Category: Nevin Manimala

Proc Natl Acad Sci U S A. 2021 Oct 26;118(43):e2100943118. doi: 10.1073/pnas.2100943118. Epub 2021 Oct 6.

ABSTRACT

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) involves the attachment of the receptor-binding domain (RBD) of its spike proteins to the ACE2 receptors on the peripheral membrane of host cells. Binding is initiated by a down-to-up conformational change in the spike protein, the change that presents the RBD to the receptor. To date, computational and experimental studies that search for therapeutics have concentrated, for good reason, on the RBD. However, the RBD region is highly prone to mutations, and is therefore a hotspot for drug resistance. In contrast, we here focus on the correlations between the RBD and residues distant to it in the spike protein. This allows for a deeper understanding of the underlying molecular recognition events and prediction of the highest-effect key mutations in distant, allosteric sites, with implications for therapeutics. Also, these sites can appear in emerging mutants with possibly higher transmissibility and virulence, and preidentifying them can give clues for designing pan-coronavirus vaccines against future outbreaks. Our model, based on time-lagged independent component analysis (tICA) and protein graph connectivity network, is able to identify multiple residues that exhibit long-distance coupling with the RBD opening. Residues involved in the most ubiquitous D614G mutation and the A570D mutation of the highly contagious UK SARS-CoV-2 variant are predicted ab initio from our model. Conversely, broad-spectrum therapeutics like drugs and monoclonal antibodies can target these key distant-but-conserved regions of the spike protein.

PMID:34615730 | DOI:10.1073/pnas.2100943118

J Sport Rehabil. 2021 Oct 6:1-7. doi: 10.1123/jsr.2021-0148. Online ahead of print.

ABSTRACT

CONTEXT: Ankle positioning gait biofeedback (GBF) has improved ankle inversion for patients with chronic ankle instability. However, the effects on proximal deficits remain unknown. The purpose of this study was to determine the effects of impairment-based rehabilitation with GBF and without biofeedback on gluteal activity during walking in patients with chronic ankle instability.

DESIGN: Randomized controlled trial.

METHODS: Eighteen patients with chronic ankle instability (14 women and 4 men; age 22 [4] y; height 171 [10] cm; mass 71.6 [13.8] kg) were recruited from a university setting, following International Ankle Consortium guidelines. Patients were randomly allocated to GBF or without biofeedback groups (N = 9 per group). Both groups performed 4 weeks of exercises and treadmill walking. The GBF group alone received feedback on frontal ankle positioning at initial contact during walking. Ultrasound videos of the gluteus maximus and medius were recorded during walking at baseline and follow-up by a blinded clinician. Gluteal activity ratios were obtained at each 10% of the gait cycle. Statistical parametric mapping repeated-measures analysis of variance were used to compare groups and time points.

RESULTS: Both groups demonstrated significantly increased gluteus medius activity across the gait cycle compared with baseline (P < .01, mean differences: 0.13-0.21, Hedge g: 0.97-1.89); however, there were no significant between-group differences. There were no statistically significant changes noted for the gluteus maximus. No adverse events were observed.

CONCLUSIONS: Impairment-based rehabilitation led to increased gluteus medius activity, but GBF did not provide any additional improvement to this parameter. Clinicians may consider implementing impairment-based strengthening interventions to improve gluteus medius function during gait for patients with CAI.

PMID:34615741 | DOI:10.1123/jsr.2021-0148

Emerg Med Australas. 2021 Oct 6. doi: 10.1111/1742-6723.13875. Online ahead of print.

ABSTRACT

OBJECTIVE: This research aims to (i) identify latent subgroups of ED presentations in Australian public EDs using a data-driven approach and (ii) compare clinical, socio-demographic and time-related characteristics of ED presentations broadly using the subgroups.

METHODS: We examined presentations to four public hospital EDs in Queensland from 2009 to 2014. An unsupervised machine learning algorithm, Clustering Large Applications, was used to cluster ED presentations.

RESULTS: There were six subgroups common across the EDs, primarily distinguishable by age, and subsequently by triage category, ED length of stay, arrival mode, departure status and several time-related attributes. Around 10% to 30% of the total presentations had high resource utilisation, with half of these from older patients (55+ years). ED resource utilisation per population was highest among the oldest cohort (75+ years). Children and young adults more frequently presented to the ED outside general-practitioner hours, mostly on Sundays. Older persons were more likely to present at any time, rather than specific hours, days or seasons. ED service performance measured against commonly used access-target indicators were rarely satisfied for older people and frequently satisfied for children.

CONCLUSION: Clustering Large Applications is effective in finding latent groups in large-scale mixed-type data, as demonstrated in the present study. Six types of ED presentations were identified and described using clinically relevant characteristics. The present study provides evidence for policy makers in Australia to develop alternative ED models of care tailored around the care needs of the differing groups of patients and thereby supports the sustainable delivery of acute healthcare.

PMID:34614544 | DOI:10.1111/1742-6723.13875

Chronic Obstr Pulm Dis. 2021 Oct 1. doi: 10.15326/jcopdf.2021.0235. Online ahead of print.

ABSTRACT

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) struggle with respiratory symptoms that impair their daily activities and quality of life. Understanding a treatment’s ability to relieve symptoms requires precise assessment. The Evaluating Respiratory Symptoms in COPD (E-RS^TM:COPD) was developed to quantify respiratory symptoms in clinical trials. This study aimed to better understand how trials use this patient-reported outcome measure as an endpoint, as well as its responsiveness and performance relative to other outcome measures.

OBJECTIVES: To summarize the use of the E-RS:COPD in pharmacological trials since its qualification by regulatory authorities.

METHODS: A rapid systematic literature review, using key biomedical databases to identify English language full-text publications of randomized controlled clinical trials (RCTs) that included the E-RS:COPD as an endpoint (2010-2020). Two investigators independently screened the publications and extracted data.

MEASUREMENTS AND MAIN RESULTS: Of 219 screened records, 28 publications were included, and data from 20 unique double-blind RCTs were synthesized. The E-RS:COPD was positioned as a primary or secondary endpoint in six publications (35%), and served as an exploratory or additional endpoint in 11 (65%). Statistically significant E-RS:COPD treatment effects versus placebo/comparator were found in 13 of the 14 publications reporting symptom results. E-RS:COPD effects corresponded well with other outcome measures (e.g., St. George’s Respiratory Questionnaire [SGRQ] and forced expiratory volume [FEV₁]). Two publications reported the number of responders.

CONCLUSIONS: E-RS:COPD is sensitive to treatment effects in clinical trials testing drug therapies. Presentation of trial results should include responder analyses to facilitate interpretation and application of results.

PMID:34614551 | DOI:10.15326/jcopdf.2021.0235

Respiration. 2021 Oct 6:1-10. doi: 10.1159/000519216. Online ahead of print.

ABSTRACT

BACKGROUND: Benign tracheal stenosis may relapse after management.

OBJECTIVES: This study aimed to assess the value of dyspnea and spirometry in detecting relapse of benign tracheal stenosis.

METHODS: Patients with benign tracheal stenosis were evaluated post-management, at regular follow-up and emergency visits, with the Medical Research Council (MRC) dyspnea scale, spirometry, and flexible bronchoscopy. Patient visits were categorized and compared, in terms of change in clinical and functional parameters, in 2 groups: visits with relapse (case group) and visits with no relapse (control group). The ability of the MRC dyspnea scale and spirometry to predict relapse was evaluated.

RESULTS: Thirty-five patients with benign tracheal stenosis were included. Mean follow-up duration was 3.2 years (standard deviation = 3.3). Spirometry data were analyzed from 43 relapse visits (23 patients) versus 90 nonrelapse visits. The MRC dyspnea score and most spirometric indices were associated with relapse. In the receiver operating characteristic analysis, forced expiratory volume in 1 s, forced expiratory flow when 25% of forced vital capacity has been expired, peak expiratory flow (PEF), and total peak flow were superior to the MRC dyspnea score in predicting relapse. Among spirometric indices, >10.8% of PEF reduction has been very sensitive and specific.

CONCLUSIONS: This study supports the role of dyspnea and spirometry in monitoring benign tracheal stenosis, with spirometry predicting relapse even in clinically stable patients. PEF being a very sensitive index has the additional advantage of being assessed by peak flow meter and could potentially be used for remote monitoring.

PMID:34614495 | DOI:10.1159/000519216

Diabetes Metab Res Rev. 2021 Oct 6:e3501. doi: 10.1002/dmrr.3501. Online ahead of print.

ABSTRACT

OBJECTIVES: Fulminant type 1 diabetes (FT1D) could present diabetes ketoacidosis (DKA) at early onset. It is crucial to identify FT1D from DKA manifestations in time at clinical practice. This study was aimed at investigating whether the fulminant index (FI), encompassing plasma glucose (PG) to glycated hemoglobin (HbA1c) ratio (PG/HbA1c), serum potassium ion (K⁺ ) to HbA1c ratio (K⁺ /HbA1c), and serum sodium ion (Na⁺ ) multiplied by HbA1c (Na⁺ *HbA1c), is a feasible indicator for early FT1D diagnosis.

METHODS: A total of 78 subjects were enrolled, including 40 FT1D patients and 38 non-FT1D patients with DKA. We utilized receiver operating characteristic (ROC) curve analysis to determine the FI cut-off values between FT1D and non-FT1D groups and examined efficacies of FI based on statistics.

RESULTS: ROC curve analyses showed that the maximum Youden’s index for PG/HbA1c bonding to a cut-off value of 4.389, with the sensitivity of 75.0% and specificity of 81.6% in identifying FT1D from DKA. And optimal K⁺ /HbA1c cut-off value was 0.728 with a sensitivity of 90.0% and specificity of 84.2%. For Na⁺ *HbA1c, the best cut-off value was 923.65, and its sensitivity and specificity were 85% and 73.7%, respectively.

CONCLUSIONS: These results suggested FI could work as a valid and convenient indicator for differentiating FT1D from initial DKA patients. FI (K⁺ /HbA1c) presented the best efficacy as an independent index. This article is protected by copyright. All rights reserved.

PMID:34614535 | DOI:10.1002/dmrr.3501

J Affect Disord. 2021 Sep 25;296:224-232. doi: 10.1016/j.jad.2021.09.060. Online ahead of print.

ABSTRACT

BACKGROUND: Previous research has indicated the association of perceived stress with mental health problems. In China, Confucian collectivism and an exam-centered culture encourage parents to have high educational expectations that impose great pressure on their children’s learning. However, limited research has focused on adolescents’ perceptions of the negative consequences of academic stress stemming from their parents’ educational expectations. This study addressed this research gap by examining the direct effect of adolescents’ perceptions of academic stress on their depressive symptoms and the indirect effects of both parent-child communication and interaction. We further explored the pathway differences between overweight and non-overweight adolescents.

METHODS: By using a sample (n = 6,566) from the first two waves of the China Education Panel Survey, moderated mediation analysis was performed to simultaneously analyze the mediating roles of parent-children communication and parent-children interaction and the moderating role of adolescent overweight status.

RESULTS: Adolescents’ perceived academic stress (W1) was positively associated with their depressive symptoms (W2). This association was partially mediated by both parent-child communication (W1) and parent-child interaction (W1). Moreover, adolescent overweight status significantly moderated the paths between the adolescents’ perceived academic stress and their depressive symptoms, between their perceived academic stress and parent-child interaction, and the indirect relationship via parent-child interaction.

LIMITATIONS: Some measurement biases including self-reported, unverified, and single-item measures, alongside not considering all variations in controlled variables should be noted.

CONCLUSION: The study’s findings identify the significant roles of parent-child communication and parent-children interaction in contemporary China and indicate overweight adolescents’ susceptibility to stress.

PMID:34614439 | DOI:10.1016/j.jad.2021.09.060

Photodiagnosis Photodyn Ther. 2021 Oct 3:102569. doi: 10.1016/j.pdpdt.2021.102569. Online ahead of print.

ABSTRACT

PURPOSE: To determine the effect of angiotensin-converting enzyme (ACE) inhibitors on choroidal vascularity using the binarization method in a group of treatment-naïve hypertensive patients.

METHODS: There were 48 treatment-naive hypertensive patients who were diagnosed according to the “2013 European Society of Hypertension/European Society of Cardiology” guideline and started angiotensin-converting enzyme inhibitor perindopril (Coversyl) in the study. As a control group, 48 healthy volunteers were randomly selected among people who attended the outpatient clinic for routine ophthalmological examination. Enhanced-depth imaging optical coherence tomography (EDI-OCT) images were captured at baseline and at 1 month after treatment. Binarization of the EDI-OCT images was performed by Image-J software. The choroidal thickness (CT), total choroidal area, luminal area, stromal area, and choroidal vascularity index (CVI) were measured.

RESULTS: There was a statistically significant increase in CT at all locations (subfoveal, nasal, and temporal) at 1 month after treatment compared with baseline (for all, p˂0.001). Choroidal structural parameters and the mean CVI were statistically significantly increased at 1 month after treatment (for all, p˂0.001). When compared, there was no statistically significant difference for the vascular parameters between the control group and the patient group at 1 month (for all, p>0.05).

CONLUSION: A statistically significant improvement was demonstrated in the choroidal vascular parameters except for the stromal area after treating with an ACE inhibitor in a group of hypertensive patients.

PMID:34614428 | DOI:10.1016/j.pdpdt.2021.102569

J Hepatobiliary Pancreat Sci. 2021 Oct 6. doi: 10.1002/jhbp.1054. Online ahead of print.

ABSTRACT

BACKGROUND: The prognostic implication of mutant KRAS (mKRAS) among patients with primary disease in the rectum remains unknown.

METHODS: From 2000 to 2018, patients undergoing hepatectomy for colorectal liver metastases at 10 collaborating international institutions with documented KRAS status were surveyed.

RESULTS: A total of 834 (65.8%) patients with primary colon cancer and 434 (34.2%) patients with primary rectal cancer were included. In patients with primary colon cancer, mKRAS served as a reliable prognostic biomarker of poor overall survival (OS) (hazard ratio (HR): 1.58, 95%CI 1.28-1.95) in the multivariable analysis. Although a trend towards significance was noted, mKRAS was not found to be an independent predictor of OS in patients with primary rectal tumors (HR 1.34, 95%CI 0.98-1.80). For colon cancer, the specific codon impacted in mKRAS appears to reflect underlying disease biology and oncologic outcomes, with codon 13 being associated with particularly poor OS in patients with left-sided tumors (codon 12, HR 1.56, 95%CI 1.22-1.99; codon 13, HR 2.10 95%CI 1.43-3.08;). Stratifying the rectal patient population by codon mutation did not confer prognostic significance following hepatectomy.

CONCLUSIONS: While the left-sided colonic disease is frequently grouped with rectal disease, our analysis suggests that there exist fundamental biologic differences that drive disparate outcomes. Although there was a trend toward significance of KRAS mutations for patients with primary rectal cancers, it failed to achieve statistical significance.

PMID:34614304 | DOI:10.1002/jhbp.1054

N Engl J Med. 2021 Oct 6. doi: 10.1056/NEJMoa2114114. Online ahead of print.

ABSTRACT

BACKGROUND: Waning of vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (Covid-19) is a concern. The persistence of BNT162b2 (Pfizer-BioNTech) vaccine effectiveness against infection and disease in Qatar, where the B.1.351 (or beta) and B.1.617.2 (or delta) variants have dominated incidence and polymerase-chain-reaction testing is done on a mass scale, is unclear.

METHODS: We used a matched test-negative, case-control study design to estimate vaccine effectiveness against any SARS-CoV-2 infection and against any severe, critical, or fatal case of Covid-19, from January 1 to September 5, 2021.

RESULTS: Estimated BNT162b2 effectiveness against any SARS-CoV-2 infection was negligible in the first 2 weeks after the first dose. It increased to 36.8% (95% confidence interval [CI], 33.2 to 40.2) in the third week after the first dose and reached its peak at 77.5% (95% CI, 76.4 to 78.6) in the first month after the second dose. Effectiveness declined gradually thereafter, with the decline accelerating after the fourth month to reach approximately 20% in months 5 through 7 after the second dose. Effectiveness against symptomatic infection was higher than effectiveness against asymptomatic infection but waned similarly. Variant-specific effectiveness waned in the same pattern. Effectiveness against any severe, critical, or fatal case of Covid-19 increased rapidly to 66.1% (95% CI, 56.8 to 73.5) by the third week after the first dose and reached 96% or higher in the first 2 months after the second dose; effectiveness persisted at approximately this level for 6 months.

CONCLUSIONS: BNT162b2-induced protection against SARS-COV-2 infection appeared to wane rapidly following its peak after the second dose, but protection against hospitalization and death persisted at a robust level for 6 months after the second dose. (Funded by Weill Cornell Medicine-Qatar and others.).

PMID:34614327 | DOI:10.1056/NEJMoa2114114