Systematic review and meta-analysis of prevalence, trajectories, and clinical outcomes for frailty in COPD

This systematic review synthesised measurement and prevalence of frailty in COPD and associations between frailty and adverse health outcomes. We searched Medline, Embase and Web of Science (1 January 2001–8 September 2021) for observational studies in adults with COPD assessing frailty prevalence, trajectories, or association with health-related outcomes. We performed narrative synthesis and random-effects meta-analyses. We found 53 eligible studies using 11 different frailty measures. Most common were frailty phenotype (n = 32), frailty index (n = 5) and Kihon checklist (n = 4). Prevalence estimates varied by frailty definitions, setting, and age (2.6–80.9%). Frailty was associated with mortality (5/7 studies), COPD exacerbation (7/11), hospitalisation (3/4), airflow obstruction (11/14), dyspnoea (15/16), COPD severity (10/12), poorer quality of life (3/4) and disability (1/1). In conclusion, frailty is a common among people with COPD and associated with increased risk of adverse outcomes. Proactive identification of frailty may aid risk stratification and identify candidates for targeted intervention

Identifying frailty in trials: an analysis of individual participant data from trials of novel pharmacological interventions

Background: Frailty is common in clinical practice, but trials rarely report on participant frailty. Consequently, clinicians and guideline-developers assume frailty is largely absent from trials and have questioned the relevance of trial findings to frail people. Therefore, we examined frailty in phase 3/4 industry-sponsored clinical trials of pharmacological interventions for three exemplar conditions: type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD). Methods: We constructed a 40-item frailty index (FI) in 19 clinical trials (7 T2DM, 8 RA, 4 COPD, mean age 42–65 years) using individual-level participant data. Participants with a FI > 0.24 were considered ‘frail’. Baseline disease severity was assessed using HbA1c for T2DM, Disease Activity Score-28 (DAS28) for RA, and % predicted FEV1 for COPD. Using generalised gamma regression, we modelled FI on age, sex, and disease severity. In negative binomial regression, we modelled serious adverse event rates on FI and combined results for each index condition in a random-effects meta-analysis. Results: All trials included frail participants: prevalence 7–21% in T2DM trials, 33–73% in RA trials, and 15–22% in COPD trials. The 99th centile of the FI ranged between 0.35 and 0.45. Female sex was associated with higher FI in all trials. Increased disease severity was associated with higher FI in RA and COPD, but not T2DM. Frailty was associated with age in T2DM and RA trials, but not in COPD. Across all trials, and after adjusting for age, sex, and disease severity, higher FI predicted increased risk of serious adverse events; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21–1.75), 1.45 (1.13–1.87), and 1.99 (1.43–2.76) for T2DM, RA, and COPD, respectively. Conclusion: The upper limit of frailty in trials is lower than has been described in the general population. However, mild to moderate frailty was common, suggesting trial data may be harnessed to inform disease management in people living with frailty. Participants with higher FI experienced more serious adverse events, suggesting screening for frailty in trial participants would enable identification of those that merit closer monitoring. Frailty is identifiable and prevalent among middle-aged and older participants in phase 3/4 drug trials and has clinically important safety implications

Frailty in randomised controlled trials for dementia or mild cognitive impairment measured via the frailty index: prevalence and prediction of serious adverse events and attrition

Background: Frailty and dementia have a bidirectional relationship. However, frailty is rarely reported in clinical trials for dementia and mild cognitive impairment (MCI) which limits assessment of trial applicability. This study aimed to use a frailty index (FI)—a cumulative deficit model of frailty—to measure frailty using individual participant data (IPD) from clinical trials for MCI and dementia. Moreover, the study aimed to quantify the prevalence of frailty and its association with serious adverse events (SAEs) and trial attrition. Methods: We analysed IPD from dementia (n = 1) and MCI (n = 2) trials. An FI comprising physical deficits was created for each trial using baseline IPD. Poisson and logistic regression were used to examine associations with SAEs and attrition, respectively. Estimates were pooled in random effects meta-analysis. Analyses were repeated using an FI incorporating cognitive as well as physical deficits, and results compared. Results: Frailty could be estimated in all trial participants. The mean physical FI was 0.14 (SD 0.06) and 0.14 (SD 0.06) in the MCI trials and 0.24 (SD 0.08) in the dementia trial. Frailty prevalence (FI > 0.24) was 6.9%/7.6% in MCI trials and 48.6% in the dementia trial. After including cognitive deficits, the prevalence was similar in MCI (6.1% and 6.7%) but higher in dementia (75.4%). The 99th percentile of FI (0.31 and 0.30 in MCI, 0.44 in dementia) was lower than in most general population studies. Frailty was associated with SAEs: physical FI IRR = 1.60 [1.40, 1.82]; physical/cognitive FI IRR = 1.64 [1.42, 1.88]. In a meta-analysis of all three trials, the estimated association between frailty and trial attrition included the null (physical FI OR = 1.17 [0.92, 1.48]; physical/cognitive FI OR = 1.16 [0.92, 1.46]), although higher frailty index values were associated with attrition in the dementia trial. Conclusion: Measuring frailty from baseline IPD in dementia and MCI trials is feasible. Those living with more severe frailty may be under-represented. Frailty is associated with SAEs. Including only physical deficits may underestimate frailty in dementia. Frailty can and should be measured in future and existing trials for dementia and MCI, and efforts should be made to facilitate inclusion of people living with frailty

Demonstration of the multimaterial coating concept to reduce thermal noise in gravitational-wave detectors

Thermal noise associated with the mechanical loss of current highly reflective mirror coatings is a critical limit to the sensitivity of gravitational-wave detectors. Several alternative coating materials show potential for reducing thermal noise, but cannot be used due to their high optical absorption. Multimaterial coatings have been proposed to enable the use of such materials to reduce thermal noise while minimizing their impact on the total absorption of the mirror coating. Here we present experimental verification of the multimaterial concept, by integrating aSi into a highly reflective SiO2 and Ta2O5 multilayer coating. We show a significant thermal noise improvement and demonstrate consistent optical and mechanical performance. The multimaterial coating survives the heat treatment required to minimize the absorption of the aSi layers, with no adverse effects from the different thermomechanical properties of the three materials

Associations between multimorbidity and adverse health outcomes in UK Biobank and the SAIL Databank: a comparison of longitudinal cohort studies

Background: Cohorts such as UK Biobank are increasingly used to study multimorbidity; however, there are concerns that lack of representativeness may lead to biased results. This study aims to compare associations between multimorbidity and adverse health outcomes in UK Biobank and a nationally representative sample. Methods and findings: These are observational analyses of cohorts identified from linked routine healthcare data from UK Biobank participants (n = 211,597 from England, Scotland, and Wales with linked primary care data, age 40 to 70, mean age 56.5 years, 54.6% women, baseline assessment 2006 to 2010) and from the Secure Anonymised Information Linkage (SAIL) databank (n = 852,055 from Wales, age 40 to 70, mean age 54.2, 50.0% women, baseline January 2011). Multimorbidity (n = 40 long-term conditions [LTCs]) was identified from primary care Read codes and quantified using a simple count and a weighted score. Individual LTCs and LTC combinations were also assessed. Associations with all-cause mortality, unscheduled hospitalisation, and major adverse cardiovascular events (MACEs) were assessed using Weibull or negative binomial models adjusted for age, sex, and socioeconomic status, over 7.5 years follow-up for both datasets. Multimorbidity was less common in UK Biobank than SAIL (26.9% and 33.0% with ≥2 LTCs in UK Biobank and SAIL, respectively). This difference was attenuated, but persisted, after standardising by age, sex, and socioeconomic status. The association between increasing multimorbidity count and mortality, hospitalisation, and MACE was similar between both datasets at LTC counts of ≤3; however, above this level, UK Biobank underestimated the risk associated with multimorbidity (e.g., mortality hazard ratio for 2 LTCs 1.62 (95% confidence interval 1.57 to 1.68) in SAIL and 1.51 (1.43 to 1.59) in UK Biobank, hazard ratio for 5 LTCs was 3.46 (3.31 to 3.61) in SAIL and 2.88 (2.63 to 3.15) in UK Biobank). Absolute risk of mortality, hospitalisation, and MACE, at all levels of multimorbidity, was lower in UK Biobank than SAIL (adjusting for age, sex, and socioeconomic status). Both cohorts produced similar hazard ratios for some LTCs (e.g., hypertension and coronary heart disease), but UK Biobank underestimated the risk for others (e.g., alcohol-related disorders or mental health conditions). Hazard ratios for some LTC combinations were similar between the cohorts (e.g., cardiovascular conditions); however, UK Biobank underestimated the risk for combinations including other conditions (e.g., mental health conditions). The main limitations are that SAIL databank represents only part of the UK (Wales only) and that in both cohorts we lacked data on severity of the LTCs included. Conclusions: In this study, we observed that UK Biobank accurately estimates relative risk of mortality, unscheduled hospitalisation, and MACE associated with LTC counts ≤3. However, for counts ≥4, and for some LTC combinations, estimates of magnitude of association from UK Biobank are likely to be conservative. Researchers should be mindful of these limitations of UK Biobank when conducting and interpreting analyses of multimorbidity. Nonetheless, the richness of data available in UK Biobank does offers opportunities to better understand multimorbidity, particularly where complementary data sources less susceptible to selection bias can be used to inform and qualify analyses of UK Biobank

Frailty measurement, prevalence, incidence, and clinical implications in people with diabetes: a systematic review and study-level meta-analysis

Background: Frailty, a state of increased vulnerability to adverse health outcomes, is important in diabetes management. We aimed to quantify the prevalence of frailty in people with diabetes, and to summarise the association between frailty and generic outcomes (eg, mortality) and diabetes-specific outcomes (eg, hypoglycaemia). Methods: In this systematic review and study-level meta-analysis, we searched MEDLINE, Embase, and Web of Science for observational studies published between Jan 1, 2001 (the year of the original publication of the Fried frailty phenotype), to Nov 26, 2019. We included studies that assessed and quantified frailty in adults with diabetes, aged 18 years and older; and excluded conference abstracts, grey literature, and studies not published in English. Data from eligible studies were extracted using a piloted data extraction form. Our primary outcome was the prevalence of frailty in people with diabetes. Secondary outcomes were incidence of frailty and generic and diabetes-specific outcomes. Data were assessed by random-effects meta-analysis where possible and by narrative synthesis where populations were too heterogeneous to allow meta-analysis. This study is registered with PROSPERO, CRD42020163109. Findings: Of the 3038 studies we identified, 118 studies using 20 different frailty measures were eligible for inclusion (n=1 375 373). The most commonly used measures of frailty were the frailty phenotype (69 [58%] of 118 studies), frailty (16 [14%]), and FRAIL scale (10 [8%]). Studies were heterogenous in setting (88 studies were community-based, 18 were outpatient-based, ten were inpatient-based, and two were based in residential care facilities), demographics, and inclusion criteria; therefore, we could not do a meta-analysis for the primary outcome and instead summarised prevalence data using a narrative synthesis. Median community frailty prevalence using frailty phenotype was 13% (IQR 9–21). Frailty was consistently associated with mortality in 13 (93%) of 14 studies assessing this outcome (pooled hazard ratio 1·51 [95% CI 1·30–1·76]), with hospital admission in seven (100%) of seven, and with disability in five (100%) of five studies. Frailty was associated with hypoglycaemia events in one study (<1%), microvascular and macrovascular complications in nine (82%) of 11 studies assessing complications, lower quality of life in three (100%) of three studies assessing quality of life, and cognitive impairment in three (100%) of three studies assessing cognitive impairment. 13 (11%) of 118 studies assessed glycated haemoglobin finding no consistent relationship with frailty. Interpretation: The identification and assessment of frailty should become a routine aspect of diabetes care. The relationship between frailty and glycaemia, and the effect of frailty in specific groups (eg, middle-aged [aged <65 years] people and people in low-income and lower-middle-income countries) needs to be better understood to enable diabetes guidelines to be tailored to individuals with frailty

The identification and prevalence of frailty in diabetes mellitus and association with clinical outcomes: a systematic review protocol

INTRODUCTION:Diabetes mellitus is common and growing in prevalence, and an increasing proportion of people with diabetes are living to older age. Frailty is, therefore, becoming an important concept in diabetes. Frailty is associated with older age and describes a state of increased susceptibility to decompensation in response to physiological stress. A range of measures have been used to quantify frailty. This systematic review aims to identify measures used to quantify frailty in people with diabetes (any type); to summarise the prevalence of frailty in diabetes; and to describe the relationship between frailty and adverse clinical outcomes in people with diabetes. METHODS AND ANALYSIS:Three electronic databases (Medline, Embase and Web of Science) will be searched from 2000 to November 2019 and supplemented by citation searching of relevant articles and hand searching of reference lists. Two reviewers will independently review titles, abstracts and full texts. Inclusion criteria include: (1) adults with any type of diabetes mellitus; (2) quantify frailty using any validated frailty measure; (3) report the prevalence of frailty and/or the association between frailty and clinical outcomes in people with diabetes; (4) studies that assess generic (eg, mortality, hospital admission and falls) or diabetes-specific outcomes (eg, hypoglycaemic episodes, cardiovascular events, diabetic nephropathy and diabetic retinopathy); (5) cross-sectional and longitudinal observational studies. Study quality will be assessed using the Newcastle-Ottawa Scale for observational studies. Clinical and methodological heterogeneity will be assessed, and a random effects meta-analysis performed if appropriate. Otherwise, a narrative synthesis will be performed. ETHICS AND DISSEMINATION:This manuscript describes the protocol for a systematic review of observational studies and does not require ethical approval. PROSPERO REGISTRATION NUMBER:CRD42020163109

Effect of vaccination on transmission of SARS-CoV-2

No abstract available

Quasi-monocrystalline silicon for low-noise end mirrors in cryogenic gravitational-wave detectors

Mirrors made of silicon have been proposed for use in future cryogenic gravitational-wave detectors, which will be significantly more sensitive than current room-temperature detectors. These mirrors are planned to have diameters of ≈50 cm and a mass of ≈200 kg. While single-crystalline float-zone silicon meets the requirements of low optical absorption and low mechanical loss, the production of this type of material is restricted to sizes much smaller than required. Here we present studies of silicon produced by directional solidification. This material can be grown as quasi-monocrystalline ingots in sizes larger than currently required. We present measurements of a low room-temperature and cryogenic mechanical loss comparable with float-zone silicon. While the optical absorption of our test sample is significantly higher than required, the low mechanical loss motivates research into further absorption reduction in the future. While it is unclear if material pure enough for the transmissive detector input mirrors can be achieved, an absorption level suitable for the highly reflective coated end mirrors seems realistic. Together with the potential to produce samples much larger than ≈50 cm, this material may be of great benefit for realizing silicon-based gravitational-wave detectors

Frailty in people with rheumatoid arthritis: a systematic review of observational studies

Background: Frailty, an age-related decline in physiological reserve, is an increasingly important concept in the management of chronic diseases. The implications of frailty in people with rheumatoid arthritis are not well understood. We undertook a systematic review to assess the prevalence of frailty in people with rheumatoid arthritis, and the relationship between frailty and clinical outcomes. Methods: We searched three electronic databases (January 2001 to April 2021) for observational studies assessing the prevalence of frailty in adults (≥18 years) with rheumatoid arthritis, or analysing the relationship between frailty and clinical outcomes in the context of rheumatoid arthritis. Titles, abstracts and full texts were assessed independently by two reviewers. Study quality was assessed using an adapted Newcastle-Ottawa Scale. Results: We identified 17 analyses, from 14 different sample populations. 15/17 were cross-sectional. These studies used 11 different measures of frailty. Frailty prevalence ranged from 10% (frailty phenotype) to 36% (comprehensive rheumatologic assessment of frailty) in general adult populations with rheumatoid arthritis. In younger populations (<60 or <65 years) prevalence ranged from 2.4% (frailty phenotype) to 19.9% (Kihon checklist) while in older populations (>60 or >65) prevalence ranged from 31.2% (Kihon checklist) to 55% (Geriatric 8 tool). Frailty was associated with higher disease activity (10/10 studies), lower physical function (7/7 studies), longer disease duration (2/5 studies), hospitalization (1/1 study) and osteoporotic fractures (1/1 study). Conclusion: Our review found that frailty is common in adults with rheumatoid arthritis, including those aged <65 years, and is associated with a range of adverse features. However, these is substantial heterogeneity in how frailty is measured in rheumatoid arthritis. We found a lack of longitudinal studies making the impact of frailty on clinical outcomes over time and the extent to which frailty is caused by rheumatoid arthritis unclear