SRT1720 improves survival and healthspan of obese mice

Sirt1 is an NAD+-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals

SRT1720 improves survival and healthspan of obese mice

Sirt1 is an NAD1-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1a-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Kinetics of Reaction of Vanadium(V) with Some Oxalato Complexes of Chromium(III) & Cobalt(III)-Oxidation of Coordinated Oxalate

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Prognosis Communication in Late-Life Disability: A Mixed Methods Study.

ImportanceLong-term prognosis informs clinical and personal decisions for older adults with late-life disability. However, many clinicians worry that telling patients their prognosis may cause harm.ObjectiveTo explore the safety of and reactions to prognosis communication in late-life disability.DesignParticipants estimated their own life expectancy and were then presented their calculated life expectancy using a validated prognostic index. We used a semi-structured interview guide to ask for their reactions. Qualitative data were analyzed using constant comparative analysis. Potential psychological and behavioral outcomes in response to receiving one's calculated prognosis were recorded and re-assessed 2-4 weeks later.SettingCommunity-dwelling older adults age 70+ residing in the San Francisco Bay Area.ParticipantsThirty five older adults with a median age of 80 requiring assistance with ≥1 Activity of Daily Living.ResultsSelf-estimates of life expectancy were similar to calculated results for 16 participants. 15 estimated their life expectancy to be longer than their calculated life expectancy by &gt;2 years, while 4 shorter by &gt;2 years. An overarching theme of, "fitting life expectancy into one's narrative" emerged from qualitative analysis. Discussing life expectancy led participants to express how they could alter their life expectancy (subtheme "locus of control"), how they saw their present health (subtheme "perceived health"), and their hopes and fears for the remaining years of their lives (subtheme "outlook on remaining years"). Feelings of anxiety and sadness in reaction to receiving calculated prognosis were rare.Conclusions and relevanceAbout half of the disabled older adults' self-estimates of prognosis were similar to calculated estimates. Evidence of sadness or anxiety was rare. These data suggest that in most cases, clinicians may offer to discuss prognosis

Vaccine Effectiveness against Symptomatic SARS-CoV-2 Infection in Adults Aged 65 Years and Older in Primary Care: I-MOVE-COVID-19 Project, Europe, December 2020 to May 2021

International audienceWe measured COVID-19 vaccine effectiveness (VE) against symptomatic SARS-CoV-2 infection at primary care/outpatient level among adults ≥q 65 years old using a multicentre test-negative design in eight European countries. We included 592 SARS-CoV-2 cases and 4,372 test-negative controls in the main analysis. The VE was 62% (95% CI: 45\textendash 74) for one dose only and 89% (95% CI: 79\textendash 94) for complete vaccination. COVID-19 vaccines provide good protection against COVID-19 presentation at primary care/outpatient level, particularly among fully vaccinated individuals

Effectiveness of complete primary vaccination against COVID-19 at primary care and community level during predominant Delta circulation in Europe: multicentre study analysis by age-group, vaccine brand and time since vaccination, I-MOVE-COVID-19 and ECDC networks, July–August 2021

Introduction In July and August 2021, the SARS-CoV-2 Delta variant dominated in Europe. We measured COVID-19 vaccine effectiveness (VE) against symptomatic infection, using a multicentre test-negative study at primary care/community level in Europe. Methods Patients presenting with COVID-19/ARI symptoms at primary care/community level in 10 countries were tested for SARS-CoV-2. We measured complete primary course overall VE among those aged 30–44, 45–59, 60–74 and ≥75 years, and among those 30–59 and ≥60 years by vaccine brand and by time since vaccination. Results Overall VE was 74% (95%CI: 69–79), 76% (95%CI: 71–80), 63% (95%CI: 48–75), 63% (95%CI: 16–83) among those aged 30–44, 45–59, 60–74 and ≥75 years, respectively. VE among those aged 30–59 years was 78% (95%CI: 75–81), 66% (95%CI: 58–73), 91% (95%CI: 87–94) and 52% (95%CI: 40–61), for Comirnaty, Vaxzevria, Spikevax and COVID-19 Vaccine Janssen, respectively. VE among those aged ≥60 years was 67% (95%CI: 52–77), 65% (95%CI: 48–76), 83% (95%CI: 64–92) for Comirnaty, Vaxzevria and Spikevax, respectively. Comirnaty VE among those aged 30–59 years was 87% (95%CI: 83–89) and 65% (95%CI: 56–71%) at 14–29 days and ≥90 days between vaccination and onset of symptoms, respectively. Conclusions VE against the symptomatic SARS-CoV-2 Delta variant infection varied among brands, ranging from 52–91%. While some waning of the vaccine effect may be present (sample size limited this analysis to only Comirnaty), protection was 65% ≥90 days between vaccination and onset