from the optimistic approaches to further investigate genistein-mediated cancer-inhibitory effects, certain hints have emerged which underscore the pro-metastatic role of genistein. Therefore, the pro-metastatic role of genistein in different cancers should be rationally tested in a broader context because these properties in the future may reduce the enthusiasm in the quest to pursue genistein as a potent cancer chemopreventive agent.

Background:\ud Determining the status of molecular pathways and key mutations in colorectal cancer is crucial for optimal therapeutic decision making. We therefore aimed to develop a novel deep learning pipeline to predict the status of key molecular pathways and mutations from whole-slide images of haematoxylin and eosin-stained colorectal cancer slides as an alternative to current tests.\ud Methods:\ud In this retrospective study, we used 502 diagnostic slides of primary colorectal tumours from 499 patients in The Cancer Genome Atlas colon and rectal cancer (TCGA-CRC-DX) cohort and developed a weakly supervised deep learning framework involving three separate convolutional neural network models. Whole-slide images were divided into equally sized tiles and model 1 (ResNet18) extracted tumour tiles from non-tumour tiles. These tumour tiles were inputted into model 2 (adapted ResNet34), trained by iterative draw and rank sampling to calculate a prediction score for each tile that represented the likelihood of a tile belonging to the molecular labels of high mutation density (vs low mutation density), microsatellite instability (vs microsatellite stability), chromosomal instability (vs genomic stability), CpG island methylator phenotype (CIMP)-high (vs CIMP-low), BRAFmut (vs BRAFWT), TP53mut (vs TP53WT), and KRASWT (vs KRASmut). These scores were used to identify the top-ranked titles from each slide, and model 3 (HoVer-Net) segmented and classified the different types of cell nuclei in these tiles. We calculated the area under the convex hull of the receiver operating characteristic curve (AUROC) as a model performance measure and compared our results with those of previously published methods.\ud Findings:\ud Our iterative draw and rank sampling method yielded mean AUROCs for the prediction of hypermutation (0·81 [SD 0·03] vs 0·71), microsatellite instability (0·86 [0·04] vs 0·74), chromosomal instability (0·83 [0·02] vs 0·73), BRAFmut (0·79 [0·01] vs 0·66), and TP53mut (0·73 [0·02] vs 0·64) in the TCGA-CRC-DX cohort that were higher than those from previously published methods, and an AUROC for KRASmut that was similar to previously reported methods (0·60 [SD 0·04] vs 0·60). Mean AUROC for predicting CIMP-high status was 0·79 (SD 0·05). We found high proportions of tumour-infiltrating lymphocytes and necrotic tumour cells to be associated with microsatellite instability, and high proportions of tumour-infiltrating lymphocytes and a low proportion of necrotic tumour cells to be associated with hypermutation.\ud Interpretation:\ud After large-scale validation, our proposed algorithm for predicting clinically important mutations and molecular pathways, such as microsatellite instability, in colorectal cancer could be used to stratify patients for targeted therapies with potentially lower costs and quicker turnaround times than sequencing-based or immunohistochemistry-based approaches.\ud Funding:\ud The UK Medical Research Council.

Introduction Severe acute respiratory syndrome coronavirus 2 is the third member of the coronavirus family to cause global concern in the twenty-first century. Pregnant women are particularly at higher risk of developing severe viral pneumonia, possibly because of a partial immune suppression during their pregnancy. Under such critical and rapidly evolving circumstances, these poor findings might be helpful for the treatment of infected pregnant women with the 2019 novel coronavirus. Case presentation In this study, we report the case of a 33-year-old Asian pregnant woman at 25 gestational weeks with coronavirus disease 2019 who developed severe complications, including hypoxemia, acute respiratory distress syndrome, pulmonary infiltration, and bilateral pleural effusion. She died 1 month after admission to the hospital. Conclusion Pregnant populations are especially at higher risk of viral pneumonia development caused by severe acute respiratory syndrome coronavirus 2. Further research on the prevention and treatment of the new coronavirus is necessary.

This study explored human papillomavirus (HPV) amplification in breast benign and malignant lesions by chromogenic in situ hybridization (CISH) and the concordance of p16 expression by immunohistochemistry.The presence of HPV6/11 and HPV16/18 in 33 cases of intraductal papilloma, 34 cases of ductal carcinoma in situ (DCIS), and 56 cases of invasive breast carcinoma (IBC) was evaluated using matched-background breast parenchyma and breast reduction as control groups. Association with clinicopathologic factors including prognosis was assessed.HPV 6/11 was observed in 0 cases (0%) of breast reduction, one case (3%) of intraductal papilloma, 11 cases (32.4%) of DCIS, and eight cases (14.3%) of IBC. HPV 16/18 was detected in three cases of (9.1%) breast reduction, six cases (18.8%) of intraductal papillomas, 14 cases (41.2%) of DCIS, and 25 cases (44.6%) of IBC. There was no difference in the HPV status between intraductal papilloma and breast reduction. HPV amplification in intraductal papilloma did not associate with developing atypia or carcinoma after long-term follow-up. However, HPV 6/11 and HPV 16/18 amplification was significantly higher in both DCIS and IBC when compared with breast reduction (P.05). Compared with background breast parenchyma, HPV 16/18 amplification was significantly higher in both DCIS and IBC (P = .003 and P = .013, respectively). No correlation between p16 immunohistochemical staining and either of the HPV CISH testing was found (P.05).HPV infection was detected in both breast lesions and background parenchyma. HPV infection may play a role in the pathogenesis of breast cancer but is not associated with intraductal papilloma. Immunohistochemical stain for p16 is not a good surrogate marker for HPV infection in breast lesions.

Motivation Machine-learning-based prediction of compound–protein interactions (CPIs) is important for drug design, screening and repurposing. Despite numerous recent publication with increasing methodological sophistication claiming consistent improvements in predictive accuracy, we have observed a number of fundamental issues in experiment design that produce overoptimistic estimates of model performance. Results We systematically analyze the impact of several factors affecting generalization performance of CPI predictors that are overlooked in existing work: (i) similarity between training and test examples in cross-validation; (ii) synthesizing negative examples in absence of experimentally verified negative examples and (iii) alignment of evaluation protocol and performance metrics with real-world use of CPI predictors in screening large compound libraries. Using both state-of-the-art approaches by other researchers as well as a simple kernel-based baseline, we have found that effective assessment of generalization performance of CPI predictors requires careful control over similarity between training and test examples. We show that, under stringent performance assessment protocols, a simple kernel-based approach can exceed the predictive performance of existing state-of-the-art methods. We also show that random pairing for generating synthetic negative examples for training and performance evaluation results in models with better generalization in comparison to more sophisticated strategies used in existing studies. Our analyses indicate that using proposed experiment design strategies can offer significant improvements for CPI prediction leading to effective target compound screening for drug repurposing and discovery of putative chemical ligands of SARS-CoV-2-Spike and Human-ACE2 proteins. Availability and implementation Code and supplementary material available at https://github.com/adibayaseen/HKRCPI. Supplementary information Supplementary data are available at Bioinformatics online.

Chronic migraine; OnabotulinumtoxinA; Predictors of response Migraña crónica; OnabotulinumtoxinA; Predictores de respuesta Migranya crònica; OnabotulinumtoxinA; Predictors de resposta The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with

To explore the spectrum of presentation, underlying monogenetic defects and outcome in very early onset inflammatory bowel disease (VEO-IBD).The prospective, observational study was conducted at the Children's Hospital, Lahore, Pakistan, from January 2017 to December 2018, and comprised children developing features of inflammatory bowel disease aged6 years. Data included demography, clinical presentation, diagnostic tools and outcome. Data was analysed using SPSS 21.Of the 60 children with relevant symptoms, 26(43.3%) were diagnosed as having very early onset inflammatory bowel disease. Of them, 13(50%) had underlying monogenic defect, and 16(61.5%) had ulcerative colitis. There were 22(84.6%) males with median age of 1.5(11) months in monogenic inflammatory bowel disease versus 24(43) months for non-monogenic inflammatory bowel disease (p0.05). In the monogenic group, isolated rectal bleeding was the major presentation 13(100%) versus non-monogenic who presented mainly with failure to thrive 13(100%). Upper and lower endoscopies with histopathology had good diagnostic yield and inflammatory infiltrates on the biopsied tissues were the major findings. Mutations detected among the subjects were XIAP, PRKDC, PIK3CD, RAG-1, LRBA, DOCK8, TTC7, MEFV and EPCAM. Mortality was significantly higher in the monogenic group 7(54%) than in the non-monogenic group 2(15%) (p0.05).Very early onset inflammatory bowel disease should be suspected when conventional management fails to rectify common disease mimickers. Testing for underlying immunological defect and genetic mutation would be helpful for managing these rare disorders.

OBJECTIVE This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.

Background: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare inborn immune error characterized by a triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP), and adrenal insufficiency (ADI).Methods: Literature search was conducted in PubMed, Web of Science, and Scopus databases using related keywords, and included studies were systematically evaluated.Results: We reviewed 938 APECED patients and the classic triad of APECED was detected in 57.3% (460 of 803) of patients. CMC (82.5%) was reported as the earliest, HP (84.2%) as the most prevalent, and ADI (72.2%) as the latest presentation within the classic triad. A broad spectrum of non-triad involvements has also been reported; mainly included ectodermal dystrophy (64.5%), infections (58.7%), gastrointestinal disorders (52.0%), gonadal failure (42.0%), neurologic involvements (36.4%), and ocular manifestations (34.3%). A significant positive correlation was detected between certain tissue-specific autoantibodies and particular manifestations including ADI and HP. Neutralizing autoantibodies were detected in at least 60.0% of patients. Nonsense and/or frameshift insertion-deletion mutations were detected in 73.8% of patients with CMC, 70.9% of patients with HP, and 74.6% of patients with primary ADI.Conclusion: Besides penetrance diversity, our review revealed a diverse affected ethnicity (mainly from Italy followed by Finland and Ireland). APECED can initially present in adolescence as 5.2% of the patients were older than 18 years at the disease onset. According to the variety of clinical conditions, which in the majority of patients appear gradually over time, clinical management deserves a separate analysis.

Inhibition of dipeptidyl peptidase-IV (DPP-IV) has been identified as a promising approach for the treatment of type 2 diabetes mellitus (T2DM). Therefore, development of DPP-IV inhibitors with new chemical scaffold is of utmost importance to medicinal chemistry. In the present study, we identified benzophenone thio- and semicarbazone scaffolds as novel DPP-IV inhibitors. For that purpose, benzophenone thio- and semicarbazone were synthesized through a 2-step reaction. These newly synthetic derivatives were characterized by different spectroscopic techniques, including HREI-MS and NMR. whereas stereochemistry of the iminic bond was predicted by NOESY experiments. Thio- and semicarbazones derivatives were evaluated for their DPP-IV inhibitory potential and found to exhibit a good to moderate enzyme inhibitory activity. Most active and non-cytotoxic derivatives were further evaluated for their DPP-IV inhibitory potential in

The aim of our study was to analyze the use of interpreter services and improve communication during health encounters with families with limited language proficiency (LLP) at the pediatric emergency department (ED) of the University Hospital of Bern.This study is a pre- and post-intervention study analyzing the use of interpreter services for LLP families. All families originating from a country with a native language other than German, English or French presenting to the ED were eligible to participate in the study. If they agreed to participate, the language proficiency of the caregiver present during the health encounter was systematically assessed during a phone interview within a few days after the consultation, using a standardized screening tool. If screened positive (relevant LLP), a second phone interview with an interpreter was conducted. Further variables were extracted including nationality, age, gender and date of visit using administrative health records. To increase the use of interpreter services, a package of interventions was implemented at the department during 3 months. It consisted of: i) in person and online transcultural teaching ii) awareness raising through the regular information channels and iii) the introduction of a pathway to systematically identify and manage LLP families.The proportion of LLP families who received an interpreter was 11.0% (14/127) in the pre-intervention period compared to 14.8% (20/135) in the post-intervention period. The interpreter use was therefore increased by 3.8% (95% CI − 0.43 to 0.21; p = 0.36).The assessed level of language proficiency of caregivers differed from the self-reported level of language proficiency. Of the study participants in the interview whose language proficiency was screened as limited, 77.1% estimated their language proficiency level as intermediate. More than half of the LLP families who did not receive an interpreter and participated in the interview reported, that they would have liked an interpreter during the consultation.Conclusions: Interpreter services are largely underused during health encounters with LLP families. Relying on caregivers´ self-assessed language proficiency and their active request for an interpreter is not sufficient to ensure safe communication during health encounters. Systematic screening of language proficiency and standardized management of LLP families is feasible and needed at health care facilities to ensure equitable care. Further studies are needed to analyze personal and institutional barriers to interpreter use and find interventions to sustainably increase the use of interpreter services for LLP families.

Esophageal, gastroesophageal, and gastric cancers are still among the leading causes of death worldwide. The introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment strategy for several cancers. The combination of conventional chemotherapy with ICIs has been hypostatized to play a synergic effect over the chemotherapy alone regimen. Thus, the present systematic review and meta-analysis was conducted to compare the efficacy and safety of ICIs plus chemotherapy versus chemotherapy alone in patients suffering from advanced esophageal, gastroesophageal, and gastric cancers.PubMed, Scopus, Web of Science, and EMBASE databases together with the conference abstracts of ASCO and ESMO were searched systematically up to March 25, 2022. The studies were selected in two steps, title/abstract and full-text screening. The primary outcome was set at the efficacy of ICIs plus chemotherapy relative to the chemotherapy alone in terms of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). The secondary outcome was the safety in terms of treatment-related adverse events (TRAEs) and immune-related AEs.A total of 11 publications involving 6,732 patients were included. First-line ICIs plus chemotherapy showed superior effect over chemotherapy alone in terms of OS (hazard ratio [HR] 0.76, 95 %CI 0.72-0.81), PFS (HR 0.68, 95 %CI 0.61-0.75), ORR (risk ratio [RR] 1.29, 95 %CI 1.20-1.40), and DCR (RR 1.06, 95 %CI 1.03-1.09). Significant predictors of OS benefit in combination therapy versus chemotherapy alone were PDL-1 combined positive score (CPS) ≥ 10 compared to CPS 10 (p = 0.012), tumor proportion score (TPS) ≥ 1 % compared to TPS 1 % (p = 0.016), and male gender compared to the females (p = 0.024). In the safety analysis, ICIs plus chemotherapy showed a higher rate of TRAEs in terms of any grade AEs (RR 1.02, 95 %CI 1.00-1.04), grade ≥ 3 AEs (RR 1.16, 95 %CI 1.06-1.26), serious AEs (RR 1.63, 95 %CI 1.44-1.85), and AEs led to treatment discontinuation (RR 1.51, 95 %CI 1.37-1.67). Furthermore, the rate of immune-related AEs of any grade (RR 2.18, 95 %CI 1.55-3.05) and immune-related grade ≥ 3 AEs (RR 2.76, 95 %CI 1.85-4.13) were also higher in ICI combination therapy group relative to chemotherapy alone group.Our findings demonstrated that first-line ICIs plus chemotherapy versus chemotherapy alone prolonged OS and PFS in patients with advanced esophagogastric cancers. Also, the rate of AEs was remarkably higher in the combination group. As a result, identifying methods to prevent AEs without affecting the efficacy of ICIs is highly warranted.

Due to COVID-19 outbreaks, most school pupils have had to be home-schooled for long periods of time. Two editions of a web-based competition “Beat the Pathologists” for school age participants in the UK ran to fill up pupils’ spare time after home-schooling and evaluate their ability on contributing to AI annotation. The two editions asked the participants to annotate different types of cells on Ki67 stained breast cancer images. The Main competition was at four levels with different level of complexity. We obtained annotations of four kinds of cells entered by school pupils and ground truth from expert pathologists. In this paper, we analyse school pupils’ performance on differentiating different kinds of cells and compare their performance with two neural networks (AlexNet and VGG16). It was observed that children tend to get very good performance in tumour cell annotation with the best F1 measure 0.81 which is a metrics taking both false positives and false negatives into account. Low accuracy was achieved with F1 score 0.75 on positive non-tumour cells and 0.59 on negative non-tumour cells. Superior performance on non-tumour cell detection was achieved by neural networks. VGG16 with training from scratch achieved an F1 score over 0.70 in all cell categories and 0.92 in tumour cell detection. We conclude that non-experts like school pupils have the potential to contribute to large-scale labelling for AI algorithm development if sufficient training activities are organised. We hope that competitions like this can promote public interest in pathology and encourage participation by more non-experts for annotation.

Sedentary life styles coupled with high-calorie diets and unhealthy social habits such as smoking, have put an ever-increasing number of people at risk of cardiovascular disorders (CVD), worldwide. A concomitant increase in the prevalence of type 2-diabetes (hyperglycemia), a risk factor for CVD, has further contributed towards escalating CVD-related mortalities. The increase in number of cases of type 2-diabetes underscores the importance of early diagnosis of cardiovascular disease in those with diabetes. In this work, we have evaluated the sensitivity and specificity of dyslipidemia and proinflammatory cytokines to be used as biomarkers for predicting the risk of CVD in those with diabetes. We hypothesize that interplay between dyslipidemia and diabetes-induced low-grade inflammation in those with type 2-diabetes increases the risk of CVD. A total of 215 participants were randomly recruited from the Cameron County Hispanic Cohort (CCHC). Of these, 99% were Mexican Americans living on Texas-Mexico border. Levels of cytokines, adipokines and lipid profile were measured. Cardiovascular disease (CVD) for this study was defined as prior diagnosis of heart attack, angina and stroke, while diabetes was defined by fasting blood glucose (FBG) of > 100 mg/dL and HbA1c of > 6.5, in accordance with American Diabetes Association (ADA) guidelines. Depending on type and distribution of data, various statistical tests were performed. Our results demonstrated higher rates of heart attack (14% vs 11.8%) and stroke (19.8% vs 10%) in those with diabetes as compared to non-diabetes. The odds of having a heart attack were eight times higher in the presence of elevated triglycerides and pro-inflammatory markers (TNFα and IL6) as compared to presence of pro-inflammatory markers only. The odds for heart attack among those with diabetes, increased by 20 fold in presence of high levels of triglycerides, TNFα, and IL6 when coupled with low levels of high-density lipid cholesterol (HDL-C). Lastly, our analysis showed that poorly controlled diabetes, characterized by HbA1c values of > 6.5 increases the odds of stroke by more than three fold. The study quantifies the role of lipid profile and pro-inflammatory markers in combination with standard risk factors towards predicting the risk of CVD in those with type 2-diabetes. The findings from the study can be directly translated for use in early diagnosis of heart disease and guiding interventions leading to a reduction in CVD-associated mortality in those with type 2-diabetes.

Management of rare hematological disorders pose unique diagnostic and therapeutic challenges due to unusual occurrence and limited treatment options. We retrospectively identified 45 patients receiving matched related donor transplant for rare hematological disorders from 2006 to 2019. Patients were divided into two groups (1) malignant and (2) non malignant. The malignant disorder group included four patients while the nonmalignant group included 41 patients divided into immune dysregulation (n = 23), bone marrow failure (n = 10), metabolic (n = 5), and bleeding diathesis (n = 3). Twenty-six (57.8%) patients received myeloablative conditioning (MAC) and 16 (35.6%) received reduced intensity conditioning (RIC), while 3 (6.6%) patients with severe combined immunodeficiency received stem cell infusion alone without conditioning. The cumulative incidence (CI) of grade II-IV acute GVHD (aGVHD) was 39.1% (n = 18) and chronic GVHD (cGVHD) 15.2% (n = 7). There was no primary graft failure while CI of secondary graft failure was 9%. Overall survival (OS) and disease-free survival (DFS) was 82.2% and 77.8% respectively. Group wise OS was 75% in the malignant group, 82.6% in the immune dysregulation group, 80% in patients with metabolic disorders and bone marrow failure, while 100% in patients with bleeding diathesis. This retrospective analysis shows that hematopoietic stem cell transplant can be a feasible treatment option for rare hematological disorders.

© 2020 The Authors. Histopathology published by John Wiley & Sons Ltd Aims: Tumour genotype and phenotype are related and can predict outcome. In this study, we hypothesised that the visual assessment of breast cancer (BC) morphological features can provide valuable insight into underlying molecular profiles. Methods and results: The Cancer Genome Atlas (TCGA) BC cohort was used (n=743) and morphological features, including Nottingham grade and its components and nucleolar prominence, were assessed utilising whole-slide images (WSIs). Two independent scores were assigned, and discordant cases were utilised to represent cases with intermediate morphological features. Differentially expressed genes (DEGs) were identified for each feature, compared among concordant/discordant cases and tested for specific pathways. Concordant grading was observed in 467 of 743 (63%) of cases. Among concordant case groups, eight common DEGs (UGT8, DDC, RGR, RLBP1, SPRR1B, CXorf49B, PSAPL1 and SPRR2G) were associated with overall tumour grade and its components. These genes are related mainly to cellular proliferation, differentiation and metabolism. The number of DEGs in cases with discordant grading was larger than those identified in concordant cases. The largest number of DEGs was observed in discordant grade 1:3 cases (n=1185). DEGs were identified for each discordant component. Some DEGs were uniquely associated with well-defined specific morphological features, whereas expression/co-expression of other genes was identified across multiple features and underlined intermediate morphological features. Conclusion: Morphological features are probably related to distinct underlying molecular profiles that drive both morphology and behaviour. This study provides further evidence to support the use of image-based analysis of WSIs, including artificial intelligence algorithms, to predict tumour molecular profiles and outcome.

Interleukin10 (IL10) and IL10 receptor (IL10R) deficiencies are monogenic inborn errors of immunity (IEI) causing early-onset inflammatory bowel diseases (IBD). In this report, we systematically reviewed articles that included related keywords using PubMed, Web of Science, and Scopus databases. The articles were screened for eligibility criteria before data extraction. We assessed 286 patients (44.5% female) with IL10 and/or IL10R deficiencies who were predominantly from China (40.7%), Italy (13.9%), and South Korea (8.5%). The median age of onset was 1.0 (0.3–4.0) months with a median age of genetic diagnosis at 16.0 (7.4–81.0) months. Consanguinity was reported in all evaluable patients with IL10 deficiency and in 38.2% of patients with IL10R deficiency (22.9% of patients with IL10RA, and 79.4% of patients with IL10RB deficiency). The most prevalent mutations in IL10RA were c.301C>T (p.R101W) and c.537G>A (p.T179T), those in IL10RB were c.139A>G (p.K47E) and c.611G>A (p.W204X). Auto-inflammation and enteropathy were present in all cases. The first presentation of both groups was protracted diarrhea (45.7%), bloody diarrhea (17.8%), and colitis (15.5%). Patients with IL10R deficiency had a high frequency of dermatologic manifestations (50.5%) and failure to thrive (60.5%), while IL10-deficient patients lacked those complications. In the majority of patients, the basic immunologic parameters were in normal ranges. Of the entire publications, 30.7% underwent hemopoietic stem cell transplantation, 57.5% surgery, and 86.6% immunosuppressive treatment. The 10-year survival rate was higher in patients with IL10 deficiency than in patients with IL10R deficiency. In conclusion, IL10/IL10R deficiency predominantly presents with treatment-resistant, early-onset IBD within the first months of life. We detected no clear correlation between the phenotype of patients carrying the same variant. The high prevalence of distinct clinical manifestations reported in IL10RA- and IL10RB-deficient patients might be attributable to the interactions between the target tissue and cytokines other than IL10 capable of binding to IL10RB. These results gain translational significance by contributing to earlier diagnosis, adequate therapy, and avoiding delay in the diagnosis and unfavorable outcomes.

Objective: To determine the association of sleep wake pattern with cognitive performance and academic achievement in young adults. Methods: It was a cross sectional study conducted in March 2019 after approval from the Institutional Review Board & Ethics Committee of the study setting on February 28, 2019. Total sample of the study was 189 calculated by using Rao software. Inclusion criteria was healthy young adults of age 18 to 24 years from Doctor of Physical Therapy department of Shifa Tameer-e-Millat University, Dar-ul-Shifa campus, Islamabad. Exclusion criteria included all those students who were married, diagnosed psychological disorder and were taking any sedatives. Data was collected through three questionnaires named Pittsburgh Sleep Quality Index (PSQI), Morningness-Eveningness Questionnaire (MEQ) and Montreal Cognitive Assessment (MOCA) in addition to inquiry regarding GPA of latest exam. Results: A total sample was 236 students with a mean age of 20.94±1.58 years with range 18-24 years. The sample comprised of males n=24 (10.2%) and females n=212(89.8%). Mean GPA was 3.10±0.53. MOCA showed that 70(29.66%) students had mild cognitive impairment, 166(70.34%) were students with normal cognition. The results obtained by applying independent T-test showed a significant difference of cognition between high and low achievers (P value: 0.029

Host-pathogen dynamics are constantly at play during enteroviral infection. Coxsackievirus B (CVB) is a common juvenile enterovirus that infects multiple organs and drives inflammatory diseases including acute pancreatitis and myocarditis. Much like other enteroviruses, CVB is capable of manipulating host machinery to hijack and subvert autophagy for its benefit. We have previously reported that CVB triggers the release of infectious extracellular vesicles (EVs) which originate from autophagosomes. These EVs facilitate efficient dissemination of infectious virus. Here, we report that TBK1 (Tank-binding kinase 1) suppresses release of CVB-induced EVs. TBK1 is a multimeric kinase that directly activates autophagy adaptors for efficient cargo recruitment and induces type-1 interferons during viral-mediated STING recruitment. Positioning itself at the nexus of pathogen elimination, we hypothesized that loss of TBK1 could exacerbate CVB infection due to its specific role in autophagosome trafficking. Here we report that infection with CVB during genetic TBK1 knockdown significantly increases viral load and potentiates the bulk release of viral EVs. Similarly, suppressing TBK1 with small interfering RNA (siRNA) caused a marked increase in intracellular virus and EV release, while treatment in vivo with the TBK1-inhibitor Amlexanox exacerbated viral pancreatitis and EV spread. We further demonstrated that viral EV release is mediated by the autophagy modifier proteins GABARAPL1 and GABARAPL2 which facilitate autophagic flux. We observe that CVB infection stimulates autophagy and increases the release of GABARAPL1/2-positive EVs. We conclude that TBK1 plays additional antiviral roles by inducing autophagic flux during CVB infection independent of interferon signaling, and the loss of TBK1 better allows CVB-laden autophagosomes to circumvent lysosomal degradation, increasing the release of virus-laden EVs. This discovery sheds new light on the mechanisms involved in viral spread and EV propagation during acute enteroviral infection and highlights novel intracellular trafficking protein targets for antiviral therapy.

Macrophages are white blood cells with diverse functions contributing to a healthy immune response as well as the pathogenesis of cancer, osteoarthritis, atherosclerosis, and obesity. Due to their pleiotropic and dynamic nature, tools for imaging and tracking these cells at scales spanning the whole body down to microns could help to understand their role in disease states. Here we report fluorescent and radioisotopic quantum dots (QDs) for multimodal imaging of macrophage cells in vivo, ex vivo, and in situ. Macrophage specificity is imparted by click-conjugation to dextran, a biocompatible polysaccharide that natively targets these cell types. The emission spectral band of the crystalline semiconductor core was tuned to the near-infrared for optical imaging deep in tissue, and probes were covalently conjugated to radioactive iodine for nuclear imaging. The performance of these probes was compared with all-organic dextran probe analogues in terms of their capacity to target macrophages in visceral adipose tissue using in vivo positron emission tomography/computed tomography (PET/CT) imaging, in vivo fluorescence imaging, ex vivo fluorescence, post-mortem isotopic analyses, and optical microscopy. All probe classes exhibited equivalent physicochemical characteristics in aqueous solution and similar in vivo targeting specificity. However, dextran-mimetic QDs provided enhanced signal-to-noise ratio for improved optical quantification, long-term photostability, and resistance to chemical fixation. In addition, the vascular circulation time for the QD-based probes was extended 9-fold compared with dextran, likely due to differences in conformational flexibility. The enhanced photophysical and photochemical properties of dextran-mimetic QDs may accelerate applications in macrophage targeting, tracking, and imaging across broad resolution scales, particularly advancing capabilities in single-cell and single-molecule imaging and quantification.

Tumours of the central nervous system, though not very common, pose a serious health burden owing to their high mortality rate. Glial tumours are the commonest type of brain tumours in Pakistani population. Diagnosis of gliomas has been greatly revolutionised over the past few years with integration of immunohistochemistry and molecular subtyping in the World Health Organisation’s updated 2016 classification of glial tumours. One of the major changes was incorporation of isocitrate dehydrogenase mutation detection that is considerably a significant prognostic and predictive marker. The published data on isocitrate dehydrogenase mutation in the local population is hard to find. The current narrative review was planned to briefly describe the international trends regarding frequency of isocitrate dehydrogenase mutation in gliomas, its predictive and prognostic significance and its impact on accurate diagnosis leading to a targeted therapeutic approach for patients. Key Words: Gliomas, Isocitrate dehydrogenase 1, Mutation, Classification, Prognosis, Treatment.

We disclose for the first time a facile synthetic methodology for the preparation of multicolor carbon dots (CDs) from a single source barring any chromatographic separations. This was achieved

Despite the utility of musculoskeletal dynamics modeling, there exists no safe, noninvasive method of measuring in vivo muscle output force in real time - limiting both biomechanical insight into dexterous motion and intuitive control of assistive devices. In this paper, we demonstrate that muscle deformation constitutes a promising, yet unexplored signal from which to 1) infer such forces and 2) build novel device control schemes. Through a case study of the elbow joint on a preliminary cohort of 10 subjects, we show that muscle deformation (specifically, thickness change of the brachioradialis, as measured via ultrasound and tracked via optical flow) correlates well with elbow output force to an extent comparable with standard surface electromyography (sEMG) activation during varied isometric elbow contraction. We then show that, given real-time visual feedback, subjects can readily perform a trajectory tracking task using this deformation signal, and that they largely prefer this method to a comparable sEMG-based control scheme and perform the tracking task with similar accuracy. Together, these contributions illustrate muscle deformation's potential utility for both biomechanical study of individual muscle dynamics and device control, in a manner that - thanks to, unlike sEMG, the localized nature of the signal and its tight mechanistic coupling to output force - is readily extensible to multiple muscles and device degrees of freedom. To enable such future extensions, all modeling, tracking, and visualization software described in this paper, as well as all raw and processed data, have been made available on SimTK as part of the Open-Arm project (https://simtk.org/projects/openarm) for general research use.

Background Sudden cardiac arrest is the leading mode of death in the United States. Epilepsy affects 1% of Americans; yet epidemiological data show a prevalence of 4% in cases of sudden cardiac arrest. Sudden unexpected death in epilepsy (SUDEP) may share features with sudden cardiac arrest. The objective of this study was to report autopsy and genomic findings in a large cohort of SUDEP cases. Methods and Results Mayo Clinic Sudden Death Registry containing cases (ages 0–90 years) of sudden unexpected and unexplained deaths 1960 to present was queried. Exome sequencing performed on decedent cases. From 13 687 cases of sudden death, 656 (4.8%) had a history of seizures, including 368 confirmed by electroencephalography, 96 classified as SUDEP, 58 as non‐SUDEP, and 214 as unknown (insufficient records). Mean age of death in SUDEP was 37 (±19.7) years; 56 (58.3%) were male; 65% of deaths occurred at night; 54% were found in bed; and 80.6% were prone. Autopsies were obtained in 83 cases; bystander coronary artery disease was frequently reported as cause of death; nonspecific fibrosis was seen in 32.6% of cases, in structurally normal hearts. There were 4 cases of Dravet syndrome with pathogenic variants in SCN1A gene. Using whole exome sequencing in 11 cases, 18 ultrarare nonsynonymous variants were identified in 6 cases including CACNB2, RYR2, CLNB, CACNA1H, and CLCN2 . Conclusions This study examined one of the largest single‐center US series of SUDEP cases. Several cases were reclassified as SUDEP, 15% had an ECG when alive, and 11 (11.4%) had blood for whole exome sequencing analysis. The most frequent antemortem genetic finding was pathogenic variants in SCN1A ; postmortem whole exome sequencing identified 18 ultrarare variants.

Objective: To study multinodular goitre patients’ surgery by direct observation of surgical technique, and to compare complications with surgeons’ skills and experience, for improved training of future thyroid surgeons. Methods: Based on positivist epistemology and analytical observational design, this prospective double-blind study of a cohort of multinodular goitre patients operated upon by variedly experienced surgeons, was conducted at Bahawal Victoria Hospital Bahawalpur and Nishtar Medical University Hospital Multan, Pakistan, from December 2016 to April 2019. Patients were admitted through outpatient department and operated upon in routine operation lists. The surgeons were specialists/senior registrars, assistant professors, associate professors and professors. The patients were divided into two virtual groups: the one operated upon by surgeons with >3 years of post-fellowship experience and the other operated upon by surgeons with

Cytokine-induced killer (CIK) cell therapy is a type of adoptive immunotherapy that due to its high proliferation rate and anti-tumor characteristics, is being investigated to treat various solid tumors. Since advanced colorectal cancer (CRC) has high mortality and poor survival rates, and the efficacy of chemotherapy and radiotherapy is limited in treatment, the application of CIK cell therapy in CRC has been evaluated in numerous studies. This review aims to summarize the clinical studies that investigated the safety and clinical efficacy of CIK cell therapy in CRC. Therefore, 1,969 enrolled CRC patients in the clinical trials, of which 842 patients received CIK cells in combination with chemotherapy with or without dendritic cell (DC) infusions, were included in the present review. Furthermore, the signaling pathways involved in CIK cell therapy and novel methods for improving migration abilities are discussed.

The recent surge in performance for image analysis of digitised pathology slides can largely be attributed to the advances in deep learning. Deep models can be used to initially localise various structures in the tissue and hence facilitate the extraction of interpretable features for biomarker discovery. However, these models are typically trained for a single task and therefore scale poorly as we wish to adapt the model for an increasing number of different tasks. Also, supervised deep learning models are very data hungry and therefore rely on large amounts of training data to perform well. In this paper, we present a multi-task learning approach for segmentation and classification of nuclei, glands, lumina and different tissue regions that leverages data from multiple independent data sources. While ensuring that our tasks are aligned by the same tissue type and resolution, we enable meaningful simultaneous prediction with a single network. As a result of feature sharing, we also show that the learned representation can be used to improve the performance of additional tasks via transfer learning, including nuclear classification and signet ring cell detection. As part of this work, we train our developed Cerberus model on a huge amount of data, consisting of over 600 thousand objects for segmentation and 440 thousand patches for classification. We use our approach to process 599 colorectal whole-slide images from TCGA, where we localise 377 million, 900 thousand and 2.1 million nuclei, glands and lumina respectively. We make this resource available to remove a major barrier in the development of explainable models for computational pathology.

Summary Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. Interpretation Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. Funding The National Institute of Allergy and Infectious Diseases (USA).

BackgroundFrontline workers (FLWs) are at a higher risk of COVID-19 infection during care interactions than the general population. Personal protective equipment (PPE) is regarded as an effective intervention for limiting the transmission of airborne viruses. However, research examining FLWs' intention to use PPE is limited.ObjectivesThis study addresses this research gap and also contributes by expanding the conceptual mechanism of planned behavior theory by incorporating three novel dimensions (perceived benefits of PPE, risk perceptions of the epidemic, and unavailability of PPE) in order to gain a better understanding of the factors that influence FLWs' intentions to use PPE.MethodAnalysis is based on a sample of 763 FLWs in Pakistan using a questionnaire survey, and the structural equation modeling approach is employed to evaluate the suppositions.ResultsStudy results indicate that attitude, perceived benefits of PPE, and risk perceptions of the epidemic have positive influence on FLWs' intention to use PPE. In comparison, the unavailability of PPE and the cost of PPE have opposite effects. Meanwhile, environmental concern has a neutral effect.ConclusionsThe study results specify the importance of publicizing COVID-19's lethal impacts on the environment and society, ensuring cheap PPE, and simultaneously enhancing workplace safety standards.