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Background: Digital cognitive tests offer several potential advantages over established paper-pencil tests but have not yet been fully evaluated for the clinical evaluation of mild cognitive impairment. Objective: The NeuroCognitive Performance Test (NCPT) is a web-based, self-directed, modular battery intended for repeated assessments of multiple cognitive domains. Our objective was to examine its relationship with the Alzheimer’s Disease Assessment Scale-Cognition Subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE) as well as with established paper-pencil tests of cognition and daily functioning in mild cognitive impairment (MCI). Methods: We used Spearman correlations, regressions and principal components analysis followed by a factor analysis (varimax rotated) to examine our objectives. Results: In MCI subjects, the NCPT composite is significantly correlated with both a composite measure of established tests (r = 0.78, p

Importance: Reconstructing cosmetically sensitive defects in an aging population undergoing multiple Mohs micrographic surgeries (MMS) may be addressed with alternatives to surgery. Objective: Patients undergoing MMS with defect reconstruction in visually prominent areas receiving placental allograft were compared with traditional autologous tissue-based procedures—flaps and full-thickness skin grafts (FTSG). Design, Setting, and Participants: This retrospective case–control study evaluated patients who underwent MMS for removal of a basal or squamous cell carcinoma with same-day repair. Main Outcomes and Measures: The primary endpoint was the incidence and comparison of postoperative morbidity. Risk for developing medical or cosmetic sequelae was determined through multivariate logistic regression. Results: The study population consisted of 143 propensity score-matched pairs (n = 286) with moderate- to high-risk defects on the face, head, and neck. Compared with autologous tissue, placental allograft cases were associated with significantly lower risk for infection (p = 0.004), poor scar cosmesis (p

INTRODUCTION: The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. METHODS: We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. RESULTS: There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3–5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. CONCLUSIONS: Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.

Glioblastoma is a fast and aggressively growing tumor in the brain and spinal cord. Mutation of amino acid residues in targets proteins, which are involved in glioblastoma, alters the structure and function and may lead to disease. In this study, we collected a set of 9386 disease-causing (drivers) mutations based on the recurrence in patient samples and experimentally annotated as pathogenic and 8728 as neutral (passenger) mutations. We observed that Arg is highly preferred at the mutant sites of drivers, whereas Met and Ile showed preferences in passengers. Inspecting neighboring residues at the mutant sites revealed that the motifs YP, CP and GRH, are preferred in drivers, whereas SI, IQ and TVI are dominant in neutral. In addition, we have computed other sequence-based features such as conservation scores, Position Specific Scoring Matrices (PSSM) and physicochemical properties, and developed a machine learning-based method, GBMDriver (GlioBlastoma Multiforme Drivers), for distinguishing between driver and passenger mutations. Our method showed an accuracy and AUC of 73.59% and 0.82, respectively, on 10-fold cross-validation and 81.99% and 0.87 in a blind set of 1809 mutants. The tool is available at https://web.iitm.ac.in/bioinfo2/GBMDriver/index.html. We envisage that the present method is helpful to prioritize driver mutations in glioblastoma and assist in identifying therapeutic targets.

Objective The purpose of this study was to determine the impact of prehabilitation exercise intervention with respect to (1) acceptability, feasibility, and safety; and (2) physical function, measured by 6‐minute‐walk test (6MWT). Data sources PRISMA guidelines were used to systematically search PubMed, Embase, and CINAHL databases evaluating prehabilitation exercise interventions. Study selection The inclusion criteria were studies investigating patients who underwent surgery for their cancer and underwent prehabilitation exercise. Data extraction and synthesis Guidelines were applied by independent extraction by multiple observers. Data were pooled using a random‐effects model. Main outcome(s) and measure(s) Acceptability, feasibility, and safety rates were calculated. 6MWT (maximum distance a person can walk at their own pace on a hard, flat surface, measured in meters, with longer distance indicative of better performance status) was compared using two arms using the DerSimonian and Laird method. Results Objective 1. Across 21 studies included in this review, 1564 patients were enrolled, 1371 (87.7%) accepted the trial; of 1371, 1230 (89.7% feasibility) completed the intervention. There was no grade 3+ toxicities. Objective 2. Meta‐analysis of five studies demonstrated a statistically significant decrease in 6MWT distance postoperatively in the control group (mean difference = +27.9 m; 95% confidence interval (CI): 9.3; 46.6) and a significant improvement postoperatively in the prehabilitation group (mean difference = −24.1 m; 95% CI: −45.7; −2.6). Meta‐analysis demonstrated improvements in 6MWT distance 4–8 weeks postoperatively in the prehabilitation group compared to the control group (mean difference = −58.0 m, 95% CI: −92.8; −23.3). Conclusions and relevance Prehabilitation exercise for cancer patients undergoing surgery was found to be safe, acceptable, and feasible with a statistically significant improvement in the 6MWT, indicating that prehabilitation can improve postoperative functional capacity., Prehabilitation exercise for cancer patients undergoing surgery was found to be safe, acceptable, and feasible.In this meta‐analysis, panel A shows that there is a 27.9 m c post operatively in the control group. Panel B shows that there is a 24.1 m increase in distance walked during the 6MWTpostoperatively in the prehab group. Panel C shows that the two groups (control andprehab) have the same 6MWT distance before randomization. Panel D shows that prehab intervention improved the 6MWT by 58.0 m, suggesting that prehabilitation can improve postoperative functional capacity.

Cortical thickness changes dramatically during development and is associated with adolescent drinking. However, previous findings have been inconsistent and limited by region-of-interest approaches that are underpowered because they do not conform to the underlying spatially heterogeneous effects of alcohol. In this study, adolescents (n = 657; 12-22 years at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study who endorsed little to no alcohol use at baseline were assessed with structural magnetic resonance imaging and followed longitudinally at four yearly intervals. Seven unique spatial patterns of covarying cortical thickness were obtained from the baseline scans by applying an unsupervised machine learning method called non-negative matrix factorization (NMF). The cortical thickness maps of all participants' longitudinal scans were projected onto vertex-level cortical patterns to obtain participant-specific coefficients for each pattern. Linear mixed-effects models were fit to each pattern to investigate longitudinal effects of alcohol consumption on cortical thickness. We found in six NMF-derived cortical thickness patterns, the longitudinal rate of decline in no/low drinkers was similar for all age cohorts. Among moderate drinkers the decline was faster in the younger adolescent cohort and slower in the older cohort. Among heavy drinkers the decline was fastest in the younger cohort and slowest in the older cohort. The findings suggested that unsupervised machine learning successfully delineated spatially coordinated patterns of vertex-level cortical thickness variation that are unconstrained by neuroanatomical features. Age-appropriate cortical thinning is more rapid in younger adolescent drinkers and slower in older adolescent drinkers, an effect that is strongest among heavy drinkers.

Functional magnetic resonance imaging (fMRI) has been widely used to examine the relationships between brain function and phenotypic features in neurodevelopmental disorders. Techniques such as resting-state functional connectivity (FC) have enabled the identification of the primary networks of the brain. One fMRI network, in particular, the default mode network (DMN), has been implicated in social-cognitive deficits in autism spectrum disorders (ASD) and attentional deficits in attention deficit hyperactivity disorder (ADHD). Given the significant clinical and genetic overlap between ASD and ADHD, surprisingly, no reviews have compared the clinical, developmental, and genetic correlates of DMN in ASD and ADHD and here we address this knowledge gap. We find that, compared with matched controls, ASD studies show a mixed pattern of both stronger and weaker FC in the DMN and ADHD studies mostly show stronger FC. Factors such as age, intelligence quotient, medication status, and heredity affect DMN FC in both ASD and ADHD. We also note that most DMN studies make ASD versus ADHD group comparisons and fail to consider ASD+ADHD comorbidity. We conclude, by identifying areas for improvement and by discussing the importance of using transdiagnostic approaches such as the Research Domain Criteria (RDoC) to fully account for the phenotypic and genotypic heterogeneity and overlap of ASD and ADHD. Impact statement In this work, we review the default mode network in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), as well as comorbid ASD+ADHD literature. Such a review has not been constructed in the field of cognitive neuroscience at this time, and it would greatly aid other behavioral and cognitive neuroscientists in identifying gaps in the field. In addition, the need to consider disorders to be on a continuum, as suggested by the Research Domain Criteria (RDoC), is important while identifying abnormal patterns in resting-state functional connectivity. This timely review will impact the field in a meaningful way, such that more research on the overlaps between ASD and ADHD is conducted along a spectrum.

Residues of veterinary drugs in poultry meat have serious health effects on humans (e.g., antimicrobial resistance, carcinogenicity, and hypersensitivity), which make the control of veterinary drug residues an important parameter in ensuring consumer protection. This work was performed to quantitatively determine two co-formulated anti-infective veterinary agents, tylosin tartrate (TYT) and doxycycline hydrochloride (DOX) in different tissues of broiler chickens (liver, muscles, and fat) using high performance liquid chromatography. The chicken was treated with the recommended dose of a binary mixture of the drugs (Tydovet). Moreover, the study aimed to estimate the withdrawal time of both drugs in chicken tissues. The analysis was done by solvent extraction and solid-phase extraction for clean-up of samples from the tissue matrix, followed by liquid chromatographic determination of the cited drugs with UV-detection. Residue decline with time was tracked, and both antibiotics were found to be more persistent in liver tissues than other tissues (muscle and fat). The effect of freezing and cooking was investigated on tissue residue levels. While freezing had little effect on the concentration of both antibiotics; cooking, as anticipated, led to a marked decline. Therefore, it is recommended to pay attention to the proper withdrawal periods before marketing to ensure the hygienic suitability of broilers edibles for safe human consumption. PRACTICAL APPLICATION: This novel study measures tylosin and doxycycline residues simultaneously in different tissues (muscle, fat, and liver) after administration of Tydovet powder to the broiler chicken. Residues in fat persisted for a longer time than in muscle in case of TYT, whereas the reverse was noticed in DOX.

Critically ill patients are often initially treated by out-of-hospital emergency medicine services. A major challenge-especially at the interface between out-of-hospital and in-hospital care-is to continue patient care without wasting time, while maintaining a high level. These include the stabilization of vital functions (e.g., airway management, noninvasive/invasive ventilation, circulatory stabilization) and implementation of a suitable diagnostic and therapeutic strategy (e.g., laboratory examinations, sonography, radiological imaging). In recent years, therefore, interest and research has focused on the topic of "nontraumatic resuscitation room care". The first monocentric data recently became available and work is ongoing to develop nontraumatic resuscitation room management for optimal care of critically ill patients in the emergency department. Based on initial studies, experiences and expert opinions, this paper describes a structured approach to nontraumatic resuscitation room management.Kritisch kranke Patienten werden regelmäßig in der prähospitalen Notfallmedizin versorgt. Gerade an der Nahtstelle zwischen prähospitaler und innerklinischer Versorgung besteht eine große Herausforderung darin, die Patientenbehandlung ohne Zeitverlust und auf hohem Niveau fortzuführen. Hierzu gehören die Stabilisierung der Vitalfunktionen (inkl. Atemwegsicherung, nichtinvasive/invasive Beatmung, Kreislaufstabilisierung) und Umsetzung einer geeigneten Diagnostik- und Therapiestrategie (inkl. Laboruntersuchungen, Sonographie, radiologischer Bildgebung). In den letzten Jahren hat sich daher ein Interessens- und Forschungsschwerpunkt zum Thema „nichttraumatologische Schockraumversorgung“ entwickelt. Mittlerweile liegen erste monozentrische Daten vor und es wird kontinuierlich an der Entwicklung eines nichttraumatologischen Schockraummanagements zur optimalen Versorgung von kritisch kranken Patienten in der zentralen Notaufnahme gearbeitet. Der vorliegende Beitrag beschreibt auf der Basis von ersten Studien, Erfahrungen und Expertenmeinungen eine strukturierte Vorgehensweise im nichttraumatologischen Schockraummanagement.

Abstract: The progressive deterioration of neurons leads to Alzheimer's disease (AD), and develop-ing a drug for this disorder is challenging. Substantial gene/transcriptome variability from multiple cell types leads to downstream pathophysiologic consequences that represent the heterogeneity of this disease. Identifying potential biomarkers for promising therapeutics is strenuous due to the fact that the transcriptome, epigenetic, or proteome changes detected in patients are not clear whether they are the cause or consequence of the disease, which eventually makes the drug discovery efforts intricate. The advancement in scRNA-sequencing technologies helps to identify cell type-specific biomarkers that may guide the selection of the pathways and related targets specific to different stages of the disease progression. This review is focussed on the analysis of multi-omics data from various perspectives (genomic and transcriptomic variants, and single-cell expression), which pro-vide insights to identify plausible molecular targets to combat this complex disease. Further, we briefly outlined the developments in machine learning techniques to prioritize the risk-associated genes, predict probable mutations and identify promising drug candidates from natural products.

The emergency department (ED) is the main port of entry for patients with infectious diseases, the place where a number of diagnostic procedures are performed and treatment is often initiated. The aim of this retrospective study was to estimate the influence of the establishment and introduction of a blood culture standard operating procedure (BC-SOP) and of the subsequent training of microbial diagnostics in an ED.In a before and after study over a study period of 3 months each (November 2017-January 2018 and November 2018-January 2019), the number of blood cultures taken, the rate of blood cultures per 1000 patients, the number of positive blood cultures and the frequency of typical skin pathogens were evaluated. In the interim time between the two study periods, a BC-SOP was developed in collaboration with the hospital's antibiotic stewardship team and subsequently introduced with staff training in the ED. The study was approved by the local ethics committee of the medical faculty of the Heinrich Heine University (2019-392-RetroDEuA).In total 92% of the nursing personnel and 93% of the medical personnel received training. The total number of blood cultures increased from 1757 to 2872 (64% increase) and the rate of blood cultures per 1000 patients from 287 to 481 (68% increase). The number of positive blood cultures decreased from 18.6% to 13.7% (p 0.05). Typical skin pathogens were found in 34.4% and 26.4% of the cases, respectively (p 0.05).The development, introduction and training of a BC-SOP in the ED can make a relevant contribution to the microbial diagnostics and increase the quantity as well as the quality.EINLEITUNG: Zentrale Notaufnahmen stellen die Eintrittspforte für viele stationär aufzunehmende Patienten in einem Krankenhaus dar und sind häufig der Ausgangspunkt für die antiinfektive Diagnostik und Therapie von Notfallpatienten. In dieser retrospektiven Untersuchung soll der Frage nachgegangen werden, wie die Etablierung einer Standard Operating Procedure (SOP) „Blutkulturen“ und deren Schulung die mikrobielle Diagnostik in einer zentralen Notaufnahme verbessern kann.In einer Vorher-und-nachher-Untersuchung wurde über einen jeweils 3‑monatigen Zeitraum (11/2017 bis 01/2018 und 11/2018 bis 01/2019) die Anzahl der abgenommenen Blutkulturen, die Rate an Blutkulturen/1000 Fälle, die Anzahl positiver Blutkulturen und die Häufigkeit typischer Hautkeime analysiert. Im Zeitraum zwischen den evaluierten Zeitabschnitten wurde eine SOP „Blutkulturen“ in Zusammenarbeit mit dem Antibiotic-Stewardship(ABS)-Teams und der zentrale Notaufnahme entwickelt, implementiert und geschult. Ein positives Votum der Ethikkommission der Heinrich-Heine-Universität (2019-392-RetroDEuA) lag vor.Die pflegerischen und ärztlichen Mitarbeiter wurden zu 92 % bzw. 93 % geschult. Die Anzahl der abgenommenen Blutkulturen stieg von 1757 auf 2872 um 64 % ebenso wie die Anzahl der Blutkulturen/1000 Fälle von 287 auf 481 (68 %). Die Anzahl der positiven Blutkulturen reduzierte sich von 18,6 auf 13,7 % (p 0,05). Typische Hautkeime fanden sich in 34,4 % und 26,4 % der Fälle (p 0,05).Die durch Schulungen begleitete Einführung einer SOP „Blutkulturen“ in der zentralen Notaufnahme kann einen relevanten Beitrag zur antimikrobiellen Diagnostik leisten und sowohl die Quantität als auch die Qualität erhöhen.

Purpose The coronavirus outbreak emerged as a severe pandemic, claiming more than 0.8 million lives across the world and raised a major global health concern. We survey the history and mechanism of coronaviruses, and the structural characteristics of the spike protein and its key residues responsible for human transmissions. Methods We have carried out a systematic review to summarize the origin, transmission and etiology of COVID-19. The structural analysis of the spike protein and its disordered residues explains the mechanism of the viral transmission. A meta-data analysis of the therapeutic compounds targeting the SARS-CoV-2 is also included. Results Coronaviruses can cross the species barrier and infect humans with unexpected consequences for public health. The transmission rate of SARS-CoV-2 infection is higher compared to that of the closely related SARS-CoV infections. In SARS-CoV-2 infection, intrinsically disordered regions are observed at the interface of the spike protein and ACE2 receptor, providing a shape complementarity to the complex. The key residues of the spike protein have stronger binding affinity with ACE2. These can be probable reasons for the higher transmission rate of SARS-CoV-2. In addition, we have also discussed the therapeutic compounds and the vaccines to target SARS-CoV-2, which can help researchers to develop effective drugs/vaccines for COVID-19. Summary The overall history and mechanism of entry of SARS-CoV-2 along with structural study of spike-ACE2 complex provide insights to understand disease pathogenesis and development of vaccines and drugs.

BACKGROUND: Psychotherapy is the gold standard treatment for posttraumatic stress disorder (PTSD), yet psychotherapy utilization and retention among veterans is low. Little is known about the barriers to care and factors associated with women veterans’ PTSD psychotherapy utilization and retention. OBJECTIVES: Using a nationally-representative sample of 986 women Veterans Health Administration (VHA) Primary Care users with PTSD and a perceived need for mental health care, we examined (1) the proportion of women who utilized psychotherapy; (2) retention in psychotherapy among women who used any psychotherapy; and (3) individual factors related to psychotherapy utilization and retention. METHODS: Women completed a survey on their mental health care experiences. Outpatient mental health care utilization in the year prior to survey was obtained from VHA administrative data. RESULTS: Most women (79.1%) utilized psychotherapy, and 41.7% of those women had a minimal therapeutic dose of psychotherapy (≥ 8 visits). Mental health diagnostic comorbidity and being African American/Black or identifying as neither African American/Black nor White were significantly associated with higher psychotherapy utilization. Mental health diagnostic comorbidity, exposure to military sexual trauma, and receiving treatment aligned with gender-related and group-related preferences were associated with higher psychotherapy retention. Being a parent was associated with lower retention. CONCLUSION: Although a significant proportion of women veterans with PTSD are utilizing psychotherapy, retention is enhanced when women are able to obtain treatment aligned with their preferences. Thus, efforts to promote patient-centered, shared decisions regarding mental health treatment options could increase the efficacy and efficiency of treatment for PTSD among women.

BACKGROUND AND PURPOSE: Total brain volume and total intracranial volume are important measures for assessing whole-brain atrophy in Alzheimer disease, dementia, and other neurodegenerative diseases. Unlike MR imaging, which has a number of well-validated fully-automated methods, only a handful of methods segment CT images. Available methods either use enhanced CT, do not estimate both volumes, or require formal validation. Reliable computation of total brain volume and total intracranial volume from CT is needed because head CTs are more widely used than head MRIs in the clinical setting. We present an automated head CT segmentation method (CTseg) to estimate total brain volume and total intracranial volume. MATERIALS AND METHODS: CTseg adapts a widely used brain MR imaging segmentation method from the Statistical Parametric Mapping toolbox using a CT-based template for initial registration. CTseg was tested and validated using head CT images from a clinical archive. RESULTS: CTseg showed excellent agreement with 20 manually segmented head CTs. The intraclass correlation was 0.97 (P < .001) for total intracranial volume and 0.94 (P < .001) for total brain volume. When CTseg was applied to a cross-sectional Alzheimer disease dataset (58 with Alzheimer disease patients and 58 matched controls), CTseg detected a loss in percentage total brain volume (as a percentage of total intracranial volume) with age (P

This study compared the Macintosh blade direct laryngoscope, Glidescope, C-Mac d-Blade, and McGrath MAC X-blade video laryngoscopes in 2 cadaveric models with severe cervical spinal instability. We hypothesized that the Glidescope video laryngoscope would allow for intubation with the least amount of cervical spine movement. Our secondary endpoints were glottic visualization and intubation success.In total, 2 fresh cadavers underwent maximal surgical destabilization from the craniocervical junction to the cervicothoracic junction by a neurosurgical spine specialist, with subsequent neutral positioning of the heads with surgical head fixation devices. On each cadaver, 8 experienced anesthesiologists performed four intubations with the 4 laryngoscopes in random order. Lateral radiographic measurements determined vertebral displacement during intubation.Cervical spine displacements were not significantly different amongst video laryngoscopes. Cormack-Lehane Grade 1 views were achieved with all attempts with each of the 3 video laryngoscopes; intubation attempts with the Macintosh blade achieved only grade 3 or grade 4 views. Intubation was successful every time with a video laryngoscope but only during 1 of 16 intubation attempts with the Macintosh blade.In a cadaveric model with maximally destabilized cervical spines, cervical spine movement was observed during attempted laryngoscopy using each of 3 video laryngoscopes, although there was no significant difference between the laryngoscopes. Given cervical spine displacement occurred, these video laryngoscopes do not prevent cervical spine motion during laryngoscopy. However, with improved glottic visualization and intubation success, video laryngoscopes are superior to the Macintosh blade in both cervical spine safety and intubation efficacy in the model studied.

Glioblastoma multiforme (GBM) is the most common infiltrating lethal tumor of the brain. Tumor heterogeneity and the precise characterization of GBM remain challenging, and the disease-specific and effective biomarkers are not available at present. To understand GBM heterogeneity and the disease prognosis mechanism, we carried out a single-cell transcriptome data analysis of 3389 cells from four primary IDH-WT (isocitrate dehydrogenase wild type) glioblastoma patients and compared the characteristic features of the tumor and periphery cells. We observed that the marker gene expression profiles of different cell types and the copy number variations (CNVs) are heterogeneous in the GBM samples. Further, we have identified 94 differentially expressed genes (DEGs) between tumor and periphery cells. We constructed a tissue-specific co-expression network and protein–protein interaction network for the DEGs and identified several hub genes, including CX3CR1, GAPDH, FN1, PDGFRA, HTRA1, ANXA2 THBS1, GFAP, PTN, TNC, and VIM. The DEGs were significantly enriched with proliferation and migration pathways related to glioblastoma. Additionally, we were able to identify the differentiation state of microglia and changes in the transcriptome in the presence of glioblastoma that might support tumor growth. This study provides insights into GBM heterogeneity and suggests novel potential disease-specific biomarkers which could help to identify the therapeutic targets in GBM.

BACKGROUND The significance of discrepant findings between histology (BMB) and flow cytometry (FC) in bone marrow (BM) examination at diffuse large B-cell lymphoma (DLBCL) diagnosis is uncertain. METHODS We performed a 5-year retrospective single-center study of patients diagnosed by DLBCL not otherwise specified (n = 82), divided into three groups according to BM infiltration at diagnosis: BMB-/FC- (75.6%), BMB+/FC+ (13.4%), and BMB-/FC+ (11%). RESULTS Median infiltration by FC analysis of the BMB-/FC+ group was 0.8% and if we considered BM infiltration as positive in all cases, 4/9 would be upstaged. Median follow was 33 months. Event-free survival (EFS) after 18 months was 82, 23, and 27% for BMB-/FC-, BMB-/FC+, and BMB+/FC+, respectively (p

Membrane proteins are unique in that segments thereof concurrently reside in vastly different physicochemical environments: the extracellular space, the lipid bilayer, and the cytoplasm. Accordingly, the effects of missense variants disrupting their sequence depend greatly on the characteristics of the environment of the protein segment affected as well as the function it performs. Because membrane proteins have many crucial roles (transport, signal transduction, cell adhesion, etc.), compromising their functionality often leads to diseases including cancers, diabetes mellitus or cystic fibrosis. Here, we report a suite of sequence-based computational methods "Pred-MutHTP" for discriminating between disease-causing and neutral alterations in their sequence. With a data set of 11,846 disease-causing and 9,533 neutral mutations, we obtained an accuracy of 74% and 78% with 10-fold group-wise cross-validation and test set, respectively. The features used in the models include evolutionary information, physiochemical properties, neighboring residue information, and specialized membrane protein attributes incorporating the number of transmembrane segments, substitution matrices specific to membrane proteins as well as residue distributions occurring in specific topological regions. Across 11 disease classes, the method achieved accuracies in the range of 75-85%. The model designed specifically for the transmembrane segments achieved an accuracy of 85% on the test set with a sensitivity and specificity of 86% and 83%, respectively. This renders our method the current state-of-the-art with regard to predicting the effects of variants in the transmembrane protein segments. Pred-MutHTP allows predicting the effect of any variant occurring in a membrane protein-available at https://www.iitm.ac.in/bioinfo/PredMutHTP/.

Mitigating the devastating effect of COVID-19 is necessary to control the infectivity and mortality rates. Hence, several strategies such as quarantine of exposed and infected individuals and restricting movement through lockdown of geographical regions have been implemented in most countries. On the other hand, standard SEIR based mathematical models have been developed to understand the disease dynamics of COVID-19, and the proper inclusion of these restrictions is the rate-limiting step for the success of these models. In this work, we have developed a hybrid Susceptible-Exposed-Infected-Quarantined-Removed (SEIQR) model to explore the influence of quarantine and lockdown on disease propagation dynamics. The model is multi-compartmental, and it considers everyday variations in lockdown regulations, testing rate and quarantine individuals. Our model predicts a considerable difference in reported and actual recovered and deceased cases in qualitative agreement with recent reports.

Background While there are clear national resuscitation room admission guidelines for major trauma patients, there are no comparable alarm criteria for critically ill nontrauma (CINT) patients in the emergency department (ED). The aim of this study was to define and validate specific trigger factor cut-offs for identification of CINT patients in need of a structured resuscitation management protocol. Methods All CINT patients at a German university hospital ED for whom structured resuscitation management would have been deemed desirable were prospectively enrolled over a 6-week period (derivation cohort, n = 108). The performance of different thresholds and/or combinations of trigger factors immediately available during triage were compared with the National Early Warning Score (NEWS) and Quick Sequential Organ Failure Assessment (qSOFA) score. Identified combinations were then tested in a retrospective sample of consecutive nontrauma patients presenting at the ED during a 4-week period (n = 996), and two large external datasets of CINT patients treated in two German university hospital EDs (validation cohorts 1 [n = 357] and 2 [n = 187]). Results The any-of-the-following trigger factor iteration with the best performance in the derivation cohort included: systolic blood pressure 80% of patients in the derivation cohort and performed better than NEWS and qSOFA scores in the internal validation cohort (sensitivity = 98.5%, specificity = 98.6%). When applied to the external validation cohorts, need for advanced resuscitation measures and hospital mortality (6.7 vs. 28.6%, p p Conclusion Our simple, any-of-the-following decision rule can serve as an objective trigger for initiating resuscitation room management of CINT patients in the ED.

The coronavirus disease 2019 (COVID‐19) has affected the lives of millions of people around the world. In an effort to develop therapeutic interventions and control the pandemic, scientists have isolated several neutralizing antibodies against SARS‐CoV‐2 from the vaccinated and convalescent individuals. These antibodies can be explored further to understand SARS‐CoV‐2 specific antigen–antibody interactions and biophysical parameters related to binding affinity, which can be utilized to engineer more potent antibodies for current and emerging SARS‐CoV‐2 variants. In the present study, we have analyzed the interface between spike protein of SARS‐CoV‐2 and neutralizing antibodies in terms of amino acid residue propensity, pair preference, and atomic interaction energy. We observed that Tyr residues containing contacts are highly preferred and energetically favorable at the interface of spike protein–antibody complexes. We have also developed a regression model to relate the experimental binding affinity for antibodies using structural features, which showed a correlation of 0.93. Moreover, several mutations at the spike protein–antibody interface were identified, which may lead to immune escape (epitope residues) and improved affinity (paratope residues) in current/emerging variants. Overall, the work provides insights into spike protein–antibody interactions, structural parameters related to binding affinity and mutational effects on binding affinity change, which can be helpful to develop better therapeutics against COVID‐19.

Background Online repetitive transcranialmagnetic stimulation (rTMS) has been shown to modulate working memory (WM) performance in a site‐specific manner, with behavioral improvements due to stimulation of the dorsolateral prefrontal cortex (DLPFC), and impairment from stimulation to the lateral parietal cortex (LPC). Neurobehavioral studies have demonstrated that subprocesses of WM allowing for the maintenance and manipulation of information in the mind involve unique cortical networks. Despite promising evidence of modulatory effects of rTMS on WM, no studies have yet demonstrated distinct modulatory control of these two subprocesses. The current study therefore sought to explore this possibility through site‐specific stimulation during an online task invoking both skills. Methods Twenty‐nine subjects completed a 4‐day protocol, in which active or sham 5Hz rTMS was applied over the DLPFC and LPC in separate blocks of trials while participants performed tasks that required either maintenance alone, or both maintenance and manipulation (alphabetization) of information. Stimulation targets were defined individually based on fMRI activation and structural network properties. Stimulation amplitude was adjusted using electric field modeling to equate induced current in the target region across participants. Results Despite the use of advanced techniques, no significant differences or interactions between active and sham stimulation were found. Exploratory analyses testing stimulation amplitude, fMRI activation, and modal controllability showed nonsignificant but interesting trends with rTMS effects. Conclusion While this study did not reveal any significant behavioral changes in WM, the results may point to parameters that contribute to positive effects, such as stimulation amplitude and functional activation., Working memory is a crucial a cognitive ability that declines rapidly with aging. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as an approach to enhance working memory abilities, however effects are often modest. In this study, advanced techniques were used (fMRI, network controllability and electric field modeling) to optimize rTMS effects. However, no significant differences were found between active and sham rTMS, as such the manuscript provides a detailed account of how stimulation and task parameters may have led to the lack of significant rTMS results.

Wearing a face mask has become essential to contain the spread of COVID-19 and has become mandatory when collecting fMRI data at most research institutions. Here, we investigate the effects of wearing a surgical mask on fMRI data in n = 37 healthy participants. Activations during finger tapping, emotional face matching, working memory tasks, and rest were examined. Preliminary fMRI analyses show that despite the different mask states, resting-state signals and task activations were relatively similar. Resting-state functional connectivity showed negligible attenuation patterns in mask-on compared with mask-off. Task-based ROI analysis also demonstrated no significant difference between the two mask states under each contrast investigated. Notwithstanding the overall insignificant effects, these results indicate that wearing a face mask during fMRI has little to no significant effect on resting-state and task activations.

Aggregation of therapeutic monoclonal antibodies (mAbs) can negatively affect their chemistry, manufacturing and control attributes and lead to undesirable immune responses in patients. Therefore, optimization of lead Monoclonal antibody (mAb) drug candidates during discovery stages to mitigate aggregation is increasingly becoming an integral part of their developability assessments. The disruption of short sequence motifs called Aggregation prone regions (APRs) found in amino acid sequences of mAb candidates can potentially mitigate their aggregation. In this work, we have performed Molecular Dynamics (MD) simulations to study the aggregation of an APR (VLVIY) found in λ light chains of human antibodies and its single point mutant KLVIY. Eighteen different multi-copy peptide simulation systems of 'VLVIY' and 'KLVIY' were constructed by varying their concentrations, temperatures, termini capping, and flanking gate-keeper regions. Within 20 ns of the simulation, peptide 'VLVIY' formed an aggregate of 100 peptides at ~0.1 M concentration with a 60% reduction in solvent accessible surface area (SASA). Further, analysis of the SASA change, peptide cluster distribution, and water residence time demonstrated how Val➔Lys mutation resists aggregation and improves solubility. Presence of Lys slows down aggregation kinetics via charge-charge repulsions and by raising the kinetic barrier to formation of large oligomers. However, the effect of the Val ➔ Lys mutation is dependent on sequence and structural contexts around the APR. This mutation also alters the solvation shell around the peptide by favoring solute-solvent interactions, thereby increasing its solubility. This work has provided a detailed mechanistic explanation of how APR disruption can mitigate aggregation in biotherapeutics and improve their developability. This article is protected by copyright. All rights reserved.

Background: Though virtual screening methods have proven to be potent in various instances, the technique is practically incomplete to quench the need of drug discovery process. Thus, the quest for novel designing approaches and chemotypes for improved efficacy of lead compounds has been intensified and logistic approaches such as scaffold hopping and hierarchical virtual screening methods were evolved. Till now, in all the previous attempts these two approaches were applied separately. Objective: In the current work, we made a novel attempt in terms of blending scaffold hopping and hierarchical virtual screening. The prime objective is to assess the hybrid method for its efficacy in identifying active lead molecules for emerging PPI target Bcl-2 (B-cell Lymphoma 2). Method: We designed novel scaffolds from the reported cores and screened a set of 8270 compounds using both scaffold hopping and hierarchical virtual screening for Bcl-2 protein. Also, we enumerated the libraries using clustering, PAINS filtering, physicochemical characterization and SAR matching. Results: We generated a focused library of compounds towards Bcl-2 interface, screened the 8270 compounds and identified top hits for seven families upon fine filtering with PAINS algorithm, features, SAR mapping, synthetic accessibility and similarity search. Our approach retrieved a set of 50 lead compounds. Conclusions: Finding rational approach meeting the needs of drug discovery process for PPI targets is the need of the hour which can be fulfilled by an extended scaffold hopping approach resulting in focused PPI targeting by providing novel leads with better potency.

Background Autocorrelation (AC) in fMRI time-series is a well-known phenomenon, typically attributed to colored noise and therefore removed from the data. We hypothesize that AC reflects systematic and meaningful signal fluctuations that may be tied to neural activity and provide evidence to support this hypothesis. New method Each fMRI time-series is modeled as an autoregressive process from which the autocorrelation is quantified. Then, autocorrelation during resting-state fMRI and auditory oddball (AOD) task in schizophrenia and healthy volunteers is examined. Results During resting-state, AC was higher in the visual cortex while during AOD task, frontal part of the brain exhibited higher AC in both groups. AC values were significantly lower in specific brain regions in schizophrenia patients (such as thalamus during resting-state) compared to healthy controls in two independent datasets. Moreover, AC values had significant negative correlation with patients’ symptoms. AC differences discriminated patients from healthy controls with high accuracy (resting-state). Comparison with existing methods Contrary to most prior works, the results suggest AC shows meaningful patterns that are discriminative between patients and controls. Our results are in line with recent works attributing autocorrelation to feedback loop of brain's regulatory circuit. Conclusions Autoconnectivity is cognitive state dependent (resting-state vs. task) and mental state dependent (healthy vs. schizophrenia). The concept of autoconnectivity resembles a recurrent neural network and provides a new perspective of functional integration in the brain. These findings may have important implications for understanding of brain function in health and disease as well as for analysis of fMRI time-series.

The selective vulnerability of distinct regions of the brain is a critical factor in neurodegenerative disorders. In Alzheimer's disease (AD), neurons in hippocampus situated in medial temporal lobe are immensely damaged. Identifying tissue-specific variants is essential in order to perceive the selective vulnerability in AD. In current work, we aligned mRNA-seq data with HG19/HG38 genomic assembly and identified specific variations present in temporal, frontal and other lobes of the AD using sequence alignment map tools. We compared the results with the genome-wide association and gene expression quantitative trait loci studies of the various neurological disorders. We also distinguished variants and epitranscriptomic modifications through the RNA-modification database and evaluated the variant effect in the coding/UTR regions. In addition, we developed genetic and functional interaction networks to understand the relationship between predicted vulnerable variations and differentially expressed genes. We found that genes involved in gliogenesis, intermediate filament organization are altered in the temporal lobe. Oxidative phosphorylation, and calcium ion homeostasis are modified in the frontal lobe, and protein degradation, apoptotic signaling are altered in other lobes. From this study, we propose that disruption of glial cell structural integrity, defective gliogenesis, and failure in glia-neuron communication are the primary factors for selective vulnerability.

C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenases often overexpressed in multiple solid tumors, including breast, colon, and ovarian cancer, and associated with poor survival. CtBPs act by repressing expression of genes responsible for apoptosis (e.g., PUMA, BIK) and metastasis-associated epithelial–mesenchymal transition (e.g., CDH1), and by activating expression of genes that promote migratory and invasive properties of cancer cells (e.g., TIAM1) and genes responsible for enhanced drug resistance (e.g., MDR1). CtBP’s transcriptional functions are also critically dependent on oligomerization and nucleation of transcriptional complexes. Recently, we have developed a family of CtBP dehydrogenase inhibitors, based on the parent 2-hydroxyimino-3-phenylpropanoic acid (HIPP), that specifically disrupt cancer cell viability, abrogate CtBP’s transcriptional function, and block polyp formation in a mouse model of intestinal polyposis that depends on CtBP’s oncogenic functions. Crystallographic analysis revealed that HIPP interacts with CtBP1/2 at a conserved active site tryptophan (W318/324; CtBP1/2) that is unique among eukaryotic D2-dehydrogenases. To better understand the mechanism of action of HIPP-class inhibitors, we investigated the contribution of W324 to CtBP2’s biochemical and physiologic activities utilizing mutational analysis. Indeed, W324 was necessary for CtBP2 self-association, as shown by analytical ultracentrifugation and in vivo cross-linking. Additionally, W324 supported CtBP’s association with the transcriptional corepressor CoREST, and was critical for CtBP2 induction of cell motility. Notably, the HIPP derivative 4-chloro-HIPP biochemically and biologically phenocopied mutational inactivation of CtBP2 W324. Our data support further optimization of W318/W324-interacting CtBP dehydrogenase inhibitors that are emerging as a novel class of cancer cell–specific therapeutic.

InCoB, one of the largest annual bioinformatics conferences in the Asia-Pacific region since its launch in 2002, returned to New Delhi, India after 12 years, with a conference attendance of 314 delegates. The 2018 conference had sessions on Big Data and Algorithms, Next Generation Sequencing and Omics Science, Structure, Function and Interactions, Disease and Drug Discovery and Plant and Agricultural Bioinformatics. The conference also featured an industry track as well as panel discussions on Women in Bioinformatics and Democratization vs. Quality control in academic publishing. Asia Pacific Bioinformatics Interaction & Networking Society (APbians) was launched as an APBionet Special Interest Group. Of the 52 oral presentations made, 22 were accepted in supplemental issues of BMC Bioinformatics, BMC Genomics or BMC Medical Genomics and are briefly reviewed here. Next year’s InCoB will be held in Jakarta, Indonesia from September 10–12, 2019.

As part of its comprehensive journey toward high reliability, Memorial Hermann Health System has implemented multiple patient safety initiatives. An instance of actual patient harm due to staff unfamiliarity with a medical device triggered a project to ensure the competence of clinical staff in the operation of all approved new and updated medical devices. Medical devices are classified by level of risk to patients if caregivers are not reliably educated. Educational rigor, with tracking and accountability management, is then scaled to that risk assessment. The objective is to decrease safety events related to use of medical devices by ensuring failure-free medical device use. An interdisciplinary team was created to design a “fail-safe” process to analyze and scale training for use of medical devices, with a risk assessment tool predicting the potential severity and frequency of harm to patients. The fail-safe process became an approved procedure and practice standard at the institution.

OBJECTIVES. Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intra-pancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase (CEL) emerged as a trypsin-independent risk gene. Here, we evaluated PNLIP encoding pancreatic lipase as a potential novel susceptibility gene for CP. METHODS. We analyzed all 13 PNLIP exons in 429 German non-alcoholic CP patients and in 600 German control subjects, in 632 patients and 957 controls from France, and in 223 patients and 1070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 CP patients and 1849 controls originating from Germany, USA and India. We assessed the cellular secretion, lipase activity and proteolytic stability of recombinant PNLIP variants. RESULTS. In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P=0.02, OR=5.7, 95% CI=1.1–38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) versus controls (1/957 [0.1%]) (P=0.04, OR=7.6, 95% CI=0.9–172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1163 cases (1.1%) and in 3/3000 controls (0.1%) (OR=11.3, 95% CI=3.0–49.9, P

Huntington disease is a neurodegenerative disorder caused by the expansion of polyglutamine (polyQ) at the N-terminal of the huntingtin exon 1 protein. The detailed structure and the mechanism behind this aggregation remain unclear and it is assumed that the polyQ undergoes a conformational transition to the β-sheet structure when it aggregates. Investigating the misfolding of polyQ facilitates the determination of the molecular mechanism of aggregation and can potentially help in developing a novel approach to inhibit polyQ aggregation. Moreover, the flanking sequences of the polyQ region play a vital role in structural changes and the aggregation mechanism. We performed all-atom molecular dynamics simulations to gain structural insights into the aggregation mechanism using eight different models with glutamine repeat lengths Q27 , Q27 P11 , Q34 , Q35 , Q36 , Q40 , Q50 , and Q50 P11 . In the models without flanking polyPs, we noticed that the transformation of a random coil to β-sheet occurs when the number of Q increases. We also found that the flanking polyPs prevent aggregation by decreasing the probability of forming a β-sheet structure. When polyQ length increases, the 17 N-terminal flanking residues are more likely to adopt a β-sheet conformation from α-helix and coil. From our simulations, we suggest that at least 34 glutamines are required for initiating aggregation and 40 residues length is critical for the aggregation of huntingtin exon 1 protein for disease onset. This study provides structural insights into misfolding and the role of flanking sequences in huntingtin aggregation which will further help in developing therapeutic strategies for Huntington's disease.

While static functional connectivity (sFC) of resting state fMRI (rfMRI) measures the average functional connectivity (FC) over the entire rfMRI scan, dynamic FC (dFC) captures the temporal variations of FC at shorter time windows. Although numerous studies have implemented dFC analyses, only a few studies have investigated the reliability of dFC and this limits the biological interpretation of dFC. Here, we used a large cohort (N = 820) of subjects and four rfMRI scans from the Human Connectome Project to systematically explore the relationship between sFC, dFC and their test-retest reliabilities through intra-class correlation (ICC). dFC ICC was explored through the sliding window approach with three dFC statistics (standard deviation, ALFF, and excursion). Excursion demonstrated the highest dFC ICC and the highest age prediction accuracy. dFC ICC was generally higher at window sizes less than 40 s. sFC and dFC were negatively correlated. Compared to sFC, dFC was less reliable. While sFC and sFC ICC were positively correlated, dFC and dFC ICC were negatively correlated, indicating that FC that was more dynamic was less reliable. Intra-network FCs in the frontal-parietal, default mode, sensorimotor and visual networks demonstrated high sFC and low dFC. Moreover, ICCs of both sFC and dFC in these regions were higher. The above results were consistent across two brain atlases and independent component analysis-based networks, multiple window sizes and all three dFC statistics. In summary, dFC is less reliable than sFC and additional experiments are required to better understand the neurophysiological relevance of dFC.

The urgent need for a treatment of COVID-19 has left researchers with limited choice of either developing an effective vaccine or identifying approved/investigational drugs developed for other medical conditions for potential repurposing, thus bypassing long clinical trials. In this work, we compared the sequences of experimentally verified SARS-CoV-2 neutralizing antibodies and sequentially/structurally similar commercialized therapeutic monoclonal antibodies. We have identified three therapeutic antibodies, Tremelimumab, Ipilimumab and Afasevikumab. Interestingly, these antibodies target CTLA4 and IL17A, levels of which have been shown to be elevated during severe SARS-CoV-2 infection. The candidate antibodies were evaluated further for epitope restriction, interaction energy and interaction surface to gauge their repurposability to tackle SARS-CoV-2 infection. Our work provides candidate antibody scaffolds with dual activities of plausible viral neutralization and immunosuppression. Further, these candidate antibodies can also be explored in diagnostic test kits for SARS-CoV-2 infection. We opine that this in silico workflow to screen and analyze antibodies for repurposing would have widespread applications.

The light chain (AL) amyloidosis is caused by the aggregation of light chain of antibodies into amyloid fibrils. There are plenty of computational resources available for the prediction of short aggregation-prone regions within proteins. However, it is still a challenging task to predict the amyloidogenic nature of the whole protein using sequence/structure information. In the case of antibody light chains, common architecture and known binding sites can provide vital information for the prediction of amyloidogenicity at physiological conditions. Here, in this work, we have compared classical sequence-based, aggregation-related features (such as hydrophobicity, presence of gatekeeper residues, disorderness, β-propensity, etc.) calculated for the CDR, FR or VL regions of amyloidogenic and non-amyloidogenic antibody light chains and implemented the insights gained in a machine learning-based webserver called “VLAmY-Pred” (https://web.iitm.ac.in/bioinfo2/vlamy-pred/). The model shows prediction accuracy of 79.7% (sensitivity: 78.7% and specificity: 79.9%) with a ROC value of 0.88 on a dataset of 1828 variable region sequences of the antibody light chains. This model will be helpful towards improved prognosis for patients that may likely suffer from diseases caused by light chain amyloidosis, understanding origins of aggregation in antibody-based biotherapeutics, large-scale in-silico analysis of antibody sequences generated by next generation sequencing, and finally towards rational engineering of aggregation resistant antibodies.

The 2019‐novel coronavirus also known as severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) is a common threat to animals and humans, and is responsible for the human SARS pandemic in 2019 to 2021. The infection of SARS‐CoV‐2 in humans involves a viral surface glycoprotein named as spike proteins, which bind to the human angiotensin‐converting enzyme 2 (ACE2) proteins. Particularly, the receptor binding domains (RBDs) mediate the interaction and contain several disordered regions, which help in the binding. Investigations on the influence of disordered residues/regions in stability and binding of spike protein with ACE2 help to understand the disease pathogenesis, which has not yet been studied. In this study, we have used molecular‐dynamics simulations to characterize the structural changes in disordered regions of the spike protein that result from ACE2 binding. We observed that the disordered regions undergo disorder‐to‐order transition (DOT) upon binding with ACE2, and the DOT residues are located at functionally important regions of RBD. Although the RBD is having rigid structure, DOT residues make conformational rearrangements for the spike protein to attach with ACE2. The binding is strengthened via hydrophilic and aromatic amino acids mainly present in the DOTs. The positively correlated motions of the DOT residues with its nearby residues also explain the binding profile of RBD with ACE2, and the residues are observed to be contributing more favorable binding energies for the spike‐ACE2 complex formation. This study emphasizes that intrinsically disordered residues in the RBD of spike protein may provide insights into its etiology and be useful for drug and vaccine discovery.

A comprehensive characterization of the spatiotemporal organization in the whole brain is critical to understand both the function and dysfunction of the human brain. Resting-state functional connectivity (FC) of gray matter (GM) has helped in uncovering the inherent baseline networks of brain. However, the white matter (WM), which composes almost half of brain, has been largely ignored in this characterization despite studies indicating that FC in WM does change during task and rest functional magnetic resonance imaging (fMRI). In this study, we identify 9 white matter functional networks (WM-FNs) and 9 gray matter functional networks (GM-FNs) of resting fMRI. Intraclass correlation coefficient (ICC) was calculated on multirun fMRI data to estimate the reliability of static functional connectivity (SFC) and dynamic functional connectivity (DFC). Associations between SFC, DFC, and their respective ICCs are estimated for GM-FNs, WM-FNs, and GM-WM-FNs. SFC of GM-FNs were stronger than that of WM-FNs, but the corresponding DFC of GM-FNs was lower, indicating that WM-FNs were more dynamic. Associations between SFC, DFC, and their ICCs were similar in both GM- and WM-FNs. These findings suggest that WM fMRI signal contains rich spatiotemporal information similar to that of GM and may hold important cues to better establish the functional organization of the whole brain.

Tethered cord syndrome (TCS) is an amalgamation of neurological, urological, orthopedic, and dermatologic signs and symptoms with radiographic evidence of a thickened filum and low-lying conus. Surgical sectioning of the filum and disconnection of any tethering entities such as dermal sinus tracts or lipomas has been shown to improve outcomes. The manifestation of TCS symptoms in the absence of a low-lying conus has been referred to as occult tethered cord syndrome (OTCS) and is much less well reviewed in the literature. To date, there has only been one randomized controlled trial examining the effect of intervention in OTCS; therefore, contemporary data is often elicited from limited cohorts.To perform a comprehensive literature review of management in OTCS and evaluate treatment response rates to sectioning of the filum terminale.Seventeen papers met inclusion criteria for our review. Sample sizes ranged from 8 to 60 children, and results were mixed, often dependent on study design, definition of typical OTCS symptoms, and follow-up intervals. Symptomatic improvement was observed in 50% of patients for all but one study; however, the recurrence rates were highly variable.The data regarding the efficacy of surgical treatment in OTCS is mixed and merits more rigorous scientific examination with strict and clear parameters regarding symptomatic operationalization and follow-up time points to monitor for TCS recurrence.

Background A utility value is a health-related quality of life metric (HRQoL) metric used in a cost-effectiveness analysis. While utilities as outcomes in the treatment of advanced Parkinson’s disease (PD) with deep brain stimulation (DBS) are available, they do not currently exist for PD with early motor complications. The objectives of this study were to predict utilities from observed disease-specific HRQoL data using two mapping algorithms, and investigate their performance in terms of longitudinal changes within and between treatment groups, and distribution by PD severity. Methods This is a post hoc analysis of data from the EARLYSTIM trial of DBS compared with best medical therapy (BMT) in PD patients with early motor complications We used two published algorithms comprising ordinal and multinomial regression models to map EQ-5D-3L utilities from observed PD-specific 39 item Questionnaire (PDQ-39) scores in EARLYSTIM. Utilities were calculated using the predicted functioning levels of EQ-5D-3L dimensions and the established EQ-5D-3L UK tariffs. Statistical analyses (analysis of variance, two-tailed Student’s t-test) were used to test the change from baseline within groups and difference in change from baseline between groups in utilities. Boxplots were developed to investigate the distribution of predicted utilities by PD severity, measured using the Hoehn and Yahr scale. Results The change from baseline in predicted mean utilities was statistically significant at all visits up to 24 months for the DBS group (p p = 0.04) for the BMT group with one algorithm. With both algorithms, the between-groups difference in change from baseline in predicted mean utilities favored DBS at all follow-up visits (p Conclusions Among PD patients with early motor complications, utilities predicted by both mapping algorithms using PDQ-39 data demonstrated a statistically and clinically meaningful improvement with DBS compared with BMT. It was not possible to conclude if one algorithm was more responsive than other. In the absence of utilities collected directly from patients, mapping is an acceptable option permitting economic evaluations to be undertaken.

Coronaviruses are responsible for several epidemics, including the 2002 SARS, 2012 MERS, and COVID‐19. The emergence of recent COVID‐19 pandemic due to SARS‐CoV‐2 virus in December 2019 has resulted in considerable research efforts to design antiviral drugs and other therapeutics against coronaviruses. In this context, it is crucial to understand the biophysical and structural features of the major proteins that are involved in virus‐host interactions. In the current study, we have compared spike proteins from three strains of coronaviruses NL63, SARS‐CoV, and SARS‐CoV, known to bind human angiotensin‐converting enzyme 2 (ACE2), in terms of sequence/structure conservation, hydrophobic cluster formation and importance of binding site residues. The study reveals that the severity of coronavirus strains correlates positively with the interaction area, surrounding hydrophobicity and interaction energy and inversely correlate with the flexibility of the binding interface. Also, we identify the conserved residues in the binding interface of spike proteins in all three strains. The systematic point mutations show that these conserved residues in the respective strains are evolutionarily favored at their respective positions. The similarities and differences in the spike proteins of the three viruses indicated in this study may help researchers to deeply understand the structural behavior, binding site properties and etiology of ACE2 binding, accelerating the screening of potential lead molecules and the development/repurposing of therapeutic drugs.

Limited therapy options exist for patients with treatment-refractory metastatic colorectal or anal cancers, prompting investigation into alternative therapies. Immunotherapy in the form of immune checkpoint blockade is one such emerging treatment that has demonstrated promising results in other tumour streams.x This review aims to assess the current use of immune checkpoint blockade in patients with lower gastrointestinal tumours.Embase, Medline and Cochrane databases were searched for included studies. Clinical trials published in English and utilising immune checkpoint blockade for primary tumours situated in the lower gastrointestinal tract were included. Databases were searched for studies reporting on at least one of overall survival, progression-free survival or response to therapy.In total, 972 abstracts were screened, with 10 studies included in the final review. Eight trials (833 patients) assessed immune checkpoint blockade in the setting of colorectal cancers. These included pembrolizumab, nivolumab, durvalumab, atezolizumab, tremelimumab and ipilimumab. A total of 20 patients across all studies achieved a complete response, and 111 patients achieved a partial response to treatment. Two trials (62 patients) assessed immune checkpoint blockade in anal cancer, utilising nivolumab and pembrolizumab. Two patients across both studies achieved a complete response, and 11 patients achieved a partial response.A number of patients with advanced lower gastrointestinal tumours achieved a complete response to treatment for what would otherwise be considered palliative disease. Presented data have highlighted that particular patients may benefit from first-line or combination immunotherapy, and thus, further investigation is warranted to individualise treatment.

A new and accurate reversed phase HPLC method with UV detection has been established for any veterinarian analyst for simultaneous determination of a veterinary quaternary mixture of sulphadimidine sodium (SDS), sulphaquinoxaline sodium (SQS), diaveridine (DVD) and vitamin K3 (VTK3) in their formulation. The stationary phase was SEA C18 column (250 × 4.6 mm i.d., 5 μm particle size) at 25°C with an isocratic mode, using a mobile phase containing a mixture of methanol:acetonitrile:distilled water in the ratio of (20:20:60, by volume). The flow rate was 0.8 mL min−1, and UV detection was performed at 230 nm. The HPLC assay was coupled with Environmental Assessment Tool (EAT), which represents a simple and proficient approach for profiling the greenness of the method. This takes into consideration the environmental, health and safety issues for all solvents that involved in the chromatographic method and calculates a total score that can be used for comparison of the greenness of different methods. The method was found to be linear over (0.5–30) μg/mL for all cited drugs with mean percentage recoveries (99.56 ± 1.141) for VTK3, (99.56 ± 1.056) for DVD, (99.62 ± 1.482) for SDS and (99.52 ± 1.205) for SQS. The results were statistically compared with those of the official and reported methods; using Student’s t-test and F-test, showing no significant difference with respect to accuracy. Specificity of the applied method was assessed by analyzing the laboratory-prepared mixtures. The developed method was validated according to ICH guidelines. The proposed methodology can be applied for rapid routine assay of this combination.