Publications by authors named "Yoav Ben-Shlomo"

409 Publications

Socio-demographic and psychosocial predictors of salivary cortisol from older male participants in the Speedwell prospective cohort study.

Psychoneuroendocrinology 2021 Oct 28;135:105577. Epub 2021 Oct 28.

Population Health Sciences, University of Bristol Medical School, Bristol, UK.

Introduction: Associations between measures of socio-economic position and cortisol remain controversial. We examined the association between social class and cortisol reactivity in an aging male population.

Methods: The Speedwell cohort study recruited 2348 men aged 45-59 years from primary care between 1979 and 1982 (phase I) where occupational social class was used to classify socioeconomic position. Men were seen on four more occasions, the last being between 1997 and 1999 (phase 5) when salivary samples were obtained capturing cortisol reactivity to stressors (cognitive test and venepuncture) and circadian variations (awakening and night-time cortisol levels, circadian slope and area under curve) at morning and afternoon clinic sessions. Longitudinal association between social class at phase 3 and log-transformed salivary cortisol measures at phase 5 was assessed using multivariable linear regression adjusted for variables associated with sampling time and age as a potential confounder, stratified by time of clinic session. We also explored possible mediation by psychosocial factors (e.g. work dislike) and health-related factors (e.g. waist-to-hip ratio and high-density lipoprotein cholesterol).

Results: From 1768 living men, 1003 men (57%) attended a clinic at phase five, 854 participants (85% of attendees) returned home cortisol samples (mean age 71.7 years). We found little evidence of association between social class and baseline cortisol (i.e. prior to stress), cortisol response to stressors, and cortisol diurnal variation. However, we found lower social class was associated with higher and delayed post-stress recovery cortisol for participants that visited the clinic in the morning (adjusted β coefficient for manual versus non-manual 0.25 ng/ml; 95% CI: 0.06-0.48; P = 0.008). This association did not appear to be mediated by any of the measured psychosocial or health-related factors.

Conclusion: Our data did not show an overall association between social class and cortisol variability either diurnal or in response to a stressor. Lower social class was associated with a slower time to recover from exposure to stress in the morning, thereby increasing overall cortisol exposure. These findings provide some evidence for a mechanism that may contribute to the association between lower social class and a higher risk of adverse health outcomes.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105577DOI Listing
October 2021

Safety and efficacy of losartan for the reduction of brain atrophy in clinically diagnosed Alzheimer's disease (the RADAR trial): a double-blind, randomised, placebo-controlled, phase 2 trial.

Lancet Neurol 2021 Nov;20(11):895-906

Translational Health Sciences, Population Health Sciences, University of Bristol, Bristol, UK; Bristol Trials Centre, University of Bristol, Bristol, UK.

Background: Drugs modifying angiotensin II signalling could reduce Alzheimer's disease pathology, thus decreasing the rate of disease progression. We investigated whether the angiotensin II receptor antagonist losartan, compared with placebo, could reduce brain volume loss, as a measure of disease progression, in clinically diagnosed mild-to-moderate Alzheimer's disease.

Methods: In this double-blind, multicentre, randomised controlled trial, eligible patients aged 55 years or older, previously untreated with angiotensin II drugs and diagnosed (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) with mild-to-moderate Alzheimer's disease, and who had capacity to consent, were recruited from 23 UK National Health Service hospital trusts. After undergoing a 4-week, open-label phase of active treatment then washout, participants were randomly assigned (1:1) oral over-encapsulated preparations of either 100 mg losartan (after an initial two-dose titration stage) or matched placebo daily for 12 months. Randomisation, minimised by age and baseline medial temporal lobe atrophy score, was undertaken online or via pin-access service by telephone. Participants, their study companions, and study personnel were masked to group assignment. The primary outcome, analysed by the intention-to-treat principle (ie, participants analysed in the group to which they were randomised, without imputation for missing data), was change in whole brain volume between baseline and 12 months, measured using volumetric MRI and determined by boundary shift interval (BSI) analysis. The trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN93682878) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2012-003641-15), and is completed.

Findings: Between July 22, 2014, and May 17, 2018, 261 participants entered the open-label phase. 211 were randomly assigned losartan (n=105) or placebo (n=106). Of 197 (93%) participants who completed the study, 171 (81%) had complete primary outcome data. The mean brain volume (BSI) reduction was 19·1 mL (SD 10·3) in the losartan group and 20·0 mL (10·8) in the placebo group. The difference in total volume reduction between groups was -2·29 mL (95% CI -6·46 to 0·89; p=0·14). The number of adverse events was low (22 in the losartan group and 20 in the placebo group) with no differences between treatment groups. There was one treatment-related death per treatment group.

Interpretation: 12 months of treatment with losartan was well tolerated but was not effective in reducing the rate of brain atrophy in individuals with clinically diagnosed mild-to-moderate Alzheimer's disease. Further research is needed to assess the potential therapeutic benefit from earlier treatment in patients with milder cognitive impairment or from longer treatment periods.

Funding: Efficacy and Mechanism Evaluation Programme (UK Medical Research Council and National Institute for Health Research).
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http://dx.doi.org/10.1016/S1474-4422(21)00263-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528717PMC
November 2021

Longitudinal Changes in Parkinson's Disease Symptoms with and Without Rapid Eye Movement Sleep Behavior Disorder: The Oxford Discovery Cohort Study.

Mov Disord 2021 Aug 26. Epub 2021 Aug 26.

Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.

Background: Parkinson's disease (PD) comorbid with rapid eye movement sleep behavior disorder (RBD) may show more severe motor and nonmotor symptoms, suggesting a distinct PD subtype.

Objective: The aim of this study was to investigate the impact of RBD on the longitudinal change of motor and nonmotor symptoms in patients with PD.

Methods: Patients with early PD (diagnosed within 3.5 years) recruited from 2010 to 2019 were followed every 18 months in the Oxford Parkinson's Disease Centre Discovery cohort. At each visit, we used standard questionnaires and measurements to assess demographic features and motor and nonmotor symptoms (including RBD, daytime sleepiness, mood, autonomic symptoms, cognition, and olfaction). Data were analyzed with linear mixed effects and Cox regression models. Possible RBD (pRBD) was longitudinally determined according to RBD Screening Questionnaire scores.

Results: A total of 923 patients were recruited (mean age: 67.1 ± 9.59 years; 35.9% female), and 788 had follow-up assessment(s) (mean: 4.8 ± 1.98 years, range: 1.3-8.3). Among them, 33.3% were identified as pRBD (PD + pRBD). Patients with PD + pRBD had more severe baseline symptoms and showed faster progression on Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts I and III, Purdue Pegboard test, and Beck Depression Inventory scores. Moreover, PD + pRBD was associated with an increased level of risk for mild cognitive impairment (hazard ratio [HR] = 1.36, 95% confidence interval [CI]: 1.01-1.83), freezing of gait (HR = 1.42, 95% CI: 1.10-1.86), and frequent falling (HR = 1.62, 95% CI: 1.02-2.60).

Conclusions: Patients with PD + pRBD progress faster on motor, mood, and cognitive symptoms, confirming a more aggressive PD subtype that can be identified at baseline and has major clinical implications. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28763DOI Listing
August 2021

Interpretation of vaccine associated neurological adverse events: a methodological and historical review.

J Neurol 2021 Aug 16. Epub 2021 Aug 16.

Division of Psychological Medicine and Clinical Neuroscience, Department of Neurology, University Hospital of Wales, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.

As a result of significant recent scientific investment, the range of vaccines available for COVID-19 prevention continues to expand and uptake is increasing globally. Although initial trial safety data have been generally reassuring, a number of adverse events, including vaccine induced thrombosis and thrombocytopenia (VITT), have come to light which have the potential to undermine the success of the vaccination program. However, it can be difficult to interpret available data and put these into context and to communicate this effectively. In this review, we discuss contemporary methodologies employed to investigate possible associations between vaccination and adverse neurological outcomes and why determining causality can be challenging. We demonstrate these issues by discussing relevant historical exemplars and explore the relevance for the current pandemic and vaccination program. We also discuss challenges in understanding and communicating such risks to clinicians and the general population within the context of the 'infodemic' facilitated by the Internet and other media.
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http://dx.doi.org/10.1007/s00415-021-10747-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366487PMC
August 2021

Clinical judgment of GPs for the diagnosis of dementia: a diagnostic test accuracy study.

BJGP Open 2021 Oct 26;5(5). Epub 2021 Oct 26.

Population Health Sciences, University of Bristol, Bristol, UK.

Background: GPs often report using clinical judgment to diagnose dementia.

Aim: To investigate the accuracy of GPs' clinical judgment for the diagnosis of dementia.

Design & Setting: Diagnostic test accuracy study, recruiting from 21 practices around Bristol, UK.

Method: The clinical judgment of the treating GP (index test) was based on the information immediately available at their initial consultation with a person aged ≥70 years who had cognitive symptoms. The reference standard was an assessment by a specialist clinician, based on a standardised clinical examination and made according to the 10th revision of the International Classification of Diseases (ICD-10) criteria for dementia.

Results: A total of 240 people were recruited, with a median age of 80 years (interquartile range [IQR] 75-84 years), of whom 126 (53%) were men and 132 (55%) had dementia. The median duration of symptoms was 24 months (IQR 12-36 months) and the median Addenbrooke's Cognitive Examination III (ACE-III) score was 75 (IQR 65-87). GP clinical judgment had sensitivity 56% (95% confidence interval [CI] = 47% to 65%) and specificity 89% (95% CI = 81% to 94%). Positive likelihood ratio was higher in people aged 70-79 years (6.5, 95% CI = 2.9 to 15) compared with people aged ≥80 years (3.6, 95% CI = 1.7 to 7.6), and in women (10.4, 95% CI = 3.4 to 31.7) compared with men (3.2, 95% CI = 1.7 to 6.2), whereas the negative likelihood ratio was similar in all groups.

Conclusion: A GP clinical judgment of dementia is specific, but confirmatory testing is needed to exclude dementia in symptomatic people whom GPs judge as not having dementia.
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http://dx.doi.org/10.3399/BJGPO.2021.0058DOI Listing
October 2021

Rationale and design to evaluate the PRIME Parkinson care model: a prospective observational evaluation of proactive, integrated and patient-centred Parkinson care in The Netherlands (PRIME-NL).

BMC Neurol 2021 Jul 23;21(1):286. Epub 2021 Jul 23.

Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Background: Culminating evidence shows that current care does not optimally meet the needs of persons with parkinsonism, their carers and healthcare professionals. Recently, a new model of care was developed to address the limitations of usual care: Proactive and Integrated Management and Empowerment in Parkinson's Disease (PRIME Parkinson). From 2021 onwards, PRIME Parkinson care will replace usual care in a well-defined region in The Netherlands. The utility of PRIME Parkinson care will be evaluated on a single primary endpoint (parkinsonism-related complications), which reflects the health of people with parkinsonism. Furthermore, several secondary endpoints will be measured for four dimensions: health, patient and carer experience, healthcare professional experience, and cost of healthcare. The reference will be usual care, which will be continued in other regions in The Netherlands.

Methods: This is a prospective observational study which will run from January 1, 2020 until December 31, 2023. Before the new model of care will replace the usual care in the PRIME Parkinson care region all baseline assessments will take place. Outcomes will be informed by two data sources. We will use healthcare claims-based data to evaluate the primary endpoint, and costs of healthcare, in all persons with parkinsonism receiving PRIME Parkinson care (estimated number: 2,000) and all persons with parkinsonism receiving usual care in the other parts of The Netherlands (estimated number: 48,000). We will also evaluate secondary endpoints by performing annual questionnaire-based assessments. These assessments will be administered to a subsample across both regions (estimated numbers: 1,200 persons with parkinsonism, 600 carers and 250 healthcare professionals).

Discussion: This prospective cohort study will evaluate the utility of a novel integrated model of care for persons with parkinsonism in The Netherlands. We anticipate that the results of this study will also provide insight for the delivery of care to persons with parkinsonism in other regions and may inform the design of a similar model for other chronic health conditions.
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http://dx.doi.org/10.1186/s12883-021-02308-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298196PMC
July 2021

Comparison between four published definitions of hyposmia in Parkinson's disease.

Brain Behav 2021 08 30;11(8):e2258. Epub 2021 Jun 30.

Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.

Objectives: Hyposmia is a common feature of Parkinson's disease (PD), yet there is no standard method to define it. A comparison of four published methods was performed to explore and highlight differences.

Materials And Methods: Olfactory testing was performed in 2097 cases of early PD in two prospective studies. Olfaction was assessed using various cut-offs, usually corrected by age and/or gender. Control data were simulated based on the age and gender structure of the PD cases and published normal ranges. Association with age, gender, and disease duration was explored by method and study cohort. Prevalence of hyposmia was compared with the age and gender-matched simulated controls. Between method agreement was measured using Cohen's kappa and Gwet's AC1.

Results: Hyposmia was present in between 69.1% and 97.9% of cases in Tracking Parkinson's cases, and between 62.2% and 90.8% of cases in the Parkinson's Progression Marker Initiative, depending on the method. Between-method agreement varied (kappa 0.09-0.80, AC1 0.55-0.86). The absolute difference between PD cases and simulated controls was similar for men and women across methods. Age and male gender were positively associated with hyposmia (p < .001, all methods). Odds of having hyposmia increased with advancing age (OR:1.06, 95% CI:1.03, 1.10, p < .001). Longer disease duration had a negative impact on overall olfactory performance.

Conclusions: Different definitions of hyposmia give different results using the same dataset. A standardized definition of hyposmia in PD is required, adjusting for age and gender, to account for the background decline in olfactory performance with ageing, especially in men.
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http://dx.doi.org/10.1002/brb3.2258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413742PMC
August 2021

Associations of GP practice characteristics with the rate of ambulatory care sensitive conditions in people living with dementia in England: an ecological analysis of routine data.

BMC Health Serv Res 2021 Jun 29;21(1):613. Epub 2021 Jun 29.

The National Institute for Health Research and Applied Research Collaboration West (NIHR ARC West), University Hospitals Bristol and Weston NHS Foundation Trust, 9th Floor, Whitefriars, Lewins Mead, Bristol, BS1 2NT, UK.

Background: Hospital admissions for Ambulatory Care Sensitive Conditions (ACSCs) are potentially avoidable. Dementia is one of the leading chronic conditions in terms of variability in ACSC admissions by general practice, as well as accounting for around a third of UK emergency admissions.

Methods: Using Bayesian multilevel linear regression models, we examined the ecological association of organizational characteristics of general practices (ACSC n=7076, non-ACSC n=7046 units) and Clinical Commissioning Groups (CCG n=212 units) in relation to ACSC and non-ACSC admissions for people with dementia in England.

Results: The rate of hospital admissions are variable between GP practices, with deprivation and being admitted from home as risk factors for admission for ACSC and non-ACSC admissions. The budget allocated by the CCG to mental health shows diverging effects for ACSC versus non-ACSC admissions, so it is likely there is some geographic variation.

Conclusions: A variety of factors that could explain avoidable admissions for PWD at the practice level were examined; most were equally predictive for avoidable and non-avoidable admissions. However, a high amount of variation found at the practice level, in conjunction with the diverging effects of the CCG mental health budget, implies that guidance may be applied inconsistently, or local services may have differences in referral criteria. This indicates there is potential scope for improvement.
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http://dx.doi.org/10.1186/s12913-021-06634-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240405PMC
June 2021

Development of an intervention to improve access to living-donor kidney transplantation (the ASK study).

PLoS One 2021 25;16(6):e0253667. Epub 2021 Jun 25.

Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, United Kingdom.

A living-donor kidney transplant (LDKT) is one of the best treatments for kidney failure. The UK's LDKT activity falls behind that of many other countries, and there is evidence of socioeconomic inequity in access. We aimed to develop a UK-specific multicomponent intervention to support eligible individuals to access a LDKT. The intervention was designed to support those who are socioeconomically-deprived and currently disadvantaged, by targeting mediators of inequity identified in earlier work. We identified three existing interventions in the literature which target these mediators: a) the Norway model (healthcare practitioners contact patients' family with information about kidney donation), b) a home education model, and c) a Transplant candidate advocate model. We undertook intervention development using the Person-Based Approach (PBA). We performed in-depth qualitative interviews with people with advanced kidney disease (n = 13), their family members (n = 4), and renal and transplant healthcare practitioners (n = 15), analysed using thematic analysis. We investigated participant views on each proposed intervention component. We drafted intervention resources and revised these in light of comments from qualitative 'think-aloud' interviews. Four general themes were identified: i) Perceived cultural and societal norms; ii) Influence of family on decision-making; iii) Resource limitation, and iv) Evidence of effectiveness. For each intervention discussed, we identified three themes: for the Norway model: i) Overcoming communication barriers and assumptions; ii) Request from an official third party, and iii) Risk of coercion; for the home education model: i) Intragroup dynamics; ii) Avoidance of hospital, and iii) Burdens on participants; and for the transplant candidate advocates model: i) Vested interest of advocates; ii) Time commitment, and iii) Risk of misinformation. We used these results to develop a multicomponent intervention which comprises components from existing interventions that have been adapted to increase acceptability and engagement in a UK population. This will be evaluated in a future randomised controlled trial.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253667PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232417PMC
November 2021

REducing unwarranted variation in the Delivery of high qUality hip fraCture services in England and Wales (REDUCE): protocol for a mixed-methods study.

BMJ Open 2021 05 19;11(5):e049763. Epub 2021 May 19.

Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

Introduction: Substantial variation in the delivery of hip fracture care, and patient outcomes persists between hospitals, despite established UK national standards and guidelines. Patients' outcomes are partly explained by patient-level risk factors, but it is hypothesised that organisational-level factors account for the persistence of unwarranted variation in outcomes. The mixed-methods REducing unwarranted variation in the Delivery of high qUality hip fraCture services in England and Wales (REDUCE) study, aims to determine key organisational factors to target to improve patient care.

Methods And Analysis: Quantitative analysis will assess the outcomes of patients treated at 172 hospitals in England and Wales (2016-2019) using National Hip Fracture Database data combined with English Hospital Episodes Statistics; Patient Episode Database for Wales; Civil Registration (deaths) and multiple organisational-level audits to characterise each service provider. Statistical analyses will identify which organisational factors explain variation in patient outcomes, and typify care pathways with high-quality consistent patient outcomes. Documentary analysis of 20 anonymised British Orthopaedic Association hospital-initiated peer-review reports, and qualitative interviews with staff from four diverse UK hospitals providing hip fracture care, will identify barriers and facilitators to care delivery. The COVID-19 pandemic has posed a major challenge to the resilience of services and interviews will explore strategies used to adapt and innovate. This system-wide understanding will inform the development, in partnership with key national stakeholders, of an 'Implementation Toolkit' to inform and improve commissioning and delivery of hip fracture services.

Ethics And Dissemination: This study was approved: quantitative study by London, City and East Research Ethics Committee (20/LO/0101); and qualitative study by Faculty of Health Sciences University of Bristol Research Ethics Committee (Ref: 108284), National Health Service (NHS) Health Research Authority (20/HRA/71) and each NHS Trust provided Research and Development approval. Findings will be disseminated through scientific conferences, peer-reviewed journals and online workshops.
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http://dx.doi.org/10.1136/bmjopen-2021-049763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137248PMC
May 2021

Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease: a propensity score-matched cohort study.

Health Technol Assess 2021 03;25(17):1-106

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK.

Background: Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects.

Objectives: The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time.

Design: This was a new-user cohort study design with propensity score matching.

Setting And Data Sources: Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1-3 and from the Danish Odense University Hospital Databases for work package 4.

Participants: Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of < 45 ml/minute/1.73 m were eligible. A second estimated glomerular filtration rate value of < 45 ml/minute/1.73 m within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1-3. Patients with < 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1-4.

Interventions/exposure: Bisphosphonate use, identified from primary care prescriptions (for work packages 1-3) or pharmacy dispensations (for work package 4), was the main exposure.

Main Outcome Measures: Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change.

Results: Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users.

Limitations: Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively.

Conclusions: Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness.

Future Work: Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data.

Study Registration: This study is registered as EUPAS10029.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 17. See the NIHR Journals Library website for further project information. The project was also supported by the National Institute for Health Research Biomedical Research Centre, Oxford.
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http://dx.doi.org/10.3310/hta25170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020200PMC
March 2021

The Association Between Frailty and Parkinson's Disease in the ReSPOnD Trial.

Can Geriatr J 2021 Mar 2;24(1):22-25. Epub 2021 Mar 2.

Royal United Hospitals Bath NHS Trust, Bath, UK.

Background: Frailty and Parkinson's disease (PD) are both highly prevalent in older people, but few studies have studied frailty in people with Parkinson's. Identifying frailty in this population is vital, to target new interventions to those who would most benefit.

Methods: Data were collected as part of the double-blind randomised controlled rivastigmine to stabilise gait ReSPonD trial in 130 people with Hoehn and Yahr 2-3, idiopathic PD who had fallen in the year prior to enrolment. Individuals were assessed at baseline and followed up at eight months, including determination of frailty status.

Results: 120 patients attended for follow-up. At follow-up, the mean (SD) age was 70.2 years (8.0), MDS-UPDRS total score 91.5 (29.1), and MDS-UPDRS motor score (Part III) 42.7 (14.8). Median disease duration was 9.2 years (IQR 4.6 to 13.1), Geriatric Depression Score 4 (IQR 2 to 6). Using the Fried frailty criteria, 31 (26%) were frail and 70 (58%) pre-frail. In univariable analysis, being female, higher depression score, and MDS-UPDRS score were associated with greater frailty. Using ordinal regression, in the multivariable model, being female (odds ratio [OR] 3.10, 95%CI 1.53 to 6.26, =.002), higher total MDS-UPDRS score (OR 2.02, 95%CI 1.42 to 2.87, <.0001) and higher depression (OR 1.47, 95%CI 1.05 to 2.06, =.03) were associated with higher number of frailty markers.

Conclusion: There was a high prevalence (84%) of pre-frail and frail individuals in patients participating in this RCT. Future research should determine the optimum tool to assess frailty in this at-risk population, and delineate the association between Parkinson's, frailty, and health outcomes.
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http://dx.doi.org/10.5770/cgj.24.437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904322PMC
March 2021

Olfactory Testing in Parkinson Disease and REM Behavior Disorder: A Machine Learning Approach.

Neurology 2021 04 24;96(15):e2016-e2027. Epub 2021 Feb 24.

From the Oxford Parkinson's Disease Centre (C.L., S.A., T.R.B., J.C.K., M.T.H.), Nuffield Department of Clinical Neurosciences (C.L., T.R.B., J.C.K., M.T.H.), and Saïd Business School (S.A.), University of Oxford; Population Health Sciences (Y.B.-S., M.L., S.K.), University of Bristol, UK; Department of Neurology (A.J., E.S., W.H.O.), Philipps University Marburg; Institute for Neurogenomics (W.H.O.), München Helmholtz Center for Health and Environment, Neuherberg München, Germany; and Institute of Neurological Sciences (D.G.G.), Queen Elizabeth University Hospital, Glasgow, UK.

Objective: We sought to identify an abbreviated test of impaired olfaction amenable for use in busy clinical environments in prodromal (isolated REM sleep behavior disorder [iRBD]) and manifest Parkinson disease (PD).

Methods: Eight hundred ninety individuals with PD and 313 controls in the Discovery cohort study underwent Sniffin' Stick odor identification assessment. Random forests were initially trained to distinguish individuals with poor (functional anosmia/hyposmia) and good (normosmia/super-smeller) smell ability using all 16 Sniffin' Sticks. Models were retrained using the top 3 sticks ranked by order of predictor importance. One randomly selected 3-stick model was tested in a second independent PD dataset (n = 452) and in 2 iRBD datasets (Discovery n = 241, Marburg n = 37) before being compared to previously described abbreviated Sniffin' Stick combinations.

Results: In differentiating poor from good smell ability, the overall area under the curve (AUC) value associated with the top 3 sticks (anise/licorice/banana) was 0.95 in the Development dataset (sensitivity 90%, specificity 92%, positive predictive value 92%, negative predictive value 90%). Internal and external validation confirmed AUCs ≥0.90. The combination of the 3-stick model determined poor smell, and an RBD screening questionnaire score of ≥5 separated those with iRBD from controls with a sensitivity, specificity, positive predictive value, and negative predictive value of 65%, 100%, 100%, and 30%.

Conclusions: Our 3-Sniffin'-Stick model holds potential utility as a brief screening test in the stratification of individuals with PD and iRBD according to olfactory dysfunction.

Classification Of Evidence: This study provides Class III evidence that a 3-Sniffin'-Stick model distinguishes individuals with poor and good smell ability and can be used to screen for individuals with iRBD.
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http://dx.doi.org/10.1212/WNL.0000000000011743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166425PMC
April 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Associations between Deprivation, Geographic Location, and Access to Pediatric Kidney Care in the United Kingdom.

Clin J Am Soc Nephrol 2021 02 19;16(2):194-203. Epub 2021 Jan 19.

Population Health Sciences, University of Bristol Medical School, Bristol, United Kingdom.

Background And Objectives: Pre-emptive kidney transplantation is advocated as best practice for children with kidney failure who are transplant eligible; however, it is limited by late presentation. We aimed to determine whether socioeconomic deprivation and/or geographic location (distance to the center and rural/urban residence) are associated with late presentation, and to what degree these factors could explain differences in accessing pre-emptive transplantation.

Design, Setting, Participants, & Measurements: A cohort study using prospectively collected United Kingdom Renal Registry and National Health Service Blood and Transplant data from January 1, 1996 to December 31, 2016 was performed. We included children aged >3 months to ≤16 years at the start of KRT. Multivariable logistic regression models were used to determine associations between the above exposures and our outcomes: late presentation (defined as starting KRT within 90 days of first nephrology review) and pre-emptive transplantation, with specified covariates.

Results: Analysis was performed on 2160 children (41% females), with a median age of 3.8 years (interquartile range, 0.2-9.9 years) at first nephrology review. Excluding missing data, 478 were late presenters (24%); 565 (26%) underwent pre-emptive transplantation, none of whom were late presenting. No association was seen between distance or socioeconomic deprivation with late presentation, in crude or adjusted analyses. Excluding late presenters, greater area affluence was associated with higher odds of pre-emptive transplantation, (odds ratio, 1.20 per quintile greater affluence; 95% confidence interval, 1.10 to 1.31), with children of South Asian (odds ratio, 0.52; 95% confidence interval, 0.36 to 0.76) or Black ethnicity (odds ratio, 0.31; 95% confidence interval, 0.12 to 0.80) less likely to receive one. A longer distance to the center was associated with pre-emptive transplantation on crude analyses; however, this relationship was attenuated (odds ratio, 1.02 per 10 km; 95% confidence interval, 0.99 to 1.05) in the multivariable model.

Conclusions: Socioeconomic deprivation or geographic location are not associated with late presentation in children in the United Kingdom. Geographic location was not independently associated with pre-emptive transplantation; however, children from more affluent areas were more likely to receive a pre-emptive transplant.
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http://dx.doi.org/10.2215/CJN.11020720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863652PMC
February 2021

Using datasets to ascertain the generalisability of clinical cohorts: the example of European QUALity Study on the treatment of advanced chronic kidney disease (EQUAL).

Nephrol Dial Transplant 2021 Jan 11. Epub 2021 Jan 11.

Population Health Sciences, University of Bristol, Bristol.

Background: Cohort studies are among the most robust of observational studies but have issues with external validity. This study assesses threats to external validity (generalisability) in the European QUALity (EQUAL) study, a cohort study of people over 65 years with stage 4/5 chronic kidney disease.

Methods: Patients meeting the EQUAL inclusion criteria were identified in The Health Improvement Network database and stratified into those attending renal units (secondary care cohort-SCC) and not (primary care cohort-PCC). Survival, progression to renal replacement therapy (RRT), and hospitalisation were compared.

Results: The analysis included 250, 633, and 2,464 patients in EQUAL, PCC, and SCC. EQUAL had a higher proportion of men in comparison to PCC and SCC (60.0% vs. 34.8% vs. 51.4%). Increasing age (≥85 years odds ratio (OR) 0.25 (95% confidence interval (CI) 0.15-0.40)) and comorbidity (Charlson Comorbidity Index ≥ 4 OR 0.69 (CI 0.52-0.91)) were associated with non-participation in EQUAL. EQUAL had a higher proportion of patients starting RRT at 1 year compared to SCC (8.1% vs. 2.1%%, p < 0.001). Patients in the PCC and SCC had increased risk of Hospitalisation (incidence rate ratio=1.76 (95% CI 1.27-2.47) & 2.13 (95% CI 1.59-2.86)) and mortality at one year (hazard ratio=3.48 (95% CI 2.1-5.7) & 1.7 (95% CI 1.1-2.7)) compared to EQUAL.

Conclusions: This study provides evidence of how participants in a cohort study can differ from the broader population of patients, which is essential when considering external validity and applying to local practice.
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http://dx.doi.org/10.1093/ndt/gfab002DOI Listing
January 2021

The incidence of and risk factors for late presentation of childhood chronic kidney disease: A systematic review and meta-analysis.

PLoS One 2020 31;15(12):e0244709. Epub 2020 Dec 31.

Population Health Sciences, University of Bristol Medical School, Bristol, United Kingdom.

Background: When detected early, inexpensive measures can slow chronic kidney disease progression to kidney failure which, for children, confers significant morbidity and impacts growth and development. Our objective was to determine the incidence of late presentation of childhood chronic kidney disease and its associated risk factors.

Methods: We searched MEDLINE, Embase, PubMed, Web of Science, Cochrane Library and CINAHL, grey literature and registry websites for observational data describing children <21 years presenting to nephrology services, with reference to late presentation (or synonyms thereof). Independent second review of eligibility, data extraction, and risk of bias was undertaken. Meta-analysis was used to generate pooled proportions for late presentation by definition and investigate risk factors. Meta-regression was undertaken to explore heterogeneity.

Results: Forty-five sources containing data from 30 countries were included, comprising 19,339 children. Most studies (37, n = 15,772) described children first presenting in kidney failure as a proportion of the chronic kidney disease population (mean proportion 0.43, 95% CI 0.34-0.54). Using this definition, the median incidence was 2.1 (IQR 0.9-3.9) per million age-related population. Risk associations included non-congenital disease and older age. Studies of hospitalised patients, or from low- or middle-income countries, that had older study populations than high-income countries, had higher proportions of late presentation.

Conclusions: Late presentation is a global problem among children with chronic kidney disease, with higher proportions seen in studies of hospitalised children or from low/middle-income countries. Children presenting late are older and more likely to have non-congenital kidney disease than timely presenting children. A consensus definition is important to further our understanding and local populations should identify modifiable barriers beyond age and disease to improve access to care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244709PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774987PMC
March 2021

Safety of Oral Bisphosphonates in Moderate-to-Severe Chronic Kidney Disease: A Binational Cohort Analysis.

J Bone Miner Res 2021 05 8;36(5):820-832. Epub 2021 Feb 8.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.

Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997-2016) and SIDIAP (2007-2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m , aged 40 years or older were identified. New bisphosphonate users were propensity score-matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4235DOI Listing
May 2021

Investigating Ethnic Disparity in Living-Donor Kidney Transplantation in the UK: Patient-Identified Reasons for Non-Donation among Family Members.

J Clin Med 2020 Nov 21;9(11). Epub 2020 Nov 21.

Bristol Medical School: Population Health Sciences, University of Bristol, Bristol BS8 2PS, UK.

There is ethnic inequity in access to living-donor kidney transplants in the UK. This study asked kidney patients from Black, Asian and minority ethnic groups why members of their family were not able to be living kidney donors. Responses were compared with responses from White individuals. This questionnaire-based mixed-methods study included adults transplanted between 1/4/13-31/3/17 at 14 UK hospitals. Participants were asked to indicate why relatives could not donate, selecting all options applicable from: Age; Health; Weight; Location; Financial/Cost; Job; Blood group; No-one to care for them after donation. A box entitled 'Other-please give details' was provided for free-text entries. Multivariable logistic regression was used to analyse the association between the likelihood of selecting each reason for non-donation and the participant's self-reported ethnicity. Qualitative responses were analysed using inductive thematic analysis. In total, 1240 questionnaires were returned (40% response). There was strong evidence that Black, Asian and minority ethnic group individuals were more likely than White people to indicate that family members lived too far away to donate (adjusted odds ratio (aOR) = 3.25, 95% Confidence Interval (CI) 2.30-4.58), were prevented from donating by financial concerns (aOR = 2.95, 95% CI 2.02-4.29), were unable to take time off work (aOR = 1.88, 95% CI 1.18-3.02), were "not the right blood group" (aOR = 1.65, 95% CI 1.35-2.01), or had no-one to care for them post-donation (aOR = 3.73, 95% CI 2.60-5.35). Four qualitative themes were identified from responses from Black, Asian and minority ethnic group participants: 'Burden of disease within the family'; 'Differing religious interpretations'; 'Geographical concerns'; and 'A culture of silence'. Patients perceive barriers to living kidney donation in the UK Black, Asian and minority ethnic population. If confirmed, these could be targeted by interventions to redress the observed ethnic inequity.
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http://dx.doi.org/10.3390/jcm9113751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700269PMC
November 2020

Metabolic profiles of socio-economic position: a multi-cohort analysis.

Int J Epidemiol 2021 07;50(3):768-782

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Background: Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear.

Methods: We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in ∼30 000 adults and 4000 children across 10 UK and Finnish cohort studies.

Results: In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents) and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids.

Conclusions: Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities.
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http://dx.doi.org/10.1093/ije/dyaa188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271201PMC
July 2021

Economic evaluation of GPs' direct access to computed tomography for identification of brain tumours.

Eur J Cancer Care (Engl) 2021 Jan 13;30(1):e13345. Epub 2020 Nov 13.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: When GPs suspect a brain tumour, a referral for specialist assessment and subsequent brain imaging is generally the first option. NICE has recommended that GPs have rapid direct access to brain imaging for adults with progressive sub-acute loss of central nervous function; however, no studies have evaluated the cost-effectiveness.

Methods: We developed a cost-effectiveness model based on data from one region of the UK with direct access computed tomography (DACT), routine data from GP records and the literature, to explore whether unrestricted DACT for patients with suspected brain tumour might be more cost-effective than criteria-based DACT or no DACT.

Results: Although criteria-based DACT allows some patients without brain tumour to avoid imaging, our model suggests this may increase costs of diagnosis due to non-specific risk criteria and high costs of diagnosing or 'ruling out' brain tumours by other pathways. For patients diagnosed with tumours, differences in outcomes between the three diagnostic strategies are small.

Conclusions: Unrestricted DACT may reduce diagnostic costs; however, the evidence is not strong and further controlled studies are required. Criteria-based access to CT for GPs might reduce demand for DACT, but imperfect sensitivity and specificity of current risk stratification mean that it will not necessarily be cost-effective.
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http://dx.doi.org/10.1111/ecc.13345DOI Listing
January 2021

A Comparison of the Surgical Practice of Potential Revision Outlier Joint Replacement Surgeons With Non-outliers: A Case Control Study From the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.

J Arthroplasty 2021 04 20;36(4):1239-1245.e6. Epub 2020 Oct 20.

Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, Southmead Hospital, Bristol, UK; National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK.

Background: The National Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR) has monitored the performance of consultant surgeons performing primary total hip (THR) or knee replacements (KR) since 2007. The aims of this study were: 1) To describe the surgical practice of consultant hip and knee replacement surgeons in the National Joint Registry for England and Wales (NJR), stratified by potential outlier status for revisions. 2) To compare the practice of revision outlier and non-outlier surgeons.

Methods: We combined NJR primary THR and KR data from 2008-2017 separately with relevant anonymised NJR outlier notification records. We described the surgical practice of outliers and non-outliers by surgical workload, implant choice, and patients' clinical and demographic characteristics. We explored associations between surgeon-level factors and outlier status with conditional logistic regression models.

Results: We included 764,888 primary THRs by 3213 surgeons and 889,954 primary KRs by 3084 surgeons performed between 2008-2017. One hundred and eleven (3.5%) THR and 114 (3.7%) KR consultant surgeons were potential revision outliers. Surgeons who used more types of implant had increased odds of being an outlier (KR: OR/additional implant = 1.35, 95%CI 1.17-1.55; THR: OR = 1.12, 95%CI 1.06-1.18).

Conclusions: The use of more types of implant is associated with increased risk of being a potential revision outlier. Further research is required to understand why surgeons use many different implants and to what extent this is responsible for the effects observed here.
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http://dx.doi.org/10.1016/j.arth.2020.10.026DOI Listing
April 2021

Is disrupted sleep a risk factor for Alzheimer's disease? Evidence from a two-sample Mendelian randomization analysis.

Int J Epidemiol 2021 07;50(3):817-828

MRC Integrative Epidemiology Unit, at the University of Bristol, Bristol, UK.

Background: It is established that Alzheimer's disease (AD) patients experience sleep disruption. However, it remains unknown whether disruption in the quantity, quality or timing of sleep is a risk factor for the onset of AD.

Methods: We used the largest published genome-wide association studies of self-reported and accelerometer-measured sleep traits (chronotype, duration, fragmentation, insomnia, daytime napping and daytime sleepiness), and AD. Mendelian randomization (MR) was used to estimate the causal effect of self-reported and accelerometer-measured sleep parameters on AD risk.

Results: Overall, there was little evidence to support a causal effect of sleep traits on AD risk. There was some suggestive evidence that self-reported daytime napping was associated with lower AD risk [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.50-0.99). Some other sleep traits (accelerometer-measured 'eveningness' and sleep duration, and self-reported daytime sleepiness) had ORs of a similar magnitude to daytime napping, but were less precisely estimated.

Conclusions: Overall, we found very limited evidence to support a causal effect of sleep traits on AD risk. Our findings provide tentative evidence that daytime napping may reduce AD risk. Given that this is the first MR study of multiple self-report and objective sleep traits on AD risk, findings should be replicated using independent samples when such data become available.
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http://dx.doi.org/10.1093/ije/dyaa183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271193PMC
July 2021

Genome-Wide Association Studies of Cognitive and Motor Progression in Parkinson's Disease.

Mov Disord 2021 02 28;36(2):424-433. Epub 2020 Oct 28.

Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.

Background: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression.

Methods: We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression in genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis.

Results: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ε4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However, in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (P = 5.3 × 10 ).

Conclusions: We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE ε4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28342DOI Listing
February 2021

The Impact of Sex and Gender on the Multidisciplinary Management of Care for Persons With Parkinson's Disease.

Front Neurol 2020 18;11:576121. Epub 2020 Sep 18.

Department of Primary and Community Care, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

The impact of sex and gender on disease incidence, progression, and provision of care has gained increasing attention in many areas of medicine. Biological factors-sex-and sociocultural and behavioral factors-gender-greatly impact on health and disease. While sex can modulate disease progression and response to therapy, gender can influence patient-provider communication, non-pharmacological disease management, and need for assistance. Sex and gender issues are especially relevant in chronic progressive diseases, such as Parkinson's disease (PD), because affected patients require multidisciplinary care for prolonged periods of time. In this perspective paper, we draw from evidence in the field of PD and various other areas of medicine to address how sex and gender could impact PD care provision. We highlight examples for which differences have been reported and formulate research topics and considerations on how to optimize the multidisciplinary care of persons with PD.
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http://dx.doi.org/10.3389/fneur.2020.576121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530641PMC
September 2020

Association between surgical volume and failure of primary total hip replacement in England and Wales: findings from a prospective national joint replacement register.

BMJ Open 2020 09 14;10(9):e033045. Epub 2020 Sep 14.

Musculoskeletal Research Unit, Bristol Medical School, Southmead Hospital, University of Bristol, Bristol, UK.

Objective: To investigate the association of volume of total hip arthroplasty (THA) between consultants and within the same consultant in the previous year and the hazard of revision using multilevel survival models.

Design: Prospective cohort study using data from a national joint replacement register.

Setting: Elective THA across all private and public centres in England and Wales between April 2003 and February 2017.

Participants: Patients aged 50 years or more undergoing THA for osteoarthritis.

Intervention: The volume of THA conducted in the preceding 365 days to the index procedure.

Main Outcome And Measure: Revision surgery (excision, addition or replacement) of a primary THA.

Results: Of the 579 858 patients undergoing primary THA (mean baseline age 69.8 years (SD 10.2)), 61.1% were women. Multilevel survival found differing results for between and within-consultant effects. There was a strong volume-revision association between consultants, with a near-linear 43.3% (95% CI 29.1% to 57.4%) reduction of the risk of revision comparing consultants with volumes between 1 and 200 procedures annually. Changes in individual surgeons (within-consultant) case volume showed no evidence of an association with revision.

Conclusion: Separation of between-consultant and within-consultant effects of surgical volume reveals how volume contributes to the risk of revision after THA. The lack of association within-consultants suggests that individual changes to consultant volume alone will have little effect on outcomes following THA.These novel findings provide strong evidence supporting the practice of specialisation of hip arthroplasty. It does not support the practice of low-volume consultants increasing their personal volume as it is unlikely their results would improve if this is the only change. Limiting the exposure of patients to consultants with low volumes of THA and greater utilisation of centres with higher volume surgeons with better outcomes may be beneficial to patients.
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http://dx.doi.org/10.1136/bmjopen-2019-033045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490953PMC
September 2020

Interventions to reduce the time to diagnosis of brain tumours.

Cochrane Database Syst Rev 2020 09 4;9:CD013564. Epub 2020 Sep 4.

The Evidence-Based Medicine Consultancy Ltd, Bath, UK.

Background: Brain tumours are recognised as one of the most difficult cancers to diagnose because presenting symptoms, such as headache, cognitive symptoms, and seizures, may be more commonly attributable to other, more benign conditions. Interventions to reduce the time to diagnosis of brain tumours include national awareness initiatives, expedited pathways, and protocols to diagnose brain tumours, based on a person's presenting symptoms and signs; and interventions to reduce waiting times for brain imaging pathways. If such interventions reduce the time to diagnosis, it may make it less likely that people experience clinical deterioration, and different treatment options may be available.

Objectives: To systematically evaluate evidence on the effectiveness of interventions that may influence: symptomatic participants to present early (shortening the patient interval), thresholds for primary care referral (shortening the primary care interval), and time to imaging diagnosis (shortening the secondary care interval and diagnostic interval). To produce a brief economic commentary, summarising the economic evaluations relevant to these interventions.

Search Methods: For evidence on effectiveness, we searched CENTRAL, MEDLINE, and Embase from January 2000 to January 2020; Clinicaltrials.gov to May 2020, and conference proceedings from 2014 to 2018. For economic evidence, we searched the UK National Health Services Economic Evaluation Database from 2000 to December 2014.

Selection Criteria: We planned to include studies evaluating any active intervention that may influence the diagnostic pathway, e.g. clinical guidelines, direct access imaging, public health campaigns, educational initiatives, and other interventions that might lead to early identification of primary brain tumours. We planned to include randomised and non-randomised comparative studies. Included studies would include people of any age, with a presentation that might suggest a brain tumour.

Data Collection And Analysis: Two review authors independently assessed titles identified by the search strategy, and the full texts of potentially eligible studies. We resolved discrepancies through discussion or, if required, by consulting another review author.

Main Results: We did not identify any studies for inclusion in this review. We excluded 115 studies. The main reason for exclusion of potentially eligible intervention studies was their study design, due to a lack of control groups. We found no economic evidence to inform a brief economic commentary on this topic.

Authors' Conclusions: In this version of the review, we did not identify any studies that met the review inclusion criteria for either effectiveness or cost-effectiveness. Therefore, there is no evidence from good quality studies on the best strategies to reduce the time to diagnosis of brain tumours, despite the prioritisation of research on early diagnosis by the James Lind Alliance in 2015. This review highlights the need for research in this area.
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http://dx.doi.org/10.1002/14651858.CD013564.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082957PMC
September 2020
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