Patient-reported satisfaction with thyroid hormone replacement therapy for subclinical hypothyroidism in older adults: A pooled analysis of individual participant data from two randomized controlled trials.

Background The benefit of levothyroxine treatment of subclinical hypothyroidism (SCH) is subject to debate. This study compared treatment satisfaction between older adults with SCH using levothyroxine or placebo. Methods We analyzed pooled individual participant data from two randomized, double-blind, placebo-controlled trials investigating the effects of levothyroxine treatment in older adults with SCH. Community-dwelling participants aged ≥65 years, with SCH (persistent thyrotropin levels 4.60-19.99 mIU/L for >3 months and normal free thyroxine level) were included. Intervention: dose titration until thyrotropin levels normalized, with a mock dose adjustment of placebo. Treatment satisfaction was determined during the final study visit using the Treatment Satisfaction Questionnaire for Medication (TSQM), encompassing perceived effectiveness, side effects, convenience, and global satisfaction, along with the participants' desire to continue study medication after the trial. Results We included 536 participants. At baseline, the median (IQR) age was 74.9 (69.7-81.4) years, and 292 (55%) were women. The median (IQR) thyrotropin levels were 5.80 (5.10-7.00) mIU/L at baseline in both groups; at final visit 4.97 (3.90-6.35) mIU/L in the placebo and 3.24 (2.49-4.41) mIU/L in the levothyroxine group. After treatment, the groups did not differ significantly in global satisfaction (mean difference [95%CI]: -1.1 [-4.5-2.1], p=0.48), nor in any other domain of treatment satisfaction. These results held true regardless of baseline thyrotropin levels or symptom burden. No major differences were found in the numbers of participants who wished to continue medication after the trial (levothyroxine 35% vs placebo 27%), did not wish to continue (levothyroxine 27% vs placebo 30%), or did not know (levothyroxine 37% vs placebo 42%)(p=0.14). In a subpopulation with high symptom burden from hypothyroid symptoms at baseline, those using levothyroxine more often desired to continue the medication after the trial than those using placebo (mean difference [95% CI] -21.1% [-35.6% to -6.5%]). Conclusion These pooled data from two RCTs, showed no major differences in treatment satisfaction between older adults receiving levothyroxine or placebo. This finding has important implications for decision-making regarding initiating levothyroxine treatment for SCH. Our findings generally support refraining from routinely prescribing levothyroxine in older adults with SCH. Clinical Trial Registration ClinicalTrials.gov: NCT01660126; Netherlands Trial Register: NL3641.

Evaluating the effect of inequalities in oral anti-coagulant prescribing on outcomes in people with atrial fibrillation.

Aims: Whilst anti-coagulation is typically recommended for thromboprophylaxis in atrial fibrillation (AF), it is often never prescribed or prematurely discontinued. The aim of this study was to evaluate the effect of inequalities in anti-coagulant prescribing by assessing stroke/systemic embolism (SSE) and bleeding risk in people with AF who continue anti-coagulation compared with those who stop transiently, permanently, or never start. Methods and results: This retrospective cohort study utilized linked Scottish healthcare data to identify adults diagnosed with AF between January 2010 and April 2016, with a CHA2DS2-VASC score of ≥2. They were sub-categorized based on anti-coagulant exposure: never started, continuous, discontinuous, and cessation. Inverse probability of treatment weighting-adjusted Cox regression and competing risk regression was utilized to compare SSE and bleeding risks between cohorts during 5-year follow-up. Of an overall cohort of 47 427 people, 26 277 (55.41%) were never anti-coagulated, 7934 (16.72%) received continuous anti-coagulation, 9107 (19.2%) temporarily discontinued, and 4109 (8.66%) permanently discontinued. Lower socio-economic status, elevated frailty score, and age ≥ 75 were associated with a reduced likelihood of initiation and continuation of anti-coagulation. Stroke/systemic embolism risk was significantly greater in those with discontinuous anti-coagulation, compared with continuous [subhazard ratio (SHR): 2.65; 2.39-2.94]. In the context of a major bleeding event, there was no significant difference in bleeding risk between the cessation and continuous cohorts (SHR 0.94; 0.42-2.14). Conclusion: Our data suggest significant inequalities in anti-coagulation prescribing, with substantial opportunity to improve initiation and continuation. Decision-making should be patient-centred and must recognize that discontinuation or cessation is associated with considerable thromboembolic risk not offset by mitigated bleeding risk.

The Acceptability of post-stroke cognitive testing through the lens of the theory of acceptability, a qualitative study.

Background: Cognitive impairment is common after stroke and screening is recommended. However, there is a lack of evidence on the best way to assess cognition after stroke and a tendency to focus on the clinician rather than stroke survivor. The Theoretical Framework of Acceptability (TFA) was developed to better understand the factors that contribute to the acceptability of healthcare interventions from the patient perspective. We aimed to explore the acceptability of post-stroke cognitive assessment from the stroke survivor perspective, using the TFA as a lens. Methods: We analysed interviews conducted with people admitted to hospital after stroke. Inclusion criteria: ≥18 years, able to provide informed consent. Semi-structured interviews were conducted 1-3 weeks after discharge from hospital in the participant's home to explore the experience of cognitive assessment in hospital. Interviews were audio recorded and transcribed verbatim. Data were analysed using framework analysis, with a framework underpinned by the TFA. Results: Of the 13 participants interviewed, 8 were male, 6 lived in the most deprived SIMD quintile. Ages were 62-84 years. Five themes were identified that describe the factors that influence acceptability of cognitive screening from the patient perspective: (1) participation motives; (2) trust in health professionals; (3) perceived risks of harm; (4) information provision; (5) burden of testing. Conclusion: Clinical teams should be confident that stroke survivors expect cognitive testing and understand its rational. However, the provision of information and results of cognitive testing should be person-centred.

Anticholinergic deprescribing interventions for reducing risk of cognitive decline or dementia in older adults with and without prior cognitive impairment.

BACKGROUND: Anticholinergics are medications that block the action of acetylcholine in the central or peripheral nervous system. Medications with anticholinergic properties are commonly prescribed to older adults. The cumulative anticholinergic effect of all the medications a person takes is referred to as the anticholinergic burden. A high anticholinergic burden may cause cognitive impairment in people who are otherwise cognitively healthy, or cause further cognitive decline in people with pre-existing cognitive problems. Reducing anticholinergic burden through deprescribing interventions may help to prevent onset of cognitive impairment or slow the rate of cognitive decline. OBJECTIVES: Primary objective • To assess the efficacy and safety of anticholinergic medication reduction interventions for improving cognitive outcomes in cognitively healthy older adults and older adults with pre-existing cognitive issues. Secondary Objectives • To compare the effectiveness of different types of reduction interventions (e.g. pharmacist-led versus general practitioner-led, educational versus audit and feedback) for reducing overall anticholinergic burden. • To establish optimal duration of anticholinergic reduction interventions, sustainability, and lessons learnt for upscaling • To compare results according to differing anticholinergic scales used in medication reduction intervention trials • To assess the efficacy of anticholinergic medication reduction interventions for improving other clinical outcomes, including mortality, quality of life, clinical global impression, physical function, institutionalisation, falls, cardiovascular diseases, and neurobehavioral outcomes. SEARCH METHODS: We searched CENTRAL on 22 December 2022, and we searched MEDLINE, Embase, and three other databases from inception to 1 November 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of interventions that aimed to reduce anticholinergic burden in older people and that investigated cognitive outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed the risk of bias of included studies. The data were not suitable for meta-analysis, so we summarised them narratively. We used GRADE methods to rate our confidence in the review results. MAIN RESULTS: We included three trials with a total of 299 participants. All three trials were conducted in a cognitively mixed population (some cognitively healthy participants, some participants with dementia). Outcomes were assessed after one to three months. One trial reported significantly improved performance on the Digit Symbol Substitution Test (DSST) in the intervention group (treatment difference 0.70, 95% confidence interval (CI) 0.11 to 1.30), although there was no difference between the groups in the proportion of participants with reduced anticholinergic burden. Two trials successfully reduced anticholinergic burden in the intervention group. Of these, one reported no significant difference between the intervention versus control in terms of their effect on cognitive performance measured by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) immediate recall (mean between-group difference 0.54, 95% CI -0.91 to 2.05), CERAD delayed recall (mean between-group difference -0.23, 95% CI-0.85 to 0.38), CERAD recognition (mean between-group difference 0.77, 95% CI -0.39 to 1.94), and Mini-Mental State Examination (mean between-group difference 0.39, 95% CI -0.96 to 1.75). The other trial reported a significant correlation between anticholinergic burden and a test of working memory after the intervention (which suggested reducing the burden improved performance), but reported no effect on multiple other cognitive measures. In GRADE terms, the results were of very low certainty. There were no reported between-group differences for any other clinical outcome we investigated. It was not possible to investigate differences according to type of reduction intervention or type of anticholinergic scale, to measure the sustainability of interventions, or to establish lessons learnt for upscaling. No trials investigated safety outcomes. AUTHORS' CONCLUSIONS: There is insufficient evidence to reach any conclusions on the effects of anticholinergic burden reduction interventions on cognitive outcomes in older adults with or without prior cognitive impairment. The evidence from RCTs was of very low certainty so cannot support or refute the hypothesis that actively reducing or stopping prescription of medications with anticholinergic properties can improve cognitive outcomes in older people. There is no evidence from RCTs that anticholinergic burden reduction interventions improve other clinical outcomes such as mortality, quality of life, clinical global impression, physical function, institutionalisation, falls, cardiovascular diseases, or neurobehavioral outcomes. Larger RCTs investigating long-term outcomes are needed. Future RCTs should also investigate potential benefits of anticholinergic reduction interventions in cognitively healthy populations and cognitively impaired populations separately.

In older adults, specialty geriatrics care, multicomponent interventions, and cognitive stimulation reduce nursing home admission.

SOURCE CITATION: Gaugler JE, Zmora R, Peterson CM, et al. What interventions keep older people out of nursing homes? A systematic review and meta-analysis. J Am Geriatr Soc. 2023;71:3609-3621. 37526432.

Frailty Assessment in Vascular OUtpatients Review (FAVOUR) protocol: single-centre prospective cohort study comparing feasibility and prognostic value of commonly used frailty assessment tools.

INTRODUCTION: Frailty has consistently demonstrated associations with poorer healthcare outcomes. Vascular guidelines have recognised the importance of frailty assessment. However, an abundance of frailty tools and a lack of prospective studies confirming suitability of routine frailty assessment in clinical practice has delayed the uptake of these guidelines. The Frailty Assessment in Vascular OUtpatients Review study speaks to this evidence gap. The primary aim is to assess feasibility of implementing routine frailty assessment in a reproducible outpatient setting. Secondary objectives include comparing prognostic values and interuser agreement across five frailty assessment tools. METHODS AND ANALYSIS: This single-centre prospective cohort study of feasibility is conducted in a rapid-referral vascular surgery clinic, serving a population of 2 million. Adults with capacity (>18 years), attending a clinic for any reason, are eligible for inclusion. Five assessments are completed by patient (Rockwood Clinical Frailty Scale (CFS) and Frail NonDisabled Questionnaire), clinician (CFS, Healthcare Improvement Scotland FRAIL tool and 'Initial Clinical Evaluation') and researcher (11-item modified Frailty Index). Consistent with feasibility objectives, outcome measures include recruitment rates, frailty assessment completion rates, time-to-complete assessments and interuser variability. Electronic follow-up at 30 days and 1 year will assess home-time and mortality as prognostic indicators. Patients treated surgically/endovascularly will undergo additional 30-day and 1-year postoperative follow-up, outcome measures include: surgical procedure, mortality, complications (according to Clavien-Dindo Classification), length of stay, readmission rates, non-home discharge, home-time, higher social care requirements on discharge and amputation-free survival. Prognostic value will be compared by area under receiver operating characteristic curves. Continuous outcome variables will be analysed using Spearman's rank correlation coefficient. Interuser agreement will be compared by percentage agreement in Cohen's kappa coefficient.  ETHICS AND DISSEMINATION: The study is sponsored by National Health Service Greater Glasgow and Clyde (R&IUGN23CE014). London-Riverside REC (23/PR/0062) granted ethical approval. Results will be disseminated through publication in peer-reviewed vascular surgery and geriatric medicine themed journals and presentation at similar scientific conferences. TRIALS REGISTRATION NUMBER: NCT06040658. Stage of study: pre-results.

Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) for the diagnosis of delirium in adults in critical care settings.

BACKGROUND: Delirium is an underdiagnosed clinical syndrome typified by an acute alteration of mental state. It is an important problem in critical care and intensive care units (ICU) due to its high prevalence and its association with adverse outcomes. Delirium is a very distressing condition for patients, with a huge impact on their well-being. Diagnosis of delirium in the critical care setting is challenging. This is especially true for patients who are mechanically ventilated and are therefore unable to engage in a verbal interview. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is a tool specifically designed to assess for delirium in the context of ICU patients, including those on mechanical ventilation. CAM-ICU can be administered by non-specialists to give a dichotomous delirium present/absent result. OBJECTIVES: To determine the diagnostic accuracy of the CAM-ICU for the diagnosis of delirium in adult patients in critical care units. SEARCH METHODS: We searched MEDLINE (Ovid SP, 1946 to 8 July 2022), Embase (Ovid SP, 1982 to 8 July 2022), Web of Science Core Collection (ISI Web of Knowledge, 1945 to 8 July 2022), PsycINFO (Ovid SP, 1806 to 8 July 2022), and LILACS (BIREME, 1982 to 8 July 2022). We checked the reference lists of included studies and other resources for additional potentially relevant studies. We also searched the Health Technology Assessment database, the Cochrane Library, Aggressive Research Intelligence Facility database, WHO ICTRP, ClinicalTrials.gov, and websites of scientific associations to access any annual meetings and abstracts of conference proceedings in the field. SELECTION CRITERIA: We included diagnostic studies enrolling adult ICU patients assessed using the CAM-ICU tool, regardless of language or publication status and reporting sufficient data on delirium diagnosis for the construction of 2 x 2 tables. Eligible studies evaluated the diagnostic performance of the CAM-ICU versus a clinical reference standard based on any iteration of the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria applied by a clinical expert. DATA COLLECTION AND ANALYSIS: Two review authors independently selected and collated study data. We assessed the methodological quality of studies using the QUADAS-2 tool. We used two univariate fixed-effect or random-effects models to determine summary estimates of sensitivity and specificity. We performed sensitivity analyses that excluded studies considered to be at high risk of bias and high concerns in applicability, due mainly to the target population included (e.g. patients with traumatic brain injury). We also investigated potential sources of heterogeneity, assessing the effect of reference standard diagnosis and proportion of patients ventilated. MAIN RESULTS: We included 25 studies (2817 participants). The mean age of participants ranged from 48 to 69 years; 15 of the studies included critical care units admitting mixed populations (e.g. medical, trauma, surgery patients). The percentage of patients receiving mechanical ventilation ranged from 11.8% to 100%. The prevalence of delirium in the studies included ranged from 12.5% to 83.9%. Presence of delirium was determined by the application of DSM-IV criteria in 13 out of 25 included studies. We assessed 13 studies as at low risk of bias and low applicability concerns for all QUADAS-2 domains. The most common issue of concern was flow and timing of the tests, followed by patient selection. Overall, we estimated a pooled sensitivity of 0.78 (95% confidence interval (CI) 0.72 to 0.83) and a pooled specificity of 0.95 (95% CI 0.92 to 0.97). Sensitivity analysis restricted to studies at low risk of bias and without any applicability concerns (n = 13 studies) gave similar summary accuracy indices (sensitivity 0.80 (95% CI 0.72 to 0.86), specificity 0.95 (95% CI 0.93 to 0.97)). Subgroup analyses based on diagnostic assessment found summary estimates of sensitivity and specificity for studies using DSM-IV of 0.79 (95% CI 0.72 to 0.85) and 0.94 (95% CI 0.90 to 0.96). For studies that used DSM-5 criteria, summary estimates of sensitivity and specificity were 0.75 (95% CI 0.67 to 0.82) and 0.98 (95% CI 0.95 to 0.99). DSM criteria had no significant effect on sensitivity (P = 0.421), but the specificity for detection of delirium was higher when DSM-5 criteria were used (P = 0.024). The relative specificity comparing DSM-5 versus DSM-IV criteria was 1.05 (95% CI 1.02 to 1.08). Summary estimates of sensitivity and specificity for studies recruiting < 100% of patients with mechanical ventilation were 0.81 (95% CI 0.75 to 0.85) and 0.95 (95% CI 0.91 to 0.98). For studies that exclusively recruited patients with mechanical ventilation, summary estimates of sensitivity and specificity were 0.91 (95% CI 0.76 to 0.97) and 0.98 (95% CI 0.92 to 0.99). Although there was a suggestion of differential performance of CAM-ICU in ventilated patients, the differences were not significant in sensitivity (P = 0.316) or in specificity (P = 0.493). AUTHORS' CONCLUSIONS: The CAM-ICU tool may have a role in the early identification of delirium, in adult patients hospitalized in intensive care units, including those on mechanical ventilation, when non-specialized, properly trained clinical personnel apply the CAM-ICU. The test is most useful for exclusion of delirium. The test may miss a proportion of patients with incident delirium, therefore in situations where detection of all delirium cases is desirable, it may be best to repeat the test or combine CAM-ICU with another assessment. Future studies should compare different screening tests proposed for bedside assessment of delirium, as this approach will reveal which tool yields superior accuracy. In addition, future studies should consider and report the flow and timing of the tests and clearly report key characteristics related to patient selection. Finally, future research should focus on the impact of CAM-ICU screening on patient outcomes.

Physical activity and exercise for the prevention and management of mild cognitive impairment and dementia: a collaborative international guideline.

BACKGROUND: Physical activity and exercise have been suggested as effective interventions for the prevention and management of mild cognitive impairment (MCI) and dementia, but there are no international guidelines. OBJECTIVES: To create a set of evidence- and expert consensus-based prevention and management recommendations regarding physical activity (any bodily movement produced by skeletal muscles that results in energy expenditure) and exercise (a subset of physical activity that is planned, structured, repetitive), applicable to a range of individuals from healthy older adults to those with MCI/dementia. METHODS: Guideline content was developed with input from several scientific and lay representatives' societies. A systematic search across multidisciplinary databases was carried out until October 2021. Recommendations for prevention and management were developed according to the GRADE and complemented by consensus statements from the expert panels. RECOMMENDATIONS: Physical activity may be considered for the primary prevention of dementia. In people with MCI there is continued uncertainty about the role of physical activity in slowing the conversion to dementia. Mind-body interventions have the greatest supporting evidence. In people with moderate dementia, exercise may be used for maintaining disability and cognition. All these recommendations were based on a very low/low certainty of evidence. CONCLUSIONS: Although the scientific evidence on the beneficial role of physical activity and exercise in preserving cognitive functions in subjects with normal cognition, MCI or dementia is inconclusive, this panel, composed of scientific societies and other stakeholders, recommends their implementation based on their beneficial effects on almost all facets of health.

The Effect of Long Chain n-3 Fatty Acid Supplementation on Muscle Strength in Older Adults: A Systematic Review and Meta-Analysis.

The main objective of the current study was to perform a systematic literature review with the purpose of exploring the impact of long-chain n-3 polyunsaturated fatty acid (LCn-3 PUFA) relative to control oil supplementation on muscle strength, with secondary outcomes of muscle mass and physical function in older individuals under conditions of habitual physical activity/exercise. The review protocol was registered with PROSPERO (CRD42021267011) and followed the guidelines outlined in the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The search for relevant studies was performed utilizing databases such as PubMed, EMBASE, CINAHL, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to June 2023. Randomized controlled trials (RCTs) in older adults comparing the effects of LCn-3 PUFA with a control oil supplement on muscle strength were included. Five studies involving a total of 488 participants (348 females and 140 males) were identified that met the specified inclusion criteria and were included. Upon analyzing the collective data from these studies, it was observed that supplementation with LCn-3 PUFA did not have a significant impact on grip strength (standardized mean difference (SMD) 0.61, 95% confidence interval [-0.05, 1.27]; p = 0.07) in comparison to the control group. However, there was a considerable level of heterogeneity among the studies (I2 = 90%; p < 0.001). As secondary outcomes were only measured in a few studies, with significant heterogeneity in methods, meta-analyses of muscle mass and functional abilities were not performed. Papers with measures of knee extensor muscle mass as an outcome (n = 3) found increases with LCn-3 PUFA supplementation, but studies measuring whole body lean/muscle mass (n = 2) and functional abilities (n = 4) reported mixed results. With a limited number of studies, our data indicate that LCn-3 PUFA supplementation has no effect on muscle strength or functional abilities in older adults but may increase muscle mass, although, with only a few studies and considerable heterogeneity, further work is needed to confirm these findings.

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.

Multi-domain prognostic models used in middle-aged adults without known cognitive impairment for predicting subsequent dementia.

BACKGROUND: Dementia, a global health priority, has no current cure. Around 50 million people worldwide currently live with dementia, and this number is expected to treble by 2050. Some health conditions and lifestyle behaviours can increase or decrease the risk of dementia and are known as 'predictors'. Prognostic models combine such predictors to measure the risk of future dementia. Models that can accurately predict future dementia would help clinicians select high-risk adults in middle age and implement targeted risk reduction. OBJECTIVES: Our primary objective was to identify multi-domain prognostic models used in middle-aged adults (aged 45 to 65 years) for predicting dementia or cognitive impairment. Eligible multi-domain prognostic models involved two or more of the modifiable dementia predictors identified in a 2020 Lancet Commission report and a 2019 World Health Organization (WHO) report (less education, hearing loss, traumatic brain injury, hypertension, excessive alcohol intake, obesity, smoking, depression, social isolation, physical inactivity, diabetes mellitus, air pollution, poor diet, and cognitive inactivity). Our secondary objectives were to summarise the prognostic models, to appraise their predictive accuracy (discrimination and calibration) as reported in the development and validation studies, and to identify the implications of using dementia prognostic models for the management of people at a higher risk for future dementia. SEARCH METHODS: We searched MEDLINE, Embase, PsycINFO, CINAHL, and ISI Web of Science Core Collection from inception until 6 June 2022. We performed forwards and backwards citation tracking of included studies using the Web of Science platform.  SELECTION CRITERIA: We included development and validation studies of multi-domain prognostic models. The minimum eligible follow-up was five years. Our primary outcome was an incident clinical diagnosis of dementia based on validated diagnostic criteria, and our secondary outcome was dementia or cognitive impairment determined by any other method. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the references, extracted data using a template based on the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS), and assessed risk of bias and applicability of included studies using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). We synthesised the C-statistics of models that had been externally validated in at least three comparable studies.  MAIN RESULTS: We identified 20 eligible studies; eight were development studies and 12 were validation studies. There were 14 unique prognostic models: seven models with validation studies and seven models with development-only studies. The models included a median of nine predictors (range 6 to 34); the median number of modifiable predictors was five (range 2 to 11). The most common modifiable predictors in externally validated models were diabetes, hypertension, smoking, physical activity, and obesity. In development-only models, the most common modifiable predictors were obesity, diabetes, hypertension, and smoking. No models included hearing loss or air pollution as predictors. Nineteen studies had a high risk of bias according to the PROBAST assessment, mainly because of inappropriate analysis methods, particularly lack of reported calibration measures. Applicability concerns were low for 12 studies, as their population, predictors, and outcomes were consistent with those of interest for this review. Applicability concerns were high for nine studies, as they lacked baseline cognitive screening or excluded an age group within the range of 45 to 65 years. Only one model, Cardiovascular Risk Factors, Ageing, and Dementia (CAIDE), had been externally validated in multiple studies, allowing for meta-analysis. The CAIDE model included eight predictors (four modifiable predictors): age, education, sex, systolic blood pressure, body mass index (BMI), total cholesterol, physical activity and APOEƐ4 status. Overall, our confidence in the prediction accuracy of CAIDE was very low; our main reasons for downgrading the certainty of the evidence were high risk of bias across all the studies, high concern of applicability, non-overlapping confidence intervals (CIs), and a high degree of heterogeneity. The summary C-statistic was 0.71 (95% CI 0.66 to 0.76; 3 studies; very low-certainty evidence) for the incident clinical diagnosis of dementia, and 0.67 (95% CI 0.61 to 0.73; 3 studies; very low-certainty evidence) for dementia or cognitive impairment based on cognitive scores. Meta-analysis of calibration measures was not possible, as few studies provided these data. AUTHORS' CONCLUSIONS: We identified 14 unique multi-domain prognostic models used in middle-aged adults for predicting subsequent dementia. Diabetes, hypertension, obesity, and smoking were the most common modifiable risk factors used as predictors in the models. We performed meta-analyses of C-statistics for one model (CAIDE), but the summary values were unreliable. Owing to lack of data, we were unable to meta-analyse the calibration measures of CAIDE. This review highlights the need for further robust external validations of multi-domain prognostic models for predicting future risk of dementia in middle-aged adults.

A systematic review of frailty assessment tools used in vascular surgery research.

OBJECTIVE: Frailty is common in vascular patients and is recognized for its prognostic value. In the absence of consensus, a multitude of frailty assessment tools exist. This systematic review aimed to quantify the variety in these tools and describe their content and application to inform future research and clinical practice. METHODS: Multiple cross-disciplinary electronic literature databases were searched from inception to August 2022. Studies describing frailty assessment in a vascular surgical population were eligible. Data extraction to a validated template included patient demographics, tool content, and analysis methods. A secondary systematic search for papers describing the psychometric properties of commonly used frailty tools was then performed. RESULTS: Screening 5358 records identified 111 eligible studies, with an aggregate population of 5,418,236 patients. Forty-three differing frailty assessment tools were identified. One-third of these failed to assess frailty as a multidomain deficit and there was a reliance on assessing function and presence of comorbidity. Substantial methodological variability in data analysis and lack of methodological description was also identified. Published psychometric assessment was available for only 4 of the 10 most commonly used frailty tools. The Clinical Frailty Scale was the most studied and demonstrates good psychometric properties within a surgical population. CONCLUSIONS: Substantial heterogeneity in frailty assessment is demonstrated, precluding meaningful comparisons of services and data pooling. A uniform approach to assessment is required to guide future frailty research. Based on the literature, we make the following recommendations: frailty should be considered a continuous construct and the reporting of frailty tools' application needs standardized. In the absence of consensus, the Clinical Frailty Scale is a validated tool with good psychometric properties that demonstrates usefulness in vascular surgery.

MetaBayesDTA: codeless Bayesian meta-analysis of test accuracy, with or without a gold standard.

BACKGROUND: The statistical models developed for meta-analysis of diagnostic test accuracy studies require specialised knowledge to implement. This is especially true since recent guidelines, such as those in Version 2 of the Cochrane Handbook of Systematic Reviews of Diagnostic Test Accuracy, advocate more sophisticated methods than previously. This paper describes a web-based application - MetaBayesDTA - that makes many advanced analysis methods in this area more accessible. RESULTS: We created the app using R, the Shiny package and Stan. It allows for a broad array of analyses based on the bivariate model including extensions for subgroup analysis, meta-regression and comparative test accuracy evaluation. It also conducts analyses not assuming a perfect reference standard, including allowing for the use of different reference tests. CONCLUSIONS: Due to its user-friendliness and broad array of features, MetaBayesDTA should appeal to researchers with varying levels of expertise. We anticipate that the application will encourage higher levels of uptake of more advanced methods, which ultimately should improve the quality of test accuracy reviews.

Pharmacological Interventions for Sialorrhoea in People with Parkinson's Disease: A Systematic Review and Meta-Analysis.

Background/objectives: Sialorrhoea is a common non motor complication experienced by people with Parkinson's disease (PD). Despite its prevalence there is conflicting evidence on how to effectively treat it. Our aim was to establish the efficacy and safety outcomes of pharmacological interventions used to treat sialorrhoea in people with idiopathic PD. Methods: We registered and conducted a systematic review and meta-analysis (PROSPERO: CRD42016042470). We searched seven electronic databases from inception until July 2022. Quantitative synthesis was performed where data allowed using random effects models. Results: From 1374 records we included 13 studies (n = 405 participants). Studies were conducted in Europe, North America and China. There was marked heterogeneity in the interventions used, follow up times and outcome measures investigated. The main source of risk of bias identified was reporting bias. Five studies were included in the quantitative synthesis. Summary estimates showed administration of botulinum toxin significantly reduced saliva production, improved patient reported functional outcomes and was associated with an increase in adverse events. Conclusion: Sialorrhoea in PD is an important condition, but current data does not allow for strong recommendations on optimal pharmacological treatments. There is significant heterogeneity in outcomes measures used to evaluate the burden of sialorrhoea with lack of consensus on what constitutes clinically meaningful change. More research is required to better understand the underlying mechanism and potential treatments of sialorrhoea in idiopathic PD.

Protocol for a randomised controlled trial to investigate the effects of vitamin K2 on recovery from muscle-damaging resistance exercise in young and older adults-the TAKEOVER study.

BACKGROUND: Regular participation in resistance exercise is known to have broad-ranging health benefits and for this reason is prominent in the current physical activity guidelines. Recovery after such exercise is important for several populations across the age range and nutritional strategies to enhance recovery and modulate post-exercise physiological processes are widely studied, yet effective strategies remain elusive. Vitamin K2 supplementation has emerged as a potential candidate, and the aim of the current study, therefore, is to test the hypothesis that vitamin K2 supplementation can accelerate recovery, via modulation of the underlying physiological processes, following a bout of resistance exercise in young and older adults. METHODS: The current study is a two-arm randomised controlled trial which will be conducted in 80 (40 young (≤40 years) and 40 older (≥65 years)) adults to compare post-exercise recovery in those supplemented with vitamin K2 or placebo for a 12-week period. The primary outcome is muscle strength with secondary outcomes including pain-free range of motion, functional abilities, surface electromyography (sEMG) and markers of inflammation and oxidative stress. DISCUSSION: Ethical approval has been granted by the College of Medical Veterinary and Life Sciences Ethical Committee at the University of Glasgow (Project No 200190189) and recruitment is ongoing. Study findings will be disseminated through a presentation at scientific conferences and in scientific journals. TRIAL REGISTRATION: ClinicialTrials.gov NCT04676958. Prospectively registered on 21 December 2020.

Anticholinergic burden for prediction of cognitive decline or neuropsychiatric symptoms in older adults with mild cognitive impairment or dementia.

BACKGROUND: Medications with anticholinergic properties are commonly prescribed to older adults with a pre-existing diagnosis of dementia or cognitive impairment. The cumulative anticholinergic effect of all the medications a person takes is referred to as the anticholinergic burden because of its potential to cause adverse effects. It is possible that a high anticholinergic burden may be a risk factor for further cognitive decline or neuropsychiatric disturbances in people with dementia. Neuropsychiatric disturbances are the most frequent complication of dementia that require hospitalisation, accounting for almost half of admissions; hence, identification of modifiable prognostic factors for these outcomes is crucial. There are various scales available to measure anticholinergic burden but agreement between them is often poor. OBJECTIVES: Our primary objective was to assess whether anticholinergic burden, as defined at the level of each individual scale, was a prognostic factor for further cognitive decline or neuropsychiatric disturbances in older adults with pre-existing diagnoses of dementia or cognitive impairment. Our secondary objective was to investigate whether anticholinergic burden was a prognostic factor for other adverse clinical outcomes, including mortality, impaired physical function, and institutionalisation. SEARCH METHODS: We searched these databases from inception to 29 November 2021: MEDLINE OvidSP, Embase OvidSP, PsycINFO OvidSP, CINAHL EBSCOhost, and ISI Web of Science Core Collection on ISI Web of Science. SELECTION CRITERIA: We included prospective and retrospective longitudinal cohort and case-control observational studies, with a minimum of one-month follow-up, which examined the association between an anticholinergic burden measurement scale and the above stated adverse clinical outcomes, in older adults with pre-existing diagnoses of dementia or cognitive impairment.   DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, and undertook data extraction, risk of bias assessment, and GRADE assessment. We summarised risk associations between anticholinergic burden and all clinical outcomes in a narrative fashion. We also evaluated the risk association between anticholinergic burden and mortality using a random-effects meta-analysis.  We established adjusted pooled rates for the anticholinergic cognitive burden (ACB) scale; then, as an exploratory analysis, established pooled rates on the prespecified association across scales.  MAIN RESULTS: We identified 18 studies that met our inclusion criteria (102,684 older adults). Anticholinergic burden was measured using five distinct measurement scales: 12 studies used the ACB scale; 3 studies used the Anticholinergic Risk Scale (ARS); 1 study used the Anticholinergic Drug Scale (ADS); 1 study used the Anticholinergic Effect on Cognition (AEC) Scale; and 2 studies used a list developed by Tune and Egeli.  Risk associations between anticholinergic burden and adverse clinical outcomes were highly heterogenous. Four out of 10 (40%) studies reported a significantly increased risk of greater long-term cognitive decline for participants with an anticholinergic burden compared to participants with no or minimal anticholinergic burden. No studies investigated neuropsychiatric disturbance outcomes. One out of four studies (25%) reported a significant association with reduced physical function for participants with an anticholinergic burden versus participants with no or minimal anticholinergic burden. No study (out of one investigating study) reported a significant association between anticholinergic burden and risk of institutionalisation. Six out of 10 studies (60%) found a significantly increased risk of mortality for those with an anticholinergic burden compared to those with no or minimal anticholinergic burden. Pooled analysis of adjusted mortality hazard ratios (HR) measured anticholinergic burden with the ACB scale, and suggested a significantly increased risk of death for those with a high ACB score relative to those with no or minimal ACB scores (HR 1.153, 95% confidence interval (CI) 1.030 to 1.292; 4 studies, 48,663 participants). An exploratory pooled analysis of adjusted mortality HRs across anticholinergic burden scales also suggested a significantly increased risk of death for those with a high anticholinergic burden (HR 1.102, 95% CI 1.044 to 1.163; 6 studies, 68,381 participants).   Overall GRADE evaluation of results found low- or very low-certainty evidence for all outcomes.  AUTHORS' CONCLUSIONS: There is low-certainty evidence that older adults with dementia or cognitive impairment who have a significant anticholinergic burden may be at increased risk of death. No firm conclusions can be drawn for risk of accelerated cognitive decline, neuropsychiatric disturbances, decline in physical function, or institutionalisation.

Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism: A pooled analysis of two randomized controlled trials.

BACKGROUND: Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). OBJECTIVE: To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. METHODS: We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti-thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. RESULTS: Among 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of -2.07 (95% confidence interval: -6.04 to 1.90) for positive antibodies versus 0.89 (-1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores-adjusted between-group difference 1.75 (-3.60 to 7.09) for positive antibodies versus 1.14 (-1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. CONCLUSIONS: Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.

Antithrombotic therapy to prevent cognitive decline in people with small vessel disease on neuroimaging but without dementia.

BACKGROUND: Cerebral small vessel disease is a progressive disease of the brain's deep perforating blood vessels. It is usually diagnosed based on lesions seen on brain imaging. Cerebral small vessel disease is a common cause of stroke but can also cause a progressive cognitive decline. As antithrombotic therapy is an established treatment for stroke prevention, we sought to determine whether antithrombotic therapy might also be effective in preventing cognitive decline in people with small vessel disease. OBJECTIVES: To assess the effects of antithrombotic therapy for prevention of cognitive decline in people with small vessel disease on neuroimaging but without dementia. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Review Group's Specialised Register, and the Cochrane Stroke Group's Specialised Register; the most recent search was on 21 July 2021. We also searched MEDLINE, Embase, four other databases and two trials registries. We searched the reference lists of the articles retrieved from these searches. As trials with a stroke focus may include relevant subgroup data, we complemented these searches with a focussed search of all antithrombotic titles in the Cochrane Stroke Group database.  SELECTION CRITERIA: We included randomised controlled trials (RCT) of people with neuroimaging evidence of at least mild cerebral small vessel disease (defined here as white matter hyperintensities, lacunes of presumed vascular origin and subcortical infarcts) but with no evidence of dementia. The trials had to compare antithrombotic therapy of minimum 24 weeks' duration to no antithrombotic therapy (either placebo or treatment as usual), or compare different antithrombotic treatment regimens. Antithrombotic therapy could include antiplatelet agents (as monotherapy or combination therapy), anticoagulants or a combination. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all the titles identified by the searches. We assessed full texts for eligibility for inclusion according to our prespecified selection criteria, extracted data to a proforma and assessed risk of bias using the Cochrane tool for RCTs. We evaluated the certainty of evidence using GRADE. Due to heterogeneity across included participants, interventions and outcomes of eligible trials, it was not possible to perform meta-analyses. MAIN RESULTS: We included three RCTs (3384 participants). One study investigated the effect of antithrombotic therapy in participants not yet on antithrombotic therapy; two studies investigated the effect of additional antithrombotic therapy, one in a population already taking a single antithrombotic agent and one in a mixed population (participants on an antithrombotic drug and antithrombotic-naive participants). Intervention and follow-up durations varied from 24 weeks to four years. Jia 2016 was a placebo-controlled trial assessing 24 weeks of treatment with DL-3-n-butylphthalide (a compound with multimodal actions, including a putative antiplatelet effect) in 280 Chinese participants with vascular cognitive impairment caused by subcortical ischaemic small vessel disease, but without dementia. There was very low-certainty evidence for a small difference in cognitive test scores favouring treatment with DL-3-n-butylphthalide, as measured by the 12-item Alzheimer's Disease Assessment Scale-Cognitive subscale (adjusted mean difference -1.07, 95% confidence interval (CI) -2.02 to -0.12), but this difference may not be clinically relevant. There was also very low-certainty evidence for greater proportional improvement measured with the Clinician Interview-Based Impression of Change-Plus Caregiver Input (57% with DL-3-n-butylphthalide versus 42% with placebo; P = 0.01), but there was no difference in other measures of cognition (Mini-Mental State Examination and Clinical Dementia Rating) or function. There was no evidence of a difference in adverse events between treatment groups. The SILENCE RCT compared antithrombotic therapy (aspirin) and placebo during four years of treatment in 83 participants with 'silent brain infarcts' who were on no prior antithrombotic therapy. There was very low-certainty evidence for no difference between groups across various measures of cognition and function, rates of stroke or adverse events. The Secondary Prevention of Subcortical Stroke Study (SPS3) compared dual antiplatelet therapy (clopidogrel plus aspirin) to aspirin alone in 3020 participants with recent lacunar stroke. There was low-certainty evidence of no effect on cognitive outcomes as measured by the Cognitive Abilities Screening Instruments (CASI) assessed annually over five years. There was also low-certainty evidence of no difference in the annual incidence of mild cognitive decline between the two treatment groups (9.7% with dual antiplatelet therapy versus 9.9% with aspirin), or the annual stroke recurrence rate (2.5% with dual antiplatelet therapy versus 2.7% with aspirin). Bleeding risk may be higher with dual antiplatelet therapy (hazard ratio (HR) 2.15, 95% CI 1.49 to 3.11; low certainty evidence), but there may be no significant increase in intracerebral bleeding risk (HR 1.52, 95% CI 0.79 to 2.93; low-certainty evidence). None of the included trials assessed the incidence of new dementia. AUTHORS' CONCLUSIONS: We found no convincing evidence to suggest any clinically relevant cognitive benefit of using antithrombotic therapy in addition to standard treatment in people with cerebral small vessel disease but without dementia, but there may be an increased bleeding risk with this approach. There was marked heterogeneity across the trials and the certainty of the evidence was generally poor.

Quantifying bias in psychological and physical health in the UK Biobank imaging sub-sample.

UK Biobank is a prospective cohort study of around half-a-million general population participants, recruited between 2006 and 2010, with baseline studies at recruitment and multiple assessments since. From 2014 to date, magnetic resonance imaging (MRI) has been pursued in a participant sub-sample, with the aim to scan around n = 100k. This sub-sample is studied widely and therefore understanding its relative characteristics is important for future reports. We aimed to quantify psychological and physical health in the UK Biobank imaging sub-sample, compared with the rest of the cohort. We used t-tests and χ2 for continuous/categorical variables, respectively, to estimate average differences on a range of cognitive, mental and physical health phenotypes. We contrasted baseline values of participants who attended imaging (versus had not), and compared their values at the imaging visit versus baseline values of participants who were not scanned. We also tested the hypothesis that the associations of established risk factors with worse cognition would be underestimated in the (hypothesized) healthier imaging group compared with the full cohort. We tested these interactions using linear regression models. On a range of cognitive, mental health, cardiometabolic, inflammatory and neurological phenotypes, we found that 47 920 participants who were scanned by January 2021 showed consistent statistically significant 'healthy' bias compared with the ∼450 000 who were not scanned. These effect sizes were small to moderate based on Cohen's d/Cramer's V metrics (range = 0.02 to -0.21 for Townsend, the largest effect size). We found evidence of interaction, where stratified analysis demonstrated that associations of established cognitive risk factors were smaller in the imaging sub-sample compared with the full cohort. Of the ∼100 000 participants who ultimately will undergo MRI assessment within UK Biobank, the first ∼50 000 showed some 'healthy' bias on a range of metrics at baseline. Those differences largely remained at the subsequent (first) imaging visit, and we provide evidence that testing associations in the imaging sub-sample alone could lead to potential underestimation of exposure/outcome estimates.