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Supplemental Digital Content is available in the text., Background and Purpose: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. Methods: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis. Results: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55–1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61–1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19–1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20–1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53–1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82–1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89–1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30–0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49–1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71–0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (

ObjectiveTo estimate the incidence and HRs for bleeding for different dual antiplatelet therapies (DAPT) in a real-world population with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in England.DesignA retrospective, population-based cohort study emulating a target randomised controlled trial (tRCT).Data sourcesLinked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES).SettingPrimary and secondary care.ParticipantsPatients ≥18 years old with ACS undergoing emergency PCI.InterventionsAspirin and clopidogrel (AC, reference) versus aspirin and prasugrel (AP) or aspirin and ticagrelor (AT); AP evaluated only in patients with ST-elevation myocardial infarction (STEMI).Main outcome measuresPrimary: any bleeding up to 12 months after the index event (HES- or CPRD- recorded). Secondary: HES-recorded bleeding, CPRD-recorded bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular and cerebrovascular events (MACCE).ResultsIn ACS, the rates of any bleeding for AC and AT were 89 per 1000 person years and 134 per 1000 person years, respectively. In STEMI, rates for AC, AP and AT were 93 per 1000 person years, 138 per 1000 person years and 143 per 100 person years, respectively. In ACS, compared with AC, AT increased the hazard of any bleeding (HR: 1.47, 95% CI 1.19 to 1.82) but did not reduce MACCE (HR: 1.06, 95% CI 0.89 to 1.27). In STEMI, compared with AC, AP and AT increased the hazard of any bleeding (HR: 1.77, 95% CI 1.21 to 2.59 and HR: 1.50, 95% CI 1.10 to 2.05, respectively) but did not reduce MACCE (HR: 1.10, 95% CI 0.80 to 1.51 and HR: 1.21, 95% CI 0.94 to 1.51, respectively). Non-adherence to the prescribed DAPT regimen was 28% in AC (29% in STEMI only), 31% in AP (STEMI only) and 33% in AT (32% in STEMI only).ConclusionsIn a real-world population with ACS, DAPT with ticagrelor or prasugrel are associated with increased bleeding compared with DAPT with clopidogrel.Trial registration numberISRCTN76607611.

Purpose A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review of randomised controlled trials (RCTs) in patients with solid tumours aimed to determine the efficacy of statin therapy on mortality outcomes, their safety profile and the risk of bias of included studies. Methods Full-text articles comparing statin therapy versus control in solid tumours and reporting mortality outcomes were identified from Medline and Embase from conception to February 2020. A systematic review with qualitative (primarily) and quantitative synthesis was conducted. This systematic review was prospectively registered (Prospero registration CRD42018116364). Results Eleven trials of 2165 patients were included. Primary tumour sites investigated included lung, colorectal, gastro-oesophageal, pancreatic and liver. Most trials recruited patients with advanced malignancy and used sub-maximal statin doses for relatively short durations. Aside from one trial which demonstrated benefit with allocation to pravastatin 40 mg in hepatocellular carcinoma, the remaining ten trials did not demonstrate efficacy with statins. The pooled hazard ratio for all-cause mortality with allocation to pravastatin in patients with hepatocellular carcinoma in two trials was 0.69 (95% confidence interval CI 0.30–1.61). Study estimates were imprecise. There were no clinically important differences in statin-related adverse events between groups. Overall, included trials were deemed low risk of bias. Conclusion The trial evidence is not sufficiently robust to confirm or refute the efficacy and safety of statins in patients with solid malignant tumours. Study and patient characteristics may explain this uncertainty. The potential role of high-dose statins in adjuvant settings deserves further research.

Background:\ud Benzodiazepines and anticholinergic drugs have been implicated in causing cognitive decline and potentially increasing dementia risk. However, evidence for an association with neuropathology is limited.\ud \ud Objective:\ud To estimate the correlation between neuropathology at death and prior use of benzodiazepines and anticholinergic drugs.\ud \ud Methods:\ud We categorized 298 brain donors from the population-based Medical Research Council Cognitive Function and Ageing Study, according to their history of benzodiazepine (including Z-drugs) or anticholinergic medication (drugs scoring 3 on the Anticholinergic Cognitive Burden scale) use. We used logistic regression to compare dichotomized neuropathological features for those with and without history of benzodiazepine and anticholinergic drug use before dementia, adjusted for confounders.\ud \ud Results:\ud Forty-nine (16%) and 51 (17%) participants reported benzodiazepine and anticholinergic drug use. Alzheimer’s disease neuropathologic change was similar whether or not exposed to either drug, for example 46% and 57% had intermediate/high levels among those with and without anticholinergic drug use. Although not significant after multiple testing adjustments, we estimated an odds ratio (OR) of 0.40 (95% confidence interval [95% CI] 0.18–0.87) for anticholinergic use and cortical atrophy. For benzodiazepine use, we estimated ORs of 4.63 (1.11–19.24) and 3.30 (1.02–10.68) for neuronal loss in the nucleus basalis and substantial nigra. There was evidence of neuronal loss in the nucleus basalis with anticholinergic drug use, but the association reduced when adjusted for confounders.\ud \ud Conclusions:\ud We found no evidence that benzodiazepine or anticholinergic drug use is associated with typical pathological features of Alzheimer’s disease; however, we cannot rule out effects owing to small numbers.

Background Idiopathic pulmonary fibrosis is a progressive disease and antifibrotic therapies do not reverse existing fibrosis. There has been emerging evidence of potential role for statins in idiopathic pulmonary fibrosis. The aim of this review is to synthesise the evidence on the efficacy of statins in idiopathic pulmonary fibrosis, focusing on associations with all-cause mortality, disease-specific mortality and change in pulmonary function. Methods Medline and Embase were reviewed to identify relevant publications. Studies were selected if they examined disease-related outcomes including mortality, pulmonary function and adverse events in people with idiopathic pulmonary fibrosis receiving statin therapy. Results Five studies with a total of 3407 people with IPF were selected and analysed. The overall risk of bias of five included studies was moderate to serious. In the fixed effect meta-analysis, statin use was associated with a reduction in mortality (RR 0.8; 95% CI 0.72–0.99). However, in the random effects model, there was no longer any significant association between statin use and all-cause mortality (RR 0.87; 95% CI 0.68–1.12). There was no statistically significant association between statin use and decline in FVC % predicted. Conclusion There is currently insufficient evidence to conclude the effect of statin therapy on disease-related outcomes in idiopathic pulmonary fibrosis. Considering the limitations of available literature, we would recommend a prospective cohort study with capture of dosage and preparation of statin, statin adherence and use of concurrent antifibrotic treatment. PROSPERO registration number CRD42019122745.

BACKGROUND: Anticholinergic medication use is linked with increased cognitive decline, dementia, falls and mortality, and their use should be limited in older people. Here we estimate the prevalence of anticholinergic use in England's older population in 1991 and 2011, and describe changes in use by participant's age, sex, cognition and disability. METHODS: We compared data from participants aged 65+ years from the Cognitive Function and Ageing Studies (CFAS I and II), collected during 1990-1993 (N = 7635) and 2008-2011 (N = 7762). We estimated the prevalence of potent anticholinergic use (Anticholinergic Cognitive Burden [ACB] score = 3) and average anticholinergic burden (sum of ACB scores), using inverse probability weights standardised to the 2011 UK population. These were stratified by age, sex, Mini-Mental State Examination score, and activities of daily living (ADL) or instrumental ADL (IADL) disability. RESULTS: Prevalence of potent anticholinergic use increased from 5.7% (95% Confidence Interval [CI] 5.2-6.3%) of the older population in 1990-93 to 9.9% (9.3-10.7%) in 2008-11, adjusted odds ratio of 1.90 (95% CI 1.67-2.16). People with clinically significant cognitive impairment (MMSE [Mini Mental State Examination] 21 or less) were the heaviest users of potent anticholinergics in CFAS II (16.5% [95% CI 12.0-22.3%]). Large increases in the prevalence of the use medication with 'any' anticholinergic activity were seen in older people with clinically significant cognitive impairment (53.3% in CFAS I to 71.5% in CFAS II). CONCLUSIONS: Use of potent anticholinergic medications nearly doubled in England's older population over 20 years with some of the greatest increases amongst those particularly vulnerable to anticholinergic side-effects.

AimTo estimate the association between patterns of anticholinergic, benzodiazepine, and Z-drug medication use and change in cognitive function in middle-aged and older adults.MethodThis prospective cohort study used data from the first three waves of The Irish Longitudinal Study on Ageing (TILDA), including community-dwelling adults aged ≥50 years followed for up to four years (n=7,027).Cognitive function was assessed using the Mini Mental State Examination, animal naming test, and word recall tests. Regular medication use was self-reported at baseline and follow-up interviews at two and four years. Pharmacy dispensing claims for a subset (n=2,905) allowed assessment of medication use between interviews and cumulative dosage. Medication use at consecutive waves of TILDA was analysed in relation to change in cognitive function between waves.ResultsStrongly anticholinergic medications (Anticholinergic Cognitive Burden scale 3), benzodiazepines, and Z-drugs were reported by 7.3%, 5.8% and 5.1% of participants respectively at any time during the study. Adjusting for potential confounders, new anticholinergic use between interviews was associated with change in recall score (−1.09, 95% confidence interval −1.64, −0.53) over 2 years compared to non-use, but not with MMSE (0.07; 95%CI -0.21, 0.34) or animal naming (−0.70; −1.43, 0.03). The pharmacy claims analysis was consistent with this finding. Other hypothesised associations were not supported.DiscussionExcept for new use of anticholinergic medications, no other findings supported a risk of cognitive decline over 2-year periods in this middle-aged and older cohort. Patients and prescribers should weigh this potential risk against potential benefits of commencing anticholinergic medications.What is already known about this subject:Benzodiazepines, Z-drugs and drugs with anticholinergic activity have been linked with cognitive impairment.Most evidence is derived from observational studies of older people, with little research on middle-aged adults.Medication effects may be confounded by indication and these medications are often prescribed for early symptoms of prodromal stages of dementia.What this study adds:In this study of adults aged 50 years and older, no consistent pattern of change in cognitive function was associated with the medication exposures tested, except for reduced recall among new users of anticholinergic medications.Further research in the younger-old adult population should be conducted to confirm these findings.

BackgroundThe rates of readmission for serious cardiovascular events among patients admitted with a diagnosis of non-specific chest pain are unknown.MethodsA national retrospective cohort study in the United States was undertaken to evaluate the rates, trends and predictors of readmission for serious cardiovascular events (acute coronary syndrome (ACS), pulmonary embolism (PE) and aortic dissection (AD)) after an inpatient episode with a primary diagnosis of non-specific chest pain.ResultsAmong 1,172,430 patients with an index diagnosis of non-specific chest pain between 2010 and 2014, 2.4% were readmitted with an ACS, 0.4% with a PE and 0.06% with an AD within 6 months of discharge. Predictors of ACS readmissions were diabetes (OR 1.49 95% CI 1.17–1.32), coronary artery disease (OR 2.29 95% CI 2.15–2.44), previous percutaneous coronary intervention (OR 1.65 95% CI 1.56–1.75), previous CABG (OR 1.52 95% CI 1.43–1.61) and discharge against medical advice (OR 1.94 95% CI 1.78–2.12). Female patients (OR 0.82 95% CI 0.78–0.86) and patients in whom a coronary angiogram was undertaken (OR 0.48 95% CI 0.45–0.52) were less likely to be readmitted for ACS. For PE, predictors of readmission were pulmonary circulatory disorder (OR 2.20 95% CI 1.09–4.43), anemia (OR 1.62 95% CI 1.40–1.86) and cancer (OR 4.15 95% CI 3.43–5.02). Peripheral vascular disease (OR 8.63 95% CI 5.47–13.60), renal failure (OR 2.08 95% CI 1.34–3.24) were predictors of AD.ConclusionsNon-specific chest pain may not be a benign condition as readmissions for serious cardiovascular events occur in 3% of patients within 180 days. Research is needed to define measures that may mitigate readmissions among these patients.

Objectives Methodological research has been undertaken to investigate the many challenges in searching for adverse effects data. It is imperative that the search approach adopted in systematic reviews is based on the best available evidence. We provide a detailed summary of the results and implications of the current evidence base to assist future searches for adverse effects. Study Design and Setting This article is a narrative review from the authors of the Cochrane Handbook chapter on adverse effects. Results The specified search strategy must be based on the population, intervention, comparator, outcome(s) format for question formulation and appropriate study designs for adverse effects data. Search filters and suggested search terms are available for the adverse effects of drug, medical devices, and surgical interventions. The use of generic adverse effects terms (such as harms and complications) as text words and indexing terms and specific adverse effects terms (such as rash and wound infection) are warranted. Searching databases beyond MEDLINE has proven useful, as well as the use of nondatabase sources. Conclusion This article provides the most up-to-date evidence-based guidance in identifying adverse effects data in the literature. It will support searchers and researchers evaluating the potential for harm of medical interventions in systematic reviews.

Background Objectively derived search filters for adverse drug effects and complications in surgery have been developed but not for medical device adverse effects. Objective To develop and validate search filters to retrieve evidence on medical device adverse effects from ovid medline and embase. Methods We identified systematic reviews from Epistemonikos and the Health Technology Assessment (hta) database. Included studies within these reviews that reported on medical device adverse effects were randomly divided into three test sets and one validation set of records. Using word frequency analysis from one test set, we constructed a sensitivity maximising search strategy. This strategy was refined using two other test sets, then validated. Results From 186 systematic reviews which met our inclusion criteria, 1984 unique included studies were available from medline and 1986 from embase. Generic adverse effects searches in medline and embase achieved 84% and 83% sensitivity. Recall was improved to over 90%, however, when specific adverse effects terms were added. Conclusion We have derived and validated novel search filters that retrieve over 80% of records with medical device adverse effects data in medline and embase. The addition of specific adverse effects terms is required to achieve higher levels of sensitivity.

Aims The optimal diet for cardiovascular health is controversial. The aim of this review is to summarize the highest level of evidence and rank the risk associated with each individual component of diet within its food group. Methods and results A systematic search of PudMed was performed to identify the highest level of evidence available from systematic reviews or meta-analyses that evaluated different dietary components and their associated risk of all-cause mortality and cardiovascular disease. A total of 16 reviews were included for dietary food item and all-cause mortality and 17 reviews for cardiovascular disease. Carbohydrates were associated with a reduced risk of all-cause mortality (whole grain bread: relative risk (RR) 0.85, 95% confidence interval (CI) 0.82–0.89; breakfast cereal: RR 0.88, 95% CI 0.83–0.92; oats/oatmeal: RR 0.88, 95% CI 0.83–0.92). Fish consumption was associated with a small benefit (RR 0.98, 95% CI 0.97–1.00) and processed meat appeared to be harmful (RR 1.25, 95% CI 1.07–1.45). Root vegetables (RR 0.76, 95% CI 0.66–0.88), green leafy vegetables/salad (RR 0.78, 95% CI 0.71–0.86), cooked vegetables (RR 0.89, 95% CI 0.80–0.99) and cruciferous vegetables (RR 0.90, 95% CI 0.85–0.95) were associated with reductions in all-cause mortality. Increased mortality was associated with the consumption of tinned fruit (RR 1.14, 95% CI 1.07–1.21). Nuts were associated with a reduced risk of mortality in a dose–response relationship (all nuts: RR 0.78, 95% CI 0.72–0.84; tree nuts: RR 0.82, 95% CI 0.75–0.90; and peanuts: RR 0.77, 95% CI 0.69–0.86). For cardiovascular disease, similar associations for benefit were observed for carbohydrates, nuts and fish, but red meat and processed meat were associated with harm. Conclusions Many dietary components appear to be beneficial for cardiovascular disease and mortality, including grains, fish, nuts and vegetables, but processed meat and tinned fruit appear to be harmful.

Chest pain is a common reason for admission to hospital and little is known regarding 30-day unplanned readmissions after an admission with a primary discharge diagnosis of nonspecific chest pain. We analyzed patients with a primary diagnosis of nonspecific chest pain in the Nationwide Readmission Database who were admitted in 2010 to 2014. Rates, causes, and predictors of 30-day unplanned readmissions were determined. A total of 1, 842, 270 patients had a diagnosis of nonspecific chest pain. The 30-day unplanned readmission rate was 8.6%. From 2010 to 2014, there was an increase in 30- day unplanned readmissions from 8.1% to 9.5%. The majority of 30-day unplanned readmissions were for noncardiac reasons (73.4%). The 3 most prevalent noncardiac causes for readmissions were neuropsychiatric (10.9%), gastrointestinal (10.5%), and infections (9.9%), while the 3 most prevalent cardiac causes were coronary artery disease including angina (8.4%), arrhythmias (6.6%), and heart failure 5.5%. The strongest predictors of readmission were alcohol misuse ([OR] odds ratio 1.74 95% [CI] confidence interval 1.66– 1.81), renal failure (OR 1.82 95%CI 1.76–1.87), cancer (OR 2.40 95%CI 2.27–2.53), discharge to a nursing home (OR 2.26 95%CI 2.18–2.34), and discharge against medical advice (OR 1.94 95%CI 1.86– 2.02). The rate of 30-day unplanned readmission was 6.1% among those who received any test compared to 9.3% in those who did not receive any test. Rates of early unplanned readmissions occur following 1 in 12 admissions for nonspecific chest pain with noncardiac causes being the most common reason. Patients who receive a cardiovascular investigation appear to have fewer unplanned readmissions.

Previous estimates of whether long-term exposure to benzodiazepines increases dementia risk are conflicting and are compromised by the difficulty of controlling for confounders and by reverse causation. We investigated how estimates for the association between benzodiazepine use and later dementia incidence varied based on study design choices, using a case-control study nested within the United Kingdom’s Clinical Practice Research Datalink. A total of 40,770 dementia cases diagnosed between April 2006 and July 2015 were matched on age, sex, available data history, and deprivation to 283,933 control subjects. Benzodiazepines and Z-drug prescriptions were ascertained in a drug-exposure period 4–20 years before dementia diagnosis. Estimates varied with the inclusion of new or prevalent users, with the timing of covariate ascertainment, and with varying time between exposure and outcome. There was no association between any new prescription of benzodiazepines and dementia (adjusted odds ratio (OR) = 1.03, 95% confidence interval (CI): 1.00, 1.07), whereas an inverse association was observed among prevalent users (adjusted OR = 0.91, 95% CI: 0.87, 0.95), although this was likely induced by unintentional adjustment for colliders. By considering the choice of confounders and timing of exposure and covariate measurement, our findings overall are consistent with no causal effect of benzodiazepines or Z-drugs on dementia incidence.

AimsWe conducted a meta-analysis of serious adverse events (dementia, macro- and micro-vascular events, falls and fractures, and death) associated with hypoglycemia in older patients treated with glucose lowering drugs.Materials and MethodsMeta-analysis of studies reporting on hypoglycemia and adverse events. The search included studies from two previously published systematic reviews, and an updated search of MEDLINE and EMBASE from April 2014 to November 2019. We assessed study validity based on ascertainment of hypoglycemia, adverse events and adjustment for confounders, and conducted a random effects meta-analyses, assessing heterogeneity using the I2 statistic.ResultsWe included 44 studies involving 2,507,434 participants. Most of the studies used adjusted analysis for confounders and hypoglycaemic events were typically identified based on healthcare databases (severe events). Hypoglycemia was associated with increased likelihood of death in a meta-analysis of eighteen studies, pooled OR 2.02 (95% Confidence Interval 1.75–2.32). Studies assessing mortality signal a time-response relationship with a higher risk of adverse events occurring within the first 90 days after hypoglycemia. Our meta-analysis of nine studies demonstrated that hypoglycaemic episodes were associated with dementia – pooled OR 1.50 (95% CI 1.29–1.74). Our meta-analysis of nineteen studies demonstrated associations between hypoglycaemia and macrovascular complications, pooled OR 1.81 (95% CI 1.70–1.94), and microvascular complications (two studies) pooled OR 1.77 (95% CI 1.49–2.10). There is also an association between hypoglycemia and cardiovascular death (six studies) – pooled OR 2.11 (95% CI 1.55 to 2.87). Similarly, our meta-analysis of six studies demonstrated an association between hypoglycemia and falls and fractures, pooled OR 1.78 (95% CI 1.44–2.21) and 1.68 (95% CI 1.37–2.07) respectively.ConclusionThis meta-analysis confirms previously reported concerns of serious harm following hypoglycemia, especially in the immediate time period after a hypoglycaemic event. Avoidance of hypoglycaemic episodes should be a priority in this vulnerable population.

Despite the availability of tests to diagnose acute myocardial infarction (AMI), cases are still missed.We systematically reviewed the literature to determine how missed AMI has been defined, the reported rates of misdiagnosed AMI, the outcomes patients with misdiagnosed AMI have, what diagnosis was initially suspected in missed AMI cases, and what factors are associated with misdiagnosed AMI. We searched MEDLINE and EMBASE in September 2020 for studies that evaluated missed AMI. Data were extracted from studies that met the inclusion criteria and the results were narratively synthesized.A total of 15 studies were included in this review. The number of patients with missed AMI in individual studies ranged from 64 to 4707. There was no consistently used definition for misdiagnosed AMI, but most studies reported rates of approximately 1%-2%. Compared with AMI that was recognized, 1 study found no difference in mortality for misdiagnosed AMI at 30 days and 1 year. The common initial misdiagnoses that subsequently had AMI were ischemic heart disease, nonspecific chest pain, gastrointestinal disease, musculoskeletal pain, and arrhythmias. Reasons for missed AMI include incorrect electrocardiogram interpretation and failure to order appropriate diagnostic tests. Hospitals in rural areas and those with a low proportion of classical chest pain patients that turned out to have AMI were at greater risk of missed AMI.Misdiagnosed AMI is an unfortunate part of everyday clinical practice and better training in electrocardiogram interpretation, and education about atypical presentations of AMI may reduce the number of misdiagnosed AMIs.

Background Sleep disturbance affects around 60% of people living with dementia and can negatively affect their quality of life and that of their carers. Hypnotic Z-drugs (zolpidem, zopiclone and zaleplon) are commonly used to treat insomnia, but their safety and efficacy have not been evaluated for people living with dementia. Objectives To estimate the benefits and harms of Z-drugs in people living with dementia with sleep disturbance. Design A series of observational cohort studies using existing data from (1) primary care linked to hospital admission data and (2) clinical cohort studies of people living with dementia. Data sources Primary care study – Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data. Clinical cohort studies – the Resource Use and Disease Course in Dementia – Nursing Homes (REDIC) study, National Alzheimer’s Coordinating Centre (NACC) clinical data set and the Improving Well-being and Health for People with Dementia (WHELD) in nursing homes randomised controlled trial. Setting Primary care study – 371 primary care practices in England. Clinical cohort studies – 47 nursing homes in Norway, 34 Alzheimer’s disease centres in the USA and 69 care homes in England. Participants Primary care study – NHS England primary care patients diagnosed with dementia and aged > 55 years, with sleep disturbance or prescribed Z-drugs or low-dose tricyclic antidepressants, followed over 2 years. Clinical cohort studies – people living with dementia consenting to participate, followed over 3 years, 12 years and 9 months, for REDIC, NACC and WHELD, respectively. Interventions The primary exposure was prescription or use of Z-drugs. Secondary exposures included prescription or use of benzodiazepines, low-dose tricyclic antidepressants and antipsychotics. Main outcome measures Falls, fractures, infection, stroke, venous thromboembolism, mortality, cognitive function and quality of life. There were insufficient data to investigate sleep disturbance. Results The primary care study and combined clinical cohort studies included 6809 and 18,659 people living with dementia, with 3089 and 914 taking Z-drugs, respectively. New Z-drug use was associated with a greater risk of fractures (hazard ratio 1.40, 95% confidence interval 1.01 to 1.94), with risk increasing with greater cumulative dose (p = 0.002). The hazard ratio for Z-drug use and hip fracture was 1.59 (95% confidence interval 1.00 to 2.53) and for mortality was 1.34 (95% confidence interval 1.10 to 1.64). No excess risks of falls, infections, stroke or venous thromboembolism were detected. Z-drug use also did not have an impact on cognition, neuropsychiatric symptoms, disability or quality of life. Limitations Primary care study – possible residual confounding because of difficulties in identifying patients with sleep disturbance and by dementia severity. Clinical cohort studies – the small numbers of people living with dementia taking Z-drugs and outcomes not necessarily being measured before Z-drug initiation restricted analyses. Conclusions We observed a dose-dependent increase in fracture risk, but no other harms, with Z-drug use in dementia. However, multiple outcomes were examined, increasing the risk of false-positive findings. The mortality association was unlikely to be causal. Further research is needed to confirm the increased fracture risk. Decisions to prescribe Z-drugs may need to consider the risk of fractures, balanced against the impact of improved sleep for people living with dementia and that of their carers. Our findings suggest that when Z-drugs are prescribed, falls prevention strategies may be needed, and that the prescription should be regularly reviewed. Future work More research is needed on safe and effective management strategies for sleep disturbance in people living with dementia. Study registration This study is registered as European Union electronic Register of Post-Authorisation Studies (EU PAS) 18006. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 1. See the NIHR Journals Library website for further project information.

Objectives This systematic review (PROSPERO CRD42019115918) compared the evidence behind anticholinergic burden (ACB) measures and their ability to predict changes in older people's physical function and quality of life. Design Eligible cohort or case-control studies were identified systematically using comprehensive search terms and a validated search filter for prognostic studies. Medline (OVID), EMBASE (OVID), CINAHL (EMBSCO), and PsycINFO (OVID) databases were searched. Risk of bias, using Quality in Prognosis Studies tool, and quality of evidence, using the Grading of Recommendations, Assessment, Development and Evaluation, were assessed. Setting and Participants People aged 65 years and older from any clinical setting. Measures Any ACB measures were accepted (including the anticholinergic domain of the Drug Burden Index). Any global/multidimensional measure for physical function and/or quality of life was accepted for outcome. Results Thirteen studies reporting associations between ACB and physical function (n = 10) or quality of life (n = 4) were included. Exposure measures included Anticholinergic Cognitive Burden Scale, Anticholinergic Drug Scale, Anticholinergic Risk Scale, Clinician Rated Anticholinergic Score, and the anticholinergic domain of the Drug Burden Index. All studies were rated moderate risk of bias in ≥2 Quality in Prognosis Studies categories with 5 rated high risk in ≥1 categories. Seven of 10 studies (5251 of 7569 participants) reported significant decline in physical function with increased burden. All 4 studies (2635 participants) reporting quality of life demonstrated similar association with increased burden. High risk of biases and inadequate data reporting restricted analysis. There was no evidence to support one measure being superior to another. Conclusions and Implications The evidence supports association between increased ACB and future impairments in physical function and quality of life. No conclusion can be made regarding which ACB measure has the best prognostic value. Well-designed longitudinal studies are required to address this. Clinicians should be aware of patient's anticholinergic burden and consider alternative medications where appropriate.

The role of dietary calcium in cardiovascular disease prevention is unclear. We aimed to determine the association between calcium intake and incident cardiovascular disease and mortality. Data were extracted from the European Prospective Investigation of Cancer, Norfolk (EPIC-Norfolk). Multivariable Cox regressions analysed associations between calcium intake (dietary and supplemental) and cardiovascular disease (myocardial infarction, stroke, heart failure, aortic stenosis, peripheral vascular disease) and mortality (cardiovascular and all-cause). The results of this study were pooled with those from published prospective cohort studies in a meta-analsyis, stratifying by average calcium intake using a 700 mg/day threshold. A total of 17,968 participants aged 40–79 years were followed up for a median of 20.36 years (20.32–20.38). Compared to the first quintile of calcium intake (

BackgroundSleep disturbance is common in dementia and often treated with Z-drugs (zopiclone, zaleplon, and zolpidem). While some observational studies suggest that Z-drugs are associated with adverse events such as falls and fracture risks in older people, this has not been studied in dementia.MethodsWe used data from 27,090 patients diagnosed with dementia between January 2000 and March 2016 from the Clinical Practice Research Datalink linked to Hospital Episodes Statistics data in England. We compared adverse events for 3532 patients newly prescribed Z-drugs by time-varying dosage to (1) 1833 non-sedative-users with sleep disturbance; (2) 10,214 non-sedative-users with proximal GP consultation matched on age, sex, and antipsychotic use; and (3) 5172 patients newly prescribed benzodiazepines. We defined higher dose Z-drugs and benzodiazepines as prescriptions equivalent to ≥ 7.5 mg zopiclone or > 5 mg diazepam daily. Cox regression was used to estimate hazard ratios (HRs) for incident fracture, hip fracture, fall, mortality, acute bacterial infection, ischaemic stroke/transient ischaemic attack, and venous thromboembolism over a 2-year follow-up, adjusted for demographic- and health-related covariates.ResultsThe mean (SD) age of patients was 83 (7.7) years, and 16,802 (62%) were women. Of 3532 patients prescribed Z-drugs, 584 (17%) were initiated at higher doses. For patients prescribed higher dose Z-drugs relative to non-users with sleep disturbance, the HRs (95% confidence interval) for fractures, hip fractures, falls, and ischaemic stroke were 1.67 (1.13–2.46), 1.96 (1.16–3.31), 1.33 (1.06–1.66), and 1.88 (1.14–3.10), respectively. We observed similar associations when compared to non-sedative-users with proximal GP consultation. Minimal or inconsistent excess risks were observed at ≤ 3.75 mg zopiclone or equivalent daily, and for mortality, infection, and venous thromboembolism. We observed no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs (HR [95% confidence interval] of 0.73 [0.64–0.83]).ConclusionsHigher dose Z-drug use in dementia is associated with increased fracture and stroke risks, similar or greater to that for higher dose benzodiazepines. Higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered. Prescriptions for higher dose Z-drugs in dementia should be regularly reviewed.Trial registrationENCePP e-register of studies,EUPAS18006

Background the long-term effect of the use of drugs with anticholinergic activity on cognitive function remains unclear. Methods we conducted a systematic review and meta-analysis of the relationship between anticholinergic drugs and risk of dementia, mild cognitive impairment (MCI) and cognitive decline in the older population. We identified studies published between January 2002 and April 2018 with ≥12 weeks follow-up between strongly anticholinergic drug exposure and the study outcome measurement. We pooled adjusted odds ratios (OR) for studies reporting any, and at least short-term (90+ days) or long-term (365+ days) anticholinergic use for dementia and MCI outcomes, and standardised mean differences (SMD) in global cognition test scores for cognitive decline outcomes. Statistical heterogeneity was measured using the I2 statistic and risk of bias using ROBINS-I. Results twenty-six studies (including 621,548 participants) met our inclusion criteria. ‘Any’ anticholinergic use was associated with incident dementia (OR 1.20, 95% confidence interval [CI] 1.09–1.32, I2 = 86%). Short-term and long-term use were also associated with incident dementia (OR 1.23, 95% CI 1.17–1.29, I2 = 2%; and OR 1.50, 95% CI 1.22–1.85, I2 = 90%). ‘Any’ anticholinergic use was associated with cognitive decline (SMD 0.15; 95% CI 0.09–0.21, I2 = 3%) but showed no statistically significant difference for MCI (OR 1.24, 95% CI 0.97–1.59, I2 = 0%). Conclusions anticholinergic drug use is associated with increased dementia incidence and cognitive decline in observational studies. However, a causal link cannot yet be inferred, as studies were observational with considerable risk of bias. Stronger evidence from high-quality studies is needed to guide the management of long-term use.

Background Cognitive impairment and dementia following cerebrovascular disease are increasingly common in the UK. One potential strategy to prevent post-stroke cognitive decline is multimodal vascular risk factor management. However, its efficacy remains uncertain and its application in vulnerable patients with incident cerebrovascular disease and early cognitive impairment has not been assessed. The primary aim of this study was to assess the feasibility of recruitment and retention of patients with early cognitive impairment post-stroke or transient ischaemic attack (TIA) to a trial of enhanced vascular risk factor management combining primary and secondary care. Methods In this single centre, open label trial adults with a recent stroke or TIA and mild cognitive impairment (MCI) were randomised 1:1 to a three-monthly multimodal vascular risk factor intervention jointly delivered by the trial team and General Practitioner (GP), or control (defined as usual care from the GP). Chosen risk factors were blood pressure (BP), total cholesterol, blood glucose (HbA1C) in those with diabetes, and heart rate and adequacy of anticoagulation in those with atrial fibrillation (AF). Similar patients with normal cognition were enrolled in an embedded observational cohort and also received usual care from the GP. Repeat cognitive screening was undertaken in all participants after 12 months. Results Seventy three participants were recruited to the randomised trial and 94 to the observational cohort (21.8% of those screened). From the randomised trial 35/73 (47.9%) dropped out before final follow-up. In all groups guideline based rates of risk factor control were mostly poor at baseline and did not significantly improve during follow-up. The observational cohort demonstrated greater decline in cognitive test scores at 12 months, with no difference between the randomised groups. Conclusions Recruitment to such a study was feasible, but retention of participants was difficult and generally poor rates of risk factor control suggested insufficient application of the intervention. Consequently, successful scaling up of the trial would require protocol changes with less reliance on primary care services. Any future trial should include participants with normal cognition post-stroke as they may be at greatest risk of cognitive decline. Trial registration ISRCTN, ISRCTN42688361. Registered 16 April 2015.

BACKGROUND: Anticholinergic medication use is linked with increased cognitive decline, dementia, falls and mortality, and their use should be limited in older people. Here we estimate the prevalence of anticholinergic use in England's older population in 1991 and 2011, and describe changes in use by participant's age, sex, cognition and disability. METHODS: We compared data from participants aged 65+ years from the Cognitive Function and Ageing Studies (CFAS I and II), collected during 1990-1993 (N = 7635) and 2008-2011 (N = 7762). We estimated the prevalence of potent anticholinergic use (Anticholinergic Cognitive Burden [ACB] score = 3) and average anticholinergic burden (sum of ACB scores), using inverse probability weights standardised to the 2011 UK population. These were stratified by age, sex, Mini-Mental State Examination score, and activities of daily living (ADL) or instrumental ADL (IADL) disability. RESULTS: Prevalence of potent anticholinergic use increased from 5.7% (95% Confidence Interval [CI] 5.2-6.3%) of the older population in 1990-93 to 9.9% (9.3-10.7%) in 2008-11, adjusted odds ratio of 1.90 (95% CI 1.67-2.16). People with clinically significant cognitive impairment (MMSE [Mini Mental State Examination] 21 or less) were the heaviest users of potent anticholinergics in CFAS II (16.5% [95% CI 12.0-22.3%]). Large increases in the prevalence of the use medication with 'any' anticholinergic activity were seen in older people with clinically significant cognitive impairment (53.3% in CFAS I to 71.5% in CFAS II). CONCLUSIONS: Use of potent anticholinergic medications nearly doubled in England's older population over 20 years with some of the greatest increases amongst those particularly vulnerable to anticholinergic side-effects.

Background Anticholinergic medication use is linked with increased cognitive decline, dementia, falls and mortality, and their use should be limited in older people. Here we estimate the prevalence of anticholinergic use in England’s older population in 1991 and 2011, and describe changes in use by participant’s age, sex, cognition and disability. Methods We compared data from participants aged 65+ years from the Cognitive Function and Ageing Studies (CFAS I and II), collected during 1990–1993 (N = 7635) and 2008–2011 (N = 7762). We estimated the prevalence of potent anticholinergic use (Anticholinergic Cognitive Burden [ACB] score = 3) and average anticholinergic burden (sum of ACB scores), using inverse probability weights standardised to the 2011 UK population. These were stratified by age, sex, Mini-Mental State Examination score, and activities of daily living (ADL) or instrumental ADL (IADL) disability. Results Prevalence of potent anticholinergic use increased from 5.7% (95% Confidence Interval [CI] 5.2–6.3%) of the older population in 1990–93 to 9.9% (9.3–10.7%) in 2008–11, adjusted odds ratio of 1.90 (95% CI 1.67–2.16). People with clinically significant cognitive impairment (MMSE [Mini Mental State Examination] 21 or less) were the heaviest users of potent anticholinergics in CFAS II (16.5% [95% CI 12.0–22.3%]). Large increases in the prevalence of the use medication with ‘any’ anticholinergic activity were seen in older people with clinically significant cognitive impairment (53.3% in CFAS I to 71.5% in CFAS II). Conclusions Use of potent anticholinergic medications nearly doubled in England’s older population over 20 years with some of the greatest increases amongst those particularly vulnerable to anticholinergic side-effects.

INTRODUCTION: Older age is associated with multimorbidity and polypharmacy with high anticholinergic burden (ACB). High ACB is linked to adverse events such as poor physical functioning, dementia, cardiovascular disease, and falls. Interventions are needed to reduce this burden. AIMS/OBJECTIVES: The aim was to systematically review the literature to identify and describe studies of clinical and cost-effectiveness of interventions designed to reduce ACB in adults (≥65 years) on polypharmacy regimes, compared with usual care. The objective was to answer the following questions: What are the contents of the interventions? Were these interventions clinically effective? Were these interventions cost effective?. DESIGN, SETTING, AND PARTICIPANTS: Systematic review of interventions to reduce anticholinergic burden in adults aged 65 and older in any clinical setting. METHODS: Eligible papers reported primary or secondary research describing any type of intervention including systematic reviews, randomized controlled trials (RCTs), controlled clinical trials, or nonrandomized pre-post intervention studies (PPIs) published in English from January 2010 to February 2019. Databases searched included CINAHL, Ovid MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials (CENTRAL). RESULTS: The search yielded 5862 records. Eight studies (4 RCTs, 4 PPIs) conducted in hospital (4), community (2), nursing homes (1), and retirement villages (1) met the inclusion criteria. Pharmacists, either individually or as part of a team, provided the intervention in the majority of studies (6/8). Most (7/8) involved individual patient medication review followed by feedback to the prescriber. Two of the 4 RCTs and all non-RCTs reported a decrease in ACB following the intervention. No study reported cost outcome. CONCLUSIONS/IMPLICATIONS: Pharmacists may be well placed to implement an ACB reduction intervention. This is the first systematic review of interventions to reduce ACB in older adults, and it highlights the need for development and testing of high-quality pragmatic clinical and cost-effectiveness trials in community and specific patient populations at high risk of harm from ACB. [PROSPERO registration: CRD42018089764].

Background Statins inhibit proliferative signalling in oesophageal adenocarcinoma (OAC) and their use is associated with better survival in observational studies. The present study was undertaken to examine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III RCT. Methods For this multicentre, double‐blind, parallel‐group, randomized, placebo‐controlled feasibility trial, adults with OAC (including Siewert I–II lesions) who had undergone oesophagectomy were centrally allocated (1 : 1) to simvastatin 40 mg or matching placebo by block randomization, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Patients received treatment for up to 1 year. Feasibility outcomes were recruitment, retention, drug absorption, adherence, safety, quality of life, generalizability and survival. Results A total of 120 patients were assessed for eligibility at four centres, of whom 32 (26·7 per cent) were randomized, 16 in each group. Seven patients withdrew. Participants allocated to simvastatin had lower low‐density lipoprotein cholesterol levels by 3 months (adjusted mean difference −0·83 (95 per cent c.i. −1·4 to −0·22) mmol/l; P = 0·009). Median adherence to medication was greater than 90 per cent between 3 and 12 months' follow‐up. Adverse events were similar between the groups. Quality‐of‐life data were complete for 98·3 per cent of questionnaire items. Cardiovascular disease, diabetes and aspirin use were more prevalent in the non‐randomized group, whereas tumour site, stage and grade were similar between groups. Survival estimates were imprecise. Conclusion This RCT supports the conduct and informs the design considerations for a future phase III trial of adjuvant statin therapy in patients with OAC. Registration number: ISRCTN98060456 (http://www.isrctn/com)., After oesophagectomy for oesophageal adenocarcinoma (OAC), the 5‐year survival rate is currently only 30 per cent. There is strong observational evidence that statin use is associated with reduced all‐cause and cancer‐specific mortality in patients with OAC. This multicentre, double‐blind, parallel‐group, randomized, placebo‐controlled trial has established the feasibility of a future phase III trial of adjuvant statin therapy in patients treated with curative intent for invasive OAC. Justification for a full trial

The optimal regimen of antiplatelet therapy for secondary prevention in noncardioembolic ischemic stroke remains controversial. We aimed to determine which regimen was associated with the greatest reduction in adverse outcomes. We analysed prospectively collected data from the Norfolk and Norwich University Hospital Stroke Register. The sample population consisted of 3,572 participants (mean age 74.96 ± 12.67) with ischemic stroke, who were consecutively admitted between 2003 and 2015. Patients were placed on one of three antiplatelet regimens at hospital discharge; aspirin monotherapy, aspirin plus dipyridamole and clopidogrel. Clopidogrel and aspirin plus dipyridamole were compared to aspirin. A direct comparison between clopidogrel and aspirin plus dipyridamole was also performed. Outcomes included all-cause mortality and a combined end point of all-cause mortality and incidence of major adverse cardiac events (stroke or myocardial infarction). Cox-regression models adjusted for potential confounders at the following time periods after discharge; 0 to 90 days, 91 to 365 days, and 1 to 3 years. Aspirin plus dipyridamole was associated with a lower risk of mortality at 0 to 90 days; hazard ratio (HR) 0.62 (0.43 to 0.91). Clopidogrel was associated with a lower risk of mortality at 1 to 3 years; HR of 0.39 (0.26 to 0.60). Similar HRs were observed for the corresponding time points in the composite outcome. In conclusion, patients with noncardioembolic stroke may gain maximum benefits from aspirin plus dipyridamole initially (≤1 year) with a subsequent switch to clopidogrel, with regard to mortality and major adverse cardiac eventsoutcomes.

Introduction Adverse drug reactions (ADRs) are associated with significant health-related and financial burden, and multiple sources are currently utilized to actively discover them. Social media has been proposed as a potential resource for monitoring ADRs, but drug-specific analytical studies comparing social media with other sources are scarce. Objectives Our objective was to develop methods to compare ADRs mentioned in social media with those in traditional sources: the US FDA Adverse Event Reporting System (FAERS), drug information databases (DIDs), and systematic reviews. Methods A total of 10,188 tweets mentioning adalimumab collected between June 2014 and August 2016 were included. ADRs in the corpus were extracted semi-automatically and manually mapped to standardized concepts in the Unified Medical Language System. ADRs were grouped into 16 biologic categories for comparisons. Frequencies, relative frequencies, disproportionality analyses, and rank ordering were used as metrics. Results There was moderate agreement between ADRs in social media and traditional sources. “Local and injection site reactions” was the top ADR in Twitter, DIDs, and systematic reviews by frequency, ranked frequency, and index ranking. The next highest ADR in Twitter—fatigue—ranked fifth and seventh in FAERS and DIDs. Conclusion Social media posts often express mild and symptomatic ADRs, but rates are measured differently in scientific sources. ADRs in FAERS are reported as absolute numbers, in DIDs as percentages, and in systematic reviews as percentages, risk ratios, or other metrics, which makes comparisons challenging; however, overlap is substantial. Social media analysis facilitates open-ended investigation of patient perspectives and may reveal concepts (e.g. anxiety) not available in traditional sources. Electronic supplementary material The online version of this article (10.1007/s40264-018-0707-6) contains supplementary material, which is available to authorized users.

Background Search filter development for adverse effects has tended to focus on retrieving studies of drug interventions. However, a different approach is required for surgical interventions. Objective To develop and validate search filters for medline and Embase for the adverse effects of surgical interventions. Methods Systematic reviews of surgical interventions where the primary focus was to evaluate adverse effect(s) were sought. The included studies within these reviews were divided randomly into a development set, evaluation set and validation set. Using word frequency analysis we constructed a sensitivity maximising search strategy and this was tested in the evaluation and validation set. Results Three hundred and fifty eight papers were included from 19 surgical intervention reviews. Three hundred and fifty two papers were available on medline and 348 were available on Embase. Generic adverse effects search strategies in medline and Embase could achieve approximately 90% relative recall. Recall could be further improved with the addition of specific adverse effects terms to the search strategies. Conclusion We have derived and validated a novel search filter that has reasonable performance for identifying adverse effects of surgical interventions in medline and Embase. However, we appreciate the limitations of our methods, and recommend further research on larger sample sizes and prospective systematic reviews.

Despite advancement in medical and surgical techniques, small bowel obstruction (SBO) continues to be a challenge for general surgeons. Although hernias were the most common etiology of SBO a century ago, postoperative adhesions now account for at least 75 % of small bowel obstructions. Additional etiologies of obstruction include tumors and less commonly, Crohn’s disease, volvulus, intussusception, gallstone ileus, and bezoar. Operative versus nonoperative management strategies have been compared with respect to recurrence of SBO; one in three surgically treated patients recur compared to one in two medically managed patients. Despite this, many patients are successfully managed nonoperatively, albeit with repeat emergency department visits.

Authors and indexers are increasingly including terms for adverse drug effects in the titles, abstracts or indexing of records in MEDLINE and Embase. However, it is not clear if this is the same for studies with non-drug adverse effects data. We therefore assessed the feasibility of using adverse effects terms when searching MEDLINE or Emabse to retrieve papers of non-drug adverse effects. A collection of papers that reported data on non-drug adverse effects was sought from included studies of systematic reviews. Each included study was analysed to ascertain whether the corresponding record in MEDLINE and Embase included adverse effects terms in the title, abstract or indexing. From 9,129 records screened from DARE (Database of Abstracts of Reviews of Effects), 30 reviews evaluating non-drug adverse effects met our inclusion criteria. From these, 635 unique papers were included in our analysis. Sensitive searches for adverse effects required generic and specific named adverse effects terms using the title, abstract and indexing. Records relating to surgical interventions were more likely to contain adverse effects terms than records relating to non-surgical interventions. Using any adverse effects terms in the title, abstract or indexing in MEDLINE and Embase would have identified an average of 94% of papers on surgical adverse effect interventions per systematic review and 72% of papers on non-surgical adverse effects per systematic review. Hence, while a generic non-drug adverse effect search filter may not yet be feasible, a filter for the adverse effects of surgical interventions may be within reach.

ObjectivesOlder people with diabetes are at increased risk of harm from hypoglycaemia, particularly where there are coexisting memory problems. Continuous glucose monitoring (CGM) offers important benefits in terms of detecting hypoglycaemia, but the feasibility of use and extent of data capture has not been tested in this patient group. Our objective was to investigate the feasibility of trialling a CGM intervention in the community setting in older people with diabetes and memory problems.DesignMixed-methods feasibility study.SettingCommunity dwellings in the UK.ParticipantsPatients aged ≥65 with diabetes and abbreviated mental test score ≤8 or known dementia.InterventionFreeStyle Libre CGM.Primary and secondary outcome measuresFeasibility criteria were numbers of eligible patients, recruitment, attrition, extent of capture of glucose readings and adverse events. Qualitative interview.ResultsWe identified 49 eligible participants; 17 consented, but 5 withdrew before recording of data because they or their carers felt unable to manage study procedures. 12 participants (mean age 85 years) completed the study without adverse events. Data capture across 14 days ranged between 3% and 92% (mean 55%); 6 participants had ConclusionsThe device was acceptable to participants, and carers reported greater ease in monitoring the participant’s glucose concentrations. However, completeness of data capture varied considerably with this device due to the need for users to conduct ≥3 scans per day. Real-time devices with automated data transfer may be more suitable in older people with memory problems.

Real-world epidemiology gives us the unique opportunity to observe large numbers of people, and the actions and events that characterize their encounters with healthcare providers. However, the heterogeneity and sheer diversity of the population and healthcare systems makes it impossible for researchers to compare "like with like" when attempting to draw causal inferences about interventions and outcomes. The critical issue in epidemiological datasets relates to high risk of bias due to confounders that stem from baseline differences between groups. Propensity score (PS) techniques are statistical approaches that have been used to tackle potential imbalance in the comparison groups. The PS is the estimated probability (based on measured baseline covariates) that the patient receives a particular intervention. Patients that share similar PS will most likely have the same distributions of underlying covariates included in the PS. Implementation of PS methods may achieve better balance of covariates, but there is no consensus on the best way of capturing all relevant confounders for incorporation into the PS model. Should covariates be selected by clinical or epidemiological experts, or would data-driven algorithms (machine learning) offer more efficient and reliable methods of estimating PS and controlling for confounding? The PS can be incorporated into the analysis in different ways, each with its own strengths and limitations, and researchers must choose the best fit for their study objectives. PS methods are particularly advantageous in situations where there are large numbers of measured covariates but relatively few outcome events captured in healthcare administrative databases.

Older individuals with diabetes are susceptible to harm as the result of hypoglycaemia; however, the consequences of hypoglycaemia in older individuals with dementia are not known. We aimed to test the association between hypoglycaemia and serious adverse events in older patients with diabetes and dementia, and whether the consequences of hypoglycaemia were affected by the presence of dementia.This was a cohort study using the Clinical Practice Research Datalink in England (1997-2016). We selected participants, intervention (exposure) and follow-up to mirror two hypothetical target randomized controlled trials. The exposure of target trial 1 was hypoglycaemia in patients with dementia. Target trial 2 examined adverse effects of hypoglycaemia according to dementia status. We used Cox proportional hazard regression to estimate adjusted hazard ratios (aHR) for falls, fractures, cardiovascular events and mortality.In target trial 1, hypoglycaemia was associated with increased risk during a 12-month follow-up period for falls and fractures (aHR, 1.94 [95% CI, 1.67-2.24]), for cardiovascular events (aHR, 2.00 [95% CI, 1.61-2.48]) and for mortality (aHR, 2.36 [95% CI, 2.09-2.67]). In target trial 2, the presence of dementia was associated with increased risk of adverse events, following hypoglycaemia, during a 12-month follow-up period for falls and factures (aHR, 1.72 [95% CI, 1.51-1.96]) and for mortality (aHR, 1.27 [95% CI, 1.15-1.41]), but dementia had no effect on cardiovascular events (aHR, 1.14 [95% CI, 0.95 to 1.36]).Hypoglycaemia is associated with early increased risk of serious adverse events in older individuals with diabetes and dementia.

Background Metabolomics refers to study of the metabolome, the entire set of metabolites produced by a biological system. The application of metabolomics to exhaled breath samples - breathomics - is a rapidly growing field with potential application to asthma diagnosis and management. Objectives We aimed to review the adult asthma breathomic literature and present a comprehensive list of volatile organic compounds identified by asthma breathomic models. Methods We undertook a systematic search for literature on exhaled volatile organic compounds in adult asthma. We assessed the quality of studies and performed a qualitative synthesis. Results We identified twenty studies; these were methodologically heterogenous with a variable risk of bias. Studies almost universally reported breathomics to be capable of differentiating - with moderate or greater accuracy - between samples from healthy controls and those with asthma; and to be capable of phenotyping disease. However, there was little concordance in the compounds upon which discriminatory models were based. Conclusion Results to-date are promising but validation in independent prospective cohorts is needed. This may be challenging given the high levels of inter-individual variation. However, large-scale, multi-centre studies are underway and validation efforts have been aided by the publication of technical standards likely to increase inter-study comparability. Successful validation of breathomic models for diagnosis and phenotyping would constitute an important step towards personalised medicine in asthma.

Introduction‘Real world’ bleeding in patients exposed to different regimens of dual antiplatelet therapy (DAPT) and triple therapy (TT, DAPT plus an anticoagulant) have a clinical and economic impact but have not been previously quantified.Methods and analysisWe will use linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data to assemble populations eligible for three ‘target trials’ in patient groups: percutaneous coronary intervention (PCI); coronary artery bypass grafting (CABG); conservatively managed (medication only) acute coronary syndrome (ACS). Patients ≥18 years old will be eligible if, in CPRD records, they have: ≥1 year of data before the index event; no prescription for DAPT or anticoagulants in the preceding 3 months; a prescription for aspirin or DAPT within 2 months after discharge from the index event. The primary outcome will be any bleeding event (CPRD or HES) up to 12 months after the index event. We will estimate adjusted HR for time to first bleeding event comparing: aspirin and clopidogrel (reference) versus aspirin and prasugrel or aspirin and ticagrelor after PCI; and aspirin (reference) versus aspirin and clopidogrel after CABG and ACS. We will describe rates of bleeding in patients prescribed TT (DAPT plus an anticoagulant). Potential confounders will be identified systematically using literature review, semistructured interviews with clinicians and a short survey of clinicians. We will conduct sensitivity analyses addressing the robustness of results to the study’s main limitation—that we will not be able to identify the intervention group for patients whose bleeding event occurs before a DAPT prescription in CPRD.Ethics and disseminationThis protocol was approved by the Independent Scientific Advisory Committee for the UK Medicines and Healthcare Products Regulatory Agency Database Research (protocol 16_126R) and the South West Cornwall and Plymouth Research Ethics Committee (17/SW/0092). The findings will be presented in peer-reviewed journals, lay summaries and briefing papers to commissioners/other stakeholders.Trial registration number76607611; Pre-results.

Objective: The objective of this study is to determine factors associated with loneliness in older adults presenting for hearing loss treatment. Method: A cross-sectional analysis was conducted of 145 participants (aged 50-94) who presented for hearing aids or cochlear implants and were enrolled in the Studying Multiple Outcomes After Aural Rehabilitative Treatment (SMART) study from 2011 to 2013. Social, communicative, physical, and mental health functioning were assessed using self-administered questionnaires, and loneliness using the University of California, Los Angeles (UCLA) Loneliness Scale. Results: Younger age and greater hearing loss were significantly associated with greater loneliness. Metrics of depressive symptoms and hearing-related quality of life, communication difficulties, and emotional well-being, mental health, and 36-Item Medical Outcomes Study Short-Form (SF-36) scores were moderately or highly correlated with loneliness. Discussion: Younger age and greater hearing loss are independently associated with higher levels of loneliness in older adults presenting to clinic for hearing loss treatment. Further studies needed to determine whether hearing treatment can reduce loneliness in older adults.

The primary aim of this study was to conduct a systematic review of reports of patients with cervical spondylotic myelopathy and to assess the value of intraoperative monitoring (IOM), including somatosensory evoked potentials, transcranial motor evoked potentials and electromyography, in anterior cervical procedures. A search was conducted to collect a small database of relevant papers using key words describing disorders and procedures of interest. The database was then shortlisted using selection criteria and data was extracted to identify complications as a result of anterior cervical procedures for cervical spondylotic myelopathy and outcome analysis on a continuous scale. In the 22 studies that matched the screening criteria, only two involved the use of IOM. The average sample size was 173 patients. In procedures done without IOM a mean change in Japanese Orthopaedic Association score of 3.94 points and Nurick score by 1.20 points (both less severe post-operatively) was observed. Within our sub-group analysis, worsening myelopathy and/or quadriplegia was seen in 2.71% of patients for studies without IOM and 0.91% of patients for studies with IOM. Variations persist in the existing literature in the evaluation of complications associated with anterior cervical spinal procedures. Based on the review of published studies, sufficient evidence does not exist to make recommendations regarding the use of different IOM modalities to reduce neurological complications during anterior cervical procedures. However, future studies with objective measures of neurological deficits using a specific IOM modality may establish it as an effective and reliable indicator of injury during such surgeries.

Background: Incidentally elevated cardiac troponin I (cTnI) levels are common in acutely unwell older patients. However, little is known about how this impacts on the prognosis of these patients. Objective: We aimed to investigate whether incidentally elevated cTnI levels (group 1) are associated with poorer outcome when compared to age- and sex-matched patients without an elevated cTnI level (group 2), and to patients diagnosed with acute coronary syndrome (group 3). Patients and Methods: This prospective, matched cohort study placed patients ≥75 years old who were admitted to a University teaching hospital into groups 1-3, based on the cTnI levels and underlying diagnosis. Outcomes were compared between the groups using mixed-effects regression models and adjusted for renal function and C-reactive protein. All-cause mortality at discharge, at 1 month and 3 months, alongside the length of hospital stay (LOS), were recorded. Results: In total, 315 patients were included, with 105 patients in each of the 3 groups. The mean age was 84.8 ± 5.5 years, with 41.9% males. All patients were followed up for 3 months. The percent all-cause mortality at discharge and the LOS for groups 1, 2 and 3 were 12.4, 3.8 and 8.6% and 11.2, 8.5 and 7.7 days, respectively. Group 1 had significantly increased mortality at 3 months [odds ratio (OR) 2.80, 95% confidence interval (CI) 1.12-6.96; p = 0.040] and LOS (OR 1.39, 95% CI 1.08-1.79; p = 0.008) compared to group 2 and did not differ significantly when compared to 3-month mortality (OR 2.39, 95% CI 0.91-6.29; p = 0.079) or LOS (OR 1.26, 95% CI 0.96-1.66; p = 0.097) in group 3. Conclusion: There is a significant association between an incidental rise in cTnI level with mortality and LOS in older patients. Further research is required to evaluate whether a more systematic management of these patients would improve the prognosis.

Background: Adenosine administered as an adjunct to reperfusion can reduce coronary no-reflow and limit myocardial infarct (MI) size in ST-segment elevation myocardial infarction (STEMI) patients. Whether adjunctive adenosine therapy can improve clinical outcomes in reperfused STEMI patients is not clear and is investigated in this meta-analysis of 13 randomized controlled trials (RCTs). Methods: We performed an up-to-date search for all RCTs investigating adenosine as an adjunct to reperfusion in STEMI patients. We calculated pooled relative risks using a fixed-effect meta-analysis assessing the impact of adjunctive adenosine therapy on major clinical endpoint including all-cause mortality, non-fatal myocardial infarction, and heart failure. Surrogate markers of reperfusion were also analyzed. Results: 13 RCTs (4273 STEMI patients) were identified and divided into 2 subgroups: intracoronary adenosine versus control (8 RCTs) and intravenous adenosine versus control (5 RCTs). In patients administered intracoronary adenosine, the incidence of heart failure was significantly lower (risk ratio [RR] 0.44 [95% CI 0.25–0.78], P = 0.005) and the incidence of coronary no-reflow was reduced (RR for TIMI flow

Background Evidence-based guidelines from the World Health Organization (WHO) have recommended a high (80%) fraction of inspired oxygen (FiO2) to reduce surgical site infection in adult surgical patients undergoing general anaesthesia with tracheal intubation. However, there is ongoing debate over the safety of high FiO2. We performed a systematic review to define the relative risk of clinically relevant adverse events (AE) associated with high FiO2. Methods We reviewed potentially relevant articles from the WHO review supporting the recommendation, including an updated (July 2018) search of EMBASE and PubMed for randomised and non-randomised controlled studies reporting AE in surgical patients receiving 80% FiO2 compared with 30–35% FiO2. We assessed study quality and performed meta-analyses of risk ratios (RR) comparing 80% FiO2 against 30–35% for major complications, mortality, and intensive care admission. Results We included 17 moderate–good quality trials and two non-randomised studies with serious-critical risk of bias. No evidence of harm with high FiO2 was found for major AE in the meta-analysis of randomised trials: atelectasis RR 0.91 [95% confidence interval (CI) 0.59–1.42); cardiovascular events RR 0.90 (95% CI 0.32–2.54); intensive care admission RR 0.93 (95% CI 0.7–1.12); and death during the trial RR 0.49 (95% CI 0.17–1.37). One non-randomised study reported that high FiO2 was associated with major respiratory AE [RR 1.99 (95% CI 1.72–2.31)]. Conclusions No definite signal of harm with 80% FiO2 in adult surgical patients undergoing general anaesthesia was demonstrated and there is little evidence on safety-related issues to discourage its use in this population.

Aim We conducted a systematic review of the use of continuous glucose monitoring (CGM) in older patients, in order to consolidate the growing evidence base in this area. Methods Our protocol was registered on PROSPERO (CRD42017068523). We searched SCI Web of Science, Ovid SP MEDLINE and EMBASE from January 2010 to June 2017 for observational studies and randomized controlled trial of CGM in older patients (mean age 65 or older) with diabetes. We excluded studies that involved only hospitalized patients. Two reviewers independently extracted data blood sugar values (in particular, hypoglycemic episodes) captured with the use of CGM. We also assessed adverse events and acceptability of CGM. Results After screening 901 abstracts, we included nine studies with a total of 989 older patients with diabetes. The CGM studies reveal that hypoglycemic episodes were occurring in a sizeable proportion (28–65%) of participants. Most (80–100%) of these episodes were asymptomatic, with some patients spending nearly 2 h per day in the hypoglycemic range. Older people with diabetes found CGM acceptable and experienced improved health-related well-being. Conclusion CGM frequently picks up asymptomatic hypoglycemic episodes in older patients with diabetes. Users of CGM report improved well-being, and reduction of diabetes-related stress.

Objectives To estimate the association between the duration and level of exposure to different classes of anticholinergic drugs and subsequent incident dementia. Design Case-control study. Setting General practices in the UK contributing to the Clinical Practice Research Datalink. Participants 40 770 patients aged 65-99 with a diagnosis of dementia between April 2006 and July 2015, and 283 933 controls without dementia. Interventions Daily defined doses of anticholinergic drugs coded using the Anticholinergic Cognitive Burden (ACB) scale, in total and grouped by subclass, prescribed 4-20 years before a diagnosis of dementia. Main outcome measures Odds ratios for incident dementia, adjusted for a range of demographic and health related covariates. Results 14 453 (35%) cases and 86 403 (30%) controls were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. The adjusted odds ratio for any anticholinergic drug with an ACB score of 3 was 1.11 (95% confidence interval 1.08 to 1.14). Dementia was associated with an increasing average ACB score. When considered by drug class, gastrointestinal drugs with an ACB score of 3 were not distinctively linked to dementia. The risk of dementia increased with greater exposure for antidepressant, urological, and antiparkinson drugs with an ACB score of 3. This result was also observed for exposure 15-20 years before a diagnosis. Conclusions A robust association between some classes of anticholinergic drugs and future dementia incidence was observed. This could be caused by a class specific effect, or by drugs being used for very early symptoms of dementia. Future research should examine anticholinergic drug classes as opposed to anticholinergic effects intrinsically or summing scales for anticholinergic exposure. Trial registration Registered to the European Union electronic Register of Post-Authorisation Studies EUPAS8705.

World Health Organization Responds to Concerns about Surgical Site Infection Prevention Recommendations.

Background There is growing evidence that sleep duration and quality may be associated with cardiovascular harm and mortality. Methods and Results We conducted a systematic review, meta‐analysis, and spline analysis of prospective cohort studies that evaluate the association between sleep duration and quality and cardiovascular outcomes. We searched MEDLINE and EMBASE for these studies and extracted data from identified studies. We utilized linear and nonlinear dose‐response meta‐analysis models and used DerSimonian–Laird random‐effects meta‐analysis models of risk ratios, with inverse variance weighting, and the I 2 statistic to quantify heterogeneity. Seventy‐four studies including 3 340 684 participants with 242 240 deaths among 2 564 029 participants who reported death events were reviewed. Findings were broadly similar across both linear and nonlinear dose‐response models in 30 studies with >1 000 000 participants, and we report results from the linear model. Self‐reported duration of sleep >8 hours was associated with a moderate increased risk of all‐cause mortality, with risk ratio , 1.14 (1.05–1.25) for 9 hours, risk ratio, 1.30 (1.19–1.42) for 10 hours, and risk ratio, 1.47 (1.33–1.64) for 11 hours. No significant difference was identified for periods of self‐reported sleep , 1.44; 95% confidence interval, 1.09–1.90), but no difference in mortality and other outcomes. Conclusions Divergence from the recommended 7 to 8 hours of sleep is associated with a higher risk of mortality and cardiovascular events. Longer duration of sleep may be more associated with adverse outcomes compared with shorter sleep durations.