An increasing proportion of the population is not covered by the current RDA for vitamin C - interrogation of EPIC-Norfolk and NHANES 2017/2018 cohorts.

With the rising prevalence of obesity globally, increasing proportions of the population may not be covered by current recommended daily allowances (RDAs) that are supposed to provide 97.5% of the population with a sufficient nutrient status but are typically based on a healthy young 70 kg male reference person. Using the EPIC-Norfolk (UK) and the NHANES (US) cohorts, we estimated the effect of body weight on the dose-concentration relationship to derive weight-based requirements to achieve an 'adequate' plasma concentration of vitamin C estimated to be 50 µmol/L. Inverse correlations between body weight and vitamin C were observed in both cohorts (p < 0.0001). Moreover, only about 2/3 of the cohorts achieved an adequate plasma vitamin C status by consuming the RDA or above, while only 1/3 to 1/2 of the cohorts achieved adequacy by an intake of the local RDA ± 10%. Using vitamin C as an example, the present data demonstrate that a considerable and expectedly increasing proportion of the world population is unable to achieve an adequate target plasma concentration with the current recommended daily intakes of vitamin C. This needs to be considered in future public health recommendations.

In this paper, we highlight the inverse association between body weight and vitamin C status. Our study strongly suggests that a large proportion of the population is not covered by the current recommended intakes of vitamin C.

Lower mental health related quality of life precedes dementia diagnosis: findings from the EPIC-Norfolk prospective population-based study.

Lower Health Related Quality of Life (HRQoL) precedes dementia in older adults in the USA. We explore prospective associations between HRQoL and dementia in British adults in mid and late-life, when interventions to optimise cognitive ageing may provide benefit. 7,452 community-dwelling participants (57% women; mean age 69.3 ± 8.3 years) attended the European Prospective Investigation of Cancer-Norfolk study's third health check (3HC) and reported their HRQoL using Short-Form 36 (SF-36). Cox Proportional Hazard regression models explored associations between standard deviation differences in baseline Physical Component (PCS) and Mental Component Summary (MCS) scores, as well as eight SF-36 sub-scales (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, mental health), and incident dementia over ten years. Logistic regression models explored cross-sectional relationships at the 3HC between HRQoL and objective global cognitive function (n = 4435; poor cognition = lowest performance decile). The cohort was examined as a whole and by age-group (50-69, ≥ 70), considering socio-demographics and co-morbidity. Higher MCS scores were associated with lower chance of incident dementia (Hazard Ratio [HR] = 0.74, 95% CI 0.68-0.81) and lower odds of poor cognition (Odds Ratio [OR] = 0.82, 0.76-0.89), with findings similar by age-group. Higher PCS scores were not associated with dementia in the whole cohort (HR = 0.93, 0.84-1.04) or considering age-groups; and were only associated with poor cognition in younger participants (OR = 0.81, 0.72-0.92). Similarly, associations between higher scores on subscales pertaining to mental, but not physical, HRQoL and lower dementia incidence were observed. Lower mental HRQoL precedes dementia diagnosis in middle-aged and older British adults.

Trial of Dexamethasone for Chronic Subdural Hematoma.

BACKGROUND: Chronic subdural hematoma is a common neurologic disorder that is especially prevalent among older people. The effect of dexamethasone on outcomes in patients with chronic subdural hematoma has not been well studied. METHODS: We conducted a multicenter, randomized trial in the United Kingdom that enrolled adult patients with symptomatic chronic subdural hematoma. The patients were assigned in a 1:1 ratio to receive a 2-week tapering course of oral dexamethasone, starting at 8 mg twice daily, or placebo. The decision to surgically evacuate the hematoma was made by the treating clinician. The primary outcome was a score of 0 to 3, representing a favorable outcome, on the modified Rankin scale at 6 months after randomization; scores range from 0 (no symptoms) to 6 (death). RESULTS: From August 2015 through November 2019, a total of 748 patients were included in the trial after randomization - 375 were assigned to the dexamethasone group and 373 to the placebo group. The mean age of the patients was 74 years, and 94% underwent surgery to evacuate their hematomas during the index admission; 60% in both groups had a score of 1 to 3 on the modified Rankin scale at admission. In a modified intention-to-treat analysis that excluded the patients who withdrew consent for participation in the trial or who were lost to follow-up, leaving a total of 680 patients, a favorable outcome was reported in 286 of 341 patients (83.9%) in the dexamethasone group and in 306 of 339 patients (90.3%) in the placebo group (difference, -6.4 percentage points [95% confidence interval, -11.4 to -1.4] in favor of the placebo group; P = 0.01). Among the patients with available data, repeat surgery for recurrence of the hematoma was performed in 6 of 349 patients (1.7%) in the dexamethasone group and in 25 of 350 patients (7.1%) in the placebo group. More adverse events occurred in the dexamethasone group than in the placebo group. CONCLUSIONS: Among adults with symptomatic chronic subdural hematoma, most of whom had undergone surgery to remove their hematomas during the index admission, treatment with dexamethasone resulted in fewer favorable outcomes and more adverse events than placebo at 6 months, but fewer repeat operations were performed in the dexamethasone group. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Dex-CSDH ISRCTN number, ISRCTN80782810.).

Poor outcomes in patients with sepsis undergoing emergency laparotomy and laparoscopy are attenuated by faster time to care measures.

AIM: Emergency laparotomy and laparoscopy (EmLap) are amongst the commonest surgical procedures, with high prevalence of sepsis and hence poorer outcomes. However, whether time taken to receive care influences outcomes in patients requiring antibiotics for suspected infection remains largely unexplored. The aim of this work was to determine whether (1) time to care contributes to outcome differences between patients with and without suspected infection and (2) its impact on outcomes only amongst those with suspected infection. METHOD: Clinical information was retrospectively obtained from the 2017-2018 Emergency Laparotomy and Laparoscopic Scottish Audit (ELLSA). Time to care referred to six temporal variables describing radiological investigation, anaesthetic triage and surgical management. Outcome measures [mortality, readmission, hospital death, postoperative destination and length of stay (LoS)] were compared using adjusted and unadjusted regression analyses to determine whether the outcome differences could be explained by faster or slower time to care. RESULTS: Amongst 2243 EmLap patients [median age 65 years (interquartile range 51-75 years), 51.1% female], 892 (39.77%) received antibiotics for suspected infection. Although patients with suspected infection had faster time to care (all p ≤ 0.001) and worse outcomes compared with those who did not, outcome differences were not statistically significant when accounted for time (all p > 0.050). Amongst those who received antibiotics, faster time to care was also associated with decreased risk of postoperative intensive care unit (ICU) stay and shorter LoS (all p < 0.050). CONCLUSION: Worse outcomes associated with infection in EmLap patients were attenuated by faster time to care, which additionally reduced the LoS and ICU stay risk amongst those with suspected infection.

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.

To fuse or not to fuse: The elderly patient with lumbar stenosis and low-grade spondylolisthesis. Systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The optimum surgical intervention for elderly patients with lumbar spinal stenosis (LSS) and low-grade degenerative-spondylolisthesis (LGDS) has been extensively debated. We conducted a systematic review and meta-analysis of randomised-controlled-trials (RCTs) comparing the effectiveness of decompression-alone against the gold-standard approach of decompression-with-fusion (D + F) in elderly patients with LSS and LGDS. METHODS: A systematic literature search was performed on published databases from inception to October-2021. English-language RCTs of elderly patients (mean age over-65) with LSS and LGDS, who had undergone DA or D + F were included. The quality and weight of evidence was assessed, and a meta-analysis performed. RESULTS: Six RCTs (n = 531; mean age: 66.2 years; 57.8% female) were included. There was no difference in visual-analogue-scale (VAS) scores of back-pain (BP) or leg-pain (LP) at mean follow-up of 27.4 months between both DA and D + F groups (BP: mean-difference (MD)0.24, 95%CI: -0.38-0.85; LP MD:0.39, 95%CI: -0.34-1.11). No difference in disability, measured by Oswestry-Disability-Index scores, was found between both groups (MD:0.50, 95%CI: -3.31-4.31). However, patients in DA group had less hospital complications and fewer adverse events (total-surgical-complications OR:0.57, 95%CI: 0.36-0.90), despite a higher rate of worsening DS (OR:3.49, 95%CI: 1.05-11.65). No difference in BP or LP was found in subgroup-analysis of open-laminectomy compared to posterolateral-fusion (PLF) (BP: MD: -0.24, 95%CI: -1.80-1.32; LP MD:0.80, 95%CI: -0.95-2.55). CONCLUSIONS: DA is not inferior to D + F in elderly patients with LSS and LGDS. DA carries a lower risk of hospital complications and fewer adverse events, however, surgeons should weigh these findings with the increased risk of DS progressing post-operatively.

Higher anticholinergic burden from medications is associated with significant increase in markers of inflammation in the EPIC-Norfolk prospective population-based cohort study.

BACKGROUND: Higher medication anticholinergic burden is associated with increased risk of cardiovascular disease and cognitive decline. A mechanistic pathway has not been established. We aimed to determine whether inflammation may mediate these associations. METHODS: Participants were drawn from the European Prospective Investigation into Cancer, Norfolk cohort (40-79 years at baseline). Anticholinergic burden score (ACB) was calculated at first (1HC) (1993/97) and second (2HC) (1998/2000) health checks. Fibrinogen and C-reactive protein (CRP) were measured during 1HC and tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) during 2HC. Cross-sectional associations between ACB and inflammatory markers were examined for both health checks. Prospective associations were also examined between 1HC ACB and 2HC inflammatory markers. Models were adjusted for age, sex, lifestyle factors, comorbidities and medications. RESULTS: In total, 17 678 and 22 051 participants were included in cross-sectional analyses for CRP, and fibrinogen, respectively. Furthermore, 5101 participants with data on TNF-α and IL-6 were included in the prospective analyses. Cross-sectionally, compared to ACB = 0, ACB ≥ 4 was associated with higher fibrinogen, beta (95% confidence interval) = 0.134 g/L (0.070, 0.199), CRP 1.175 mg/L (0.715, 1.634), IL-6 0.593 pg/mL (0.254, 0.932) and TNF-α 0.137 pg/mL (0.033, 0.241). In addition, a point increase in ACB was associated with higher levels of all markers. Prospectively, compared to ACB = 0, ACB ≥ 4 was associated with higher IL-6(pg/mL) of 0.019 (-0.323, 0.361) and TNF-α (pg/mL) of 0.202% (0.81, 0.323). A unit increase in ACB was associated with a significantly higher TNF-α and IL-6. CONCLUSION: Higher ACB was associated with higher inflammatory markers. Inflammation may mediate the relationship between anticholinergic medications and adverse outcomes.

Blood Pressure Variability and Cognitive Function: a Scoping Review.

PURPOSE OF REVIEW: To conduct a scoping review of articles which have evaluated BPV and cognitive function. Articles with keywords, titles or abstracts containing the terms 'cognitive' OR 'cognition' OR 'dementia' AND 'blood pressure variability' were identified from CINAHL, Medline, PMC and Web of Science. RECENT FINDINGS: Methods of acquisition and analysis of BPV and cognitive measurements and their relationship were extracted from selected articles. Of 656 studies identified, 53 articles were selected. Twenty-five evaluated long-term (LTBPV), nine mid-term (MTBPV), 12 short-term (STBPV) and nine very short-term BPV (VSTBPV) with conflicting findings on the relationship between BPV and cognition. Variations existed in devices, period and procedure for acquisition. The studies also utilized a wide range of methods of BPV calculation. Thirteen cognitive assessment tools were used to measure global cognition or domain functions which were influenced by the population of interest. The interpretation of available studies was hence limited by heterogeneity. There is an urgent need for standardization of BPV assessments to streamline research on BPV and cognition. Future studies should also establish whether BPV could be a potential modifiable risk factor for cognitive decline, as well as a marker for treatment response.

Ethnic-Specific Sociodemographic Factors as Determinants of Cognitive Performance: Cross-Sectional Analysis of the Malaysian Elders Longitudinal Research Study.

INTRODUCTION: Despite cognitive impairment being a major health issue within the older population, limited information is available on factors associated with cognitive function among Asian ethnic groups. The objective of this study was to identify ethnic-specific sociodemographic risk factors which are associated with cognitive performance. METHODS: Cross-sectional analysis of the Malaysian Elders Longitudinal Research (MELoR) study involving community-dwelling individuals aged >55 years was conducted. Information on sociodemographic factors, medical history, and lifestyle were obtained by computer-assisted interviews in participants' homes. Cognitive performance was assessed with the Montreal Cognitive Assessment (MoCA) tool during subsequent hospital-based health checks. Hierarchical multiple linear regression analyses were conducted with continuous MoCA scores as the dependent variable. RESULTS: Data were available for 1,140 participants, mean (standard deviation [SD]) = 68.48 (7.23) years, comprising 377 (33.1%) ethnic Malays, 414 (36.3%) Chinese, and 349 (30.6%) Indians. Mean (SD) MoCA scores were 20.44 (4.92), 23.97 (4.03), and 22.04 (4.83) for Malays, Chinese, and Indians, respectively (p = 0.01). Age >75 years, <12 years of education, and low functional ability were common risk factors for low cognitive performance across all three ethnic groups. Cognitive performance was positively associated with social engagement among the ethnic Chinese (ß [95% CI] = 0.06 [0.01, 0.11]) and Indians (ß [95% CI] = 0.16 [0.09, 0.23]) and with lower depression scores (ß [(95% CI] = -0.08 [-0.15, -0.01]) among the ethnic Indians. CONCLUSION: Common factors associated with cognitive performance include age, education, and functional ability, and ethnic-specific factors were social engagement and depression. Interethnic comparisons of risk factors may form the basis for identification of ethnic-specific modifiable risk factors for cognitive decline and provision of culturally acceptable prevention measures.

Prevalence of orthostatic hypertension and its association with cerebrovascular diagnoses in patients with suspected TIA and minor stroke.

PURPOSE: We aimed to compare the rate of stroke, transient ischemic attack, and cerebrovascular disease diagnoses across groups of patients based on their orthostatic blood pressure response in a transients ischemic attack clinic setting. MATERIALS AND METHODS: We retrospectively analysed prospectively collected data from 3201 patients referred to a transient ischemic attack (TIA)/minor stroke outpatients clinic. Trained nurses measured supine and standing blood pressure using an automated blood pressure device and the patients were categorized based on their orthostatic blood pressure change into four groups: no orthostatic blood pressure rise, systolic orthostatic hypertension, diastolic orthostatic hypertension, and combined orthostatic hypertension. Then, four stroke physicians, who were unaware of patients' orthostatic BP response, assessed the patients and made diagnoses based on clinical and imaging data. We compared the rate of stroke, TIA, and cerebrovascular disease (either stroke or TIA) diagnoses across the study groups using Pearson's χ2 test. The effect of confounders was adjusted using a multivariate logistic regression analysis. RESULTS: Cerebrovascular disease was significantly less common in patients with combined systolic and diastolic orthostatic hypertension compared to the "no rise" group [OR = 0.56 (95% CI 0.35-0.89]. The odds were even lower among the subgroups of patients with obesity [OR = 0.31 (0.12-0.80)], without history of smoking [OR 0.34 (0.15-0.80)], and without hypertension [OR = 0.42 (95% CI 0.19-0.92)]. We found no significant relationship between orthostatic blood pressure rise with the diagnosis of stroke. However, the odds of TIA were significantly lower in patients with diastolic [OR 0.82 (0.68-0.98)] and combined types of orthostatic hypertension [OR = 0.54 (0.32-0.93)]; especially in patients younger than 65 years [OR = 0.17 (0.04-0.73)] without a history of hypertension [OR = 0.34 (0.13-0.91)], and patients who did not take antihypertensive therapy [OR = 0.35 (0.14-0.86)]. CONCLUSION: Our data suggest that orthostatic hypertension may be a protective factor for TIA among younger and normotensive patients.

Comparison of the clinical frailty score (CFS) to the National Emergency Laparotomy Audit (NELA) risk calculator in all patients undergoing emergency laparotomy.

AIM: There is evolving evidence that preoperative frailty predicts outcomes of older adults undergoing emergency laparotomy (EmLap). We assessed frailty scoring in an emergency surgical population that included patients of all ages and then compared this to an established perioperative prognostic score. METHOD: Data from the prospective Emergency Laparoscopic and Laparotomy Scottish Audit (ELLSA; November 2017-October 2018) was used. All adults over 18 were included. Frailty was measured using 7-point clinical frailty score (CFS). OUTCOME MEASURES: 30-day mortality, hospital length of stay (LOS), 30-day readmission. Areas under the receiver-operating characteristic (ROC) curves were calculated for CFS (1-7) and compared to the National Emergency Laparotomy Audit (NELA) score with Forest plots used to compare 30-day mortality across CFS and NELA categories. RESULTS: A total of 2246 patients (median age 65 years [IQR 51-75]; female 51%) underwent EmLap (60% for colorectal pathology). A total of 10.6% were frail preoperatively (≥CFS 5). As CFS increased so did 30-day mortality (2.1% CFS1 to 25.3% CFS6 and 7; ꭓ2 78.2, p < 0.001) and median LOS (10 days CFS1 to 20 days CFS6 and 7; p < 0.001). Readmission rates did not differ significantly across CFS. ROC (95% CI) for mortality was 0.71 (0.65-0.77) for CFS and 0.84 (0.78-0.89) for NELA. Addition of CFS to NELA did not increase ROC value. CONCLUSION: This study supports the prognostic role of frailty in the emergency surgical setting, finding increasing frailty to be associated with increased mortality and longer LOS in adults of all ages. Although NELA performed better, CFS remained predictive and has the advantage of being calculated preoperatively to aid decision-making and treatment planning.

A novel Artificial Intelligence-based tool to assess anticholinergic burden: a survey.

BACKGROUND: many medications possess anticholinergic activity. Their use is associated with a number of serious adverse effects including cognitive effects. The cumulative anticholinergic effect of medications as assessed by tools such as the anticholinergic burden scale (AchB) can identify people particularly at risk of anticholinergic side-effects. Currently, >20 tools are available for clinicians to use, but there is no consensus on the most appropriate tool. METHODS: a newly created online tool-International Anticholinergic Cognitive Burden Tool (IACT)-based on natural language processing and chemical structure analysis, was developed and made available for clinicians to test its functions. We carried out a survey (between 8th of February and 31st of March 2021) to assess the overall need for an assessment tool as well as the usability of the IACT. RESULTS: a total of 110 responses were received from different countries and practitioners' groups. The majority of the participants (86.11%) stated they would use a tool for AchB assessment if available and when they were asked to rate the IACT against other tools, amongst 34 responders, 20.59% rated it better and 8.82% rated it significantly better, 44.12% rated it neither better, nor worse, 14.71% rated it worse and 11.76% somewhat worse. CONCLUSION: there is a need for an anticholinergic burden calculator to assess the anticholinergicity of medications. Tools such as the IACT potentially could meet this demand due to its ability to assign scores to current and new medications appearing on the market based both on their chemical structure and reported adverse pharmacological effects.

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.

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.

Prognostic value of estimated glomerular filtration rate in hospitalised older patients (over 65) with COVID-19: a multicentre, European, observational cohort study.

BACKGROUND: The reduced renal function has prognostic significance in COVID-19 and it has been linked to mortality in the general population. Reduced renal function is prevalent in older age and thus we set out to better understand its effect on mortality. METHODS: Patient clinical and demographic data was taken from the COVID-19 in Older People (COPE) study during two periods (February-June 2020 and October 2020-March 2021, respectively). Kidney function on admission was measured using estimated glomerular filtration rate (eGFR). The primary outcomes were time to mortality and 28-day mortality. Secondary outcome was length of hospital stay. Data were analysed with multilevel Cox proportional hazards regression, and multilevel logistic regression and adjusted for individual patient clinical and demographic characteristics. RESULTS: One thousand eight hundred two patients (55.0% male; median [IQR] 80 [73-86] years) were included in the study. 28-day mortality was 42.3% (n = 742). 48% (n = 801) had evidence of renal impairment on admission. Using a time-to-event analysis, reduced renal function was associated with increased in-hospital mortality (compared to eGFR ≥ 60 [Stage 1&2]): eGFR 45-59 [Stage 3a] aHR = 1.26 (95%CI 1.02-1.55); eGFR 30-44 [Stage 3b] aHR = 1.41 (95%CI 1.14-1.73); eGFR 1-29 [Stage 4&5] aHR = 1.42 (95%CI 1.13-1.80). In the co-primary outcome of 28-day mortality, mortality was associated with: Stage 3a adjusted odds ratio (aOR) = 1.18 (95%CI 0.88-1.58), Stage 3b aOR = 1.40 (95%CI 1.03-1.89); and Stage 4&5 aOR = 1.65 (95%CI 1.16-2.35). CONCLUSION: eGFR on admission is a good independent predictor of mortality in hospitalised older patients with COVID-19 population. We found evidence of a dose-response between reduced renal function and increased mortality.

Multiple house occupancy is associated with mortality in hospitalized patients with COVID-19.

BACKGROUND: In response to the COVID-19 pandemic, many countries mandated staying at home to reduce transmission. This study examined the association between living arrangements (house occupancy numbers) and outcomes in COVID-19. METHODS: Study population was drawn from the COPE study, a multicentre cohort study. House occupancy was defined as: living alone; living with one other person; living with multiple other people; or living in a nursing/residential home. Outcomes were time from admission to mortality and discharge (Cox regression), and Day 28 mortality (logistic regression) analyses were adjusted for key comorbidities and covariates including admission: age, sex, smoking, heart failure, admission C-reactive protein (CRP), chronic obstructive pulmonary disease, estimated glomerular filtration rate, frailty and others. RESULTS: A total of 1584 patients were included from 13 hospitals across UK and Italy: 676 (42.7%) were female, 907 (57.3%) were male, median age was 74 years (range: 19-101). At 28 days, 502 (31.7%) had died. Median admission CRP was 67, 82, 79.5 and 83 mg/l for those living alone, with someone else, in a house of multiple occupancy and in a nursing/residential home, respectively. Compared to living alone, living with anyone was associated with increased mortality: within a couple [adjusted hazard ratios (aHR) = 1.39, 95% confidence intervals (CI) 1.09-1.77, P = 0.007]; living in a house of multiple occupancy (aHR = 1.67, 95% CI 1.17-2.38, P = 0.005); and living in a residential home (aHR = 1.36, 95% CI 1.03-1.80, P = 0.031). CONCLUSION: For patients hospitalized with COVID-19, those living with one or more people had an increased association with mortality, they also exhibited higher CRP indicating increased disease severity suggesting they delayed seeking care.

Comparison between first and second wave of COVID-19 outbreak in older people: the COPE multicentre European observational cohort study.

BACKGROUND: Effective shielding measures and virus mutations have progressively modified the disease between the waves, likewise healthcare systems have adapted to the outbreak. Our aim was to compare clinical outcomes for older people with COVID-19 in Wave 1 (W1) and Wave 2 (W2). METHODS: All data, including the Clinical Frailty Scale (CFS), were collected for COVID-19 consecutive patients, aged ≥65, from 13 hospitals, in W1 (February-June 2020) and W2 (October 2020-March 2021). The primary outcome was mortality (time to mortality and 28-day mortality). Data were analysed with multilevel Cox proportional hazards, linear and logistic regression models, adjusted for wave baseline demographic and clinical characteristics. RESULTS: Data from 611 people admitted in W2 were added to and compared with data collected during W1 (N = 1340). Patients admitted in W2 were of similar age, median (interquartile range), W2 = 79 (73-84); W1 = 80 (74-86); had a greater proportion of men (59.4% vs. 53.0%); had lower 28-day mortality (29.1% vs. 40.0%), compared to W1. For combined W1-W2 sample, W2 was independently associated with improved survival: time-to-mortality adjusted hazard ratio (aHR) = 0.78 [95% confidence interval (CI) 0.65-0.93], 28-day mortality adjusted odds ratio = 0.80 (95% CI 0.62-1.03). W2 was associated with increased length of hospital stay aHR = 0.69 (95% CI 0.59-0.81). Patients in W2 were less frail, CFS [adjusted mean difference (aMD) = -0.50, 95% CI -0.81, -0.18], as well as presented with lower C-reactive protein (aMD = -22.52, 95% CI -32.00, -13.04). CONCLUSIONS: COVID-19 older adults in W2 were less likely to die than during W1. Patients presented to hospital during W2 were less frail and with lower disease severity and less likely to have renal decline.

Determinants of healthy ageing: a systematic review of contemporary literature.

BACKGROUND: Healthy ageing frameworks have been highly explored. Our objective was to assess existing frameworks for healthy ageing and to identify commonly described factors that can potentially act as determinants of healthy ageing. METHODS: We carried out a systematic review by searching five electronic databases (EMBASE, MEDLINE, Cochrane, PsychINFO, and CINAHL) from January 2010 to November 2020 to capture contemporary evidence. Eligible studies needed to report a clear framework of healthy ageing in humans, within one or more of three domains (physical, mental/cognitive, social), in English. No restriction was placed on geographical location. Retrospective studies, studies that did not report a framework of healthy ageing, and studies with a focus on diagnostic measures were excluded. RESULTS: Of 3329 identified records, nine studies met our eligibility criteria and were included. Most of the studies were qualitative or cross sectional, and a majority were carried out in Asia, followed by North America, Australia, and Africa. The ten determinants identified for healthy ageing include physical activity, diet, self-awareness, outlook/attitude, life-long learning, faith, social support, financial security, community engagement, and independence. CONCLUSIONS: We identified ten determinants of healthy ageing proposed by the contemporary evidence base. There appears to be increasing acknowledgement of the instrumental role of social and mental/cognitive well-being as determinants of healthy ageing. The extent to which each determinant contributes to healthy ageing requires further evaluation.

Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals.

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

Association between serum secretory phospholipase A2 and risk of ischaemic stroke.

BACKGROUND AND PURPOSE: Previous literature has demonstrated an association between high serum levels of type II secretory phospholipase A2 (sPLA2) concentration and an increased risk of coronary artery disease. However, such association has not been established in terms of ischaemic stroke risk. The aim was to evaluate the association between both sPLA2 concentration and activity as continuous variables with risk of future ischaemic stroke. METHODS: A nested case-control study was conducted using data from the European Prospective Investigation into Cancer-Norfolk study. Cases (n = 145) in the current study were participants who developed ischaemic stroke during follow-up, with controls (n = 290) matched in a 2:1 ratio based on age and sex. Statistical analyses were performed using SPSS (version 25.0) software. Logistic regression was used to determine odds ratios (OR) and corresponding 95% confidence intervals (95% CIs) for ischaemic stroke. RESULTS: After adjusting for a wide array of cardiovascular confounders, sPLA2 activity was found to be associated with an increased risk of ischaemic stroke using both multiple imputations with chained equations and complete case analysis: OR 1.20 (95% CI 1.01-1.43) and OR 1.23 (95% CI 1.01-1.49), respectively. However, sPLA2 concentration was not found to be associated with increased risk of ischaemic stroke. CONCLUSIONS: The activity of sPLA2, but not sPLA2 concentration, is associated with an increased risk of future ischaemic stroke. This finding may be significant in risk group stratification, allowing targeted prophylactic treatment, or the development of novel therapeutic agents.