The B.1.617.2 (delta) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has contributed to a surge in cases in ...India and has now been detected across the globe, including a notable increase in cases in the United Kingdom. The effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against this variant has been unclear.
We used a test-negative case-control design to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) over the period that the delta variant began circulating. Variants were identified with the use of sequencing and on the basis of the spike (
) gene status. Data on all symptomatic sequenced cases of Covid-19 in England were used to estimate the proportion of cases with either variant according to the patients' vaccination status.
Effectiveness after one dose of vaccine (BNT162b2 or ChAdOx1 nCoV-19) was notably lower among persons with the delta variant (30.7%; 95% confidence interval CI, 25.2 to 35.7) than among those with the alpha variant (48.7%; 95% CI, 45.5 to 51.7); the results were similar for both vaccines. With the BNT162b2 vaccine, the effectiveness of two doses was 93.7% (95% CI, 91.6 to 95.3) among persons with the alpha variant and 88.0% (95% CI, 85.3 to 90.1) among those with the delta variant. With the ChAdOx1 nCoV-19 vaccine, the effectiveness of two doses was 74.5% (95% CI, 68.4 to 79.4) among persons with the alpha variant and 67.0% (95% CI, 61.3 to 71.8) among those with the delta variant.
Only modest differences in vaccine effectiveness were noted with the delta variant as compared with the alpha variant after the receipt of two vaccine doses. Absolute differences in vaccine effectiveness were more marked after the receipt of the first dose. This finding would support efforts to maximize vaccine uptake with two doses among vulnerable populations. (Funded by Public Health England.).
Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), have been used since December 2020 in the United Kingdom. ...Real-world data have shown the vaccines to be highly effective against Covid-19 and related severe disease and death. Vaccine effectiveness may wane over time since the receipt of the second dose of the ChAdOx1-S (ChAdOx1 nCoV-19) and BNT162b2 vaccines.
We used a test-negative case-control design to estimate vaccine effectiveness against symptomatic Covid-19 and related hospitalization and death in England. Effectiveness of the ChAdOx1-S and BNT162b2 vaccines was assessed according to participant age and status with regard to coexisting conditions and over time since receipt of the second vaccine dose to investigate waning of effectiveness separately for the B.1.1.7 (alpha) and B.1.617.2 (delta) variants.
Vaccine effectiveness against symptomatic Covid-19 with the delta variant peaked in the early weeks after receipt of the second dose and then decreased by 20 weeks to 44.3% (95% confidence interval CI, 43.2 to 45.4) with the ChAdOx1-S vaccine and to 66.3% (95% CI, 65.7 to 66.9) with the BNT162b2 vaccine. Waning of vaccine effectiveness was greater in persons 65 years of age or older than in those 40 to 64 years of age. At 20 weeks or more after vaccination, vaccine effectiveness decreased less against both hospitalization, to 80.0% (95% CI, 76.8 to 82.7) with the ChAdOx1-S vaccine and 91.7% (95% CI, 90.2 to 93.0) with the BNT162b2 vaccine, and death, to 84.8% (95% CI, 76.2 to 90.3) and 91.9% (95% CI, 88.5 to 94.3), respectively. Greater waning in vaccine effectiveness against hospitalization was observed in persons 65 years of age or older in a clinically extremely vulnerable group and in persons 40 to 64 years of age with underlying medical conditions than in healthy adults.
We observed limited waning in vaccine effectiveness against Covid-19-related hospitalization and death at 20 weeks or more after vaccination with two doses of the ChAdOx1-S or BNT162b2 vaccine. Waning was greater in older adults and in those in a clinical risk group.
Targeting social isolation in older people is a growing public health concern. The proportion of older people in society has increased in recent decades, and it is estimated that approximately 25% of ...the population will be aged 60 or above within the next 20 to 40 years. Social isolation is prevalent amongst older people and evidence indicates the detrimental effect that it can have on health and wellbeing. The aim of this review was to assess the effectiveness of interventions designed to alleviate social isolation and loneliness in older people.
Relevant electronic databases (MEDLINE, EMBASE, ASSIA, IBSS, PsycINFO, PubMed, DARE, Social Care Online, the Cochrane Library and CINAHL) were systematically searched using an extensive search strategy, for randomised controlled trials and quasi-experimental studies published in English before May 2009. Additional articles were identified through citation tracking. Studies were included if they related to older people, if the intervention aimed to alleviate social isolation and loneliness, if intervention participants were compared against inactive controls and, if treatment effects were reported. Two independent reviewers extracted data using a standardised form. Narrative synthesis and vote-counting methods were used to summarise and interpret study data.
Thirty two studies were included in the review. There was evidence of substantial heterogeneity in the interventions delivered and the overall quality of included studies indicated a medium to high risk of bias. Across the three domains of social, mental and physical health, 79% of group-based interventions and 55% of one-to-one interventions reported at least one improved participant outcome. Over 80% of participatory interventions produced beneficial effects across the same domains, compared with 44% of those categorised as non-participatory. Of interventions categorised as having a theoretical basis, 87% reported beneficial effects across the three domains compared with 59% of interventions with no evident theoretical foundation. Regarding intervention type, 86% of those providing activities and 80% of those providing support resulted in improved participant outcomes, compared with 60% of home visiting and 25% of internet training interventions. Fifty eight percent of interventions that explicitly targeted socially isolated or lonely older people reported positive outcomes, compared with 80% of studies with no explicit targeting.
More, well-conducted studies of the effectiveness of social interventions for alleviating social isolation are needed to improve the evidence base. However, it appeared that common characteristics of effective interventions were those developed within the context of a theoretical basis, and those offering social activity and/or support within a group format. Interventions in which older people are active participants also appeared more likely to be effective. Future interventions incorporating all of these characteristics may therefore be more successful in targeting social isolation in older people.
The objectives of the present study were to evaluate the impact of a single bout of high-intensity aerobic exercise on 1) long-term potentiation (LTP)-like neuroplasticity via response to paired ...associative stimulation (PAS) and 2) the temporal and spatial components of sequence-specific implicit motor learning. Additionally, relationships between exercise-induced increases in systemic brain-derived neurotrophic factor (BDNF) and response to PAS and motor learning were evaluated. Sixteen young healthy participants completed six experimental sessions, including the following: 1) rest followed by PAS; 2) aerobic exercise followed by PAS; 3) rest followed by practice of a continuous tracking (CT) task and 4) a no-exercise 24-h retention test; and 5) aerobic exercise followed by CT task practice and 6) a no-exercise 24-h retention test. The CT task included an embedded repeated sequence allowing for evaluation of sequence-specific implicit learning. Slope of motor-evoked potential recruitment curves generated with transcranial magnetic stimulation showed larger increases when PAS was preceded by aerobic exercise (59.8% increase) compared with rest (14.2% increase, P = 0.02). Time lag of CT task performance on the repeated sequence improved under the aerobic exercise condition from early (-100.8 ms) to late practice (-75.2 ms, P < 0.001) and was maintained at retention (-79.2 ms, P = 0.004) but did not change under the rest condition (P > 0.16). Systemic BDNF increased on average by 3.4-fold following aerobic exercise (P = 0.003), but the changes did not relate to neurophysiological or behavioral measures (P > 0.42). These results indicate that a single bout of high-intensity aerobic exercise can prime LTP-like neuroplasticity and promote sequence-specific implicit motor learning.
Enzymes must be ordered to allow the stabilization of transition states by their active sites, yet dynamic enough to adopt alternative conformations suited to other steps in their catalytic cycles. ...The biophysical principles that determine how specific protein dynamics evolve and how remote mutations affect catalytic activity are poorly understood. Here we examine a 'molecular fossil record' that was recently obtained during the laboratory evolution of a phosphotriesterase from Pseudomonas diminuta to an arylesterase. Analysis of the structures and dynamics of nine protein variants along this trajectory, and three rationally designed variants, reveals cycles of structural destabilization and repair, evolutionary pressure to 'freeze out' unproductive motions and sampling of distinct conformations with specific catalytic properties in bi-functional intermediates. This work establishes that changes to the conformational landscapes of proteins are an essential aspect of molecular evolution and that change in function can be achieved through enrichment of preexisting conformational sub-states.
•Laboratory directed evolution and ancestral reconstruction can facilitate study of protein structural dynamics.•Advances in biophysical and computational techniques facilitate this ...investigation.•Conformational dynamism is valuable in the acquisition of new function, as multiple potentially productive conformations can be sampled.•Evolution ‘freezes out’ unproductive motions, reducing unnecessary dynamics.
This review focuses on recent work that has begun to establish specific functional roles for protein conformational dynamics, specifically how the conformational landscapes that proteins can sample can evolve under laboratory based evolutionary selection. We discuss recent technical advances in computational and biophysical chemistry, which have provided us with new ways to dissect evolutionary processes. Finally, we offer some perspectives on the emerging view of conformational dynamics and evolution, and the challenges that we face in rationally engineering conformational dynamics.
Sodium-glucose cotransporter 2 inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, ...their effects on cardiac structure and function in HFrEF are uncertain.
We designed a multicenter, randomized, double-blind, placebo-controlled trial (the SUGAR-DM-HF trial Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus, or Prediabetes, and Heart Failure) to investigate the cardiac effects of empagliflozin in patients in New York Heart Association functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomly assigned 1:1 to empagliflozin 10 mg once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The coprimary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area and LV global longitudinal strain both measured using cardiovascular magnetic resonance. Secondary efficacy outcomes included other cardiovascular magnetic resonance measures (LV end-diastolic volume index, LV ejection fraction), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, B-lines on lung ultrasound, and biomarkers (including N-terminal pro-B-type natriuretic peptide).
From April 2018 to August 2019, 105 patients were randomly assigned: mean age 68.7 (SD, 11.1) years, 77 (73.3%) male, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LV ejection fraction 32.5% (9.8%), and 81 (77.1%) New York Heart Association II and 24 (22.9%) New York Heart Association III. Patients received standard treatment for HFrEF. In comparison with placebo, empagliflozin reduced LV end-systolic volume index by 6.0 (95% CI, -10.8 to -1.2) mL/m
(
=0.015). There was no difference in LV global longitudinal strain. Empagliflozin reduced LV end-diastolic volume index by 8.2 (95% CI, -13.7 to -2.6) mL/m
(
=0.0042) and reduced N-terminal pro-B-type natriuretic peptide by 28% (2%-47%),
=0.038. There were no between-group differences in other cardiovascular magnetic resonance measures, diuretic intensification, Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, or B-lines.
The sodium-glucose cotransporter 2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which sodium-glucose cotransporter 2 inhibitors reduce heart failure hospitalization and mortality in HFrEF. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03485092.
Development of wearable sensing platforms is essential for the advancement of continuous health monitoring and point-of-care testing. Eccrine sweat pH is an analyte that can be noninvasively measured ...and used to diagnose and aid in monitoring a wide range of physiological conditions. Surface-enhanced Raman scattering (SERS) offers a rapid, optical technique for fingerprinting of biomarkers present in sweat. In this paper, a mechanically flexible, nanofibrous, SERS-active substrate was fabricated by a combination of electrospinning of thermoplastic polyurethane (TPU) and Au sputter coating. This substrate was then investigated for suitability toward wearable sweat pH sensing after functionalization with two commonly used pH-responsive molecules, 4-mercaptobenzoic acid (4-MBA), and 4-mercaptopyridine (4-MPy). The developed SERS pH sensor was found to have good resolution (0.14 pH units for 4-MBA; 0.51 pH units for 4-MPy), with only 1 μL of sweat required for a measurement, and displayed no statistically significant difference in performance after 35 days (
= 0.361). Additionally, the Au/TPU nanofibrous SERS pH sensors showed fast sweat-absorbing ability as well as good repeatability and reversibility. The proposed methodology offers a facile route for the fabrication of SERS substrates which could also be used to measure a wide range of health biomarkers beyond sweat pH.
Purpose To investigate for socially isolated older people, and older people at risk of social isolation: (1) health status and health-related quality of life (HRQL); (2) the relationship between ...social isolation and health status/HRQL; (3) the relationship between two alternative measures of health status/HRQL. Methods Older people at risk of social isolation (n = 393) completed the EQ-5D and the SF-12. Multiple regression analyses were performed to examine the relationship between levels of social isolation and health status/HRQL, controlling for demographic/clinical characteristics. The agreement between EQ-5D and SF-6D (SF-12) scores was explored using descriptive psychometric techniques. Results Health status and health state values were much lower than UK general population age-matched norms. After controlling for depression, physical co-morbidities, age, gender, living alone status, employment and accommodation, social isolation was significantly associated, to a degree that was clinically relevant, with EQ-5D DSI, SF-6D (SF-12) and SF-12 MCS scores. The potential for ceiling effects on the EQ-5D with this population was identified. Conclusion This work highlights the burden that social isolation may have on the health and well-being of older people. The potential HRQL gains from addressing social isolation may be considerable, with those at risk of social isolation also a key target group.
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