Yoav Ben-Shlomo’s research while affiliated with University Hospitals Bristol NHS Foundation Trust and other places

Background UK COVID-19 lockdowns significantly affected primary care access and delivery. Little is known about whether lockdowns disproportionally impacted vulnerable groups, including people who misuse substances, domestic violence or abuse victims, those with intellectual disability, and children with safeguarding concerns. Aim To evaluate the impact of UK COVID-19 lockdowns on primary care contact rates among vulnerable groups. Design & setting Natural experimental design using all registered patients in the OpenSAFELY platform. Method With approval from NHS England, we conducted controlled interrupted time-series analyses on 24million patients in England between September2019-September2021. Results Pre-pandemic, primary care consultation rates were 110.1 per 1000 patients per week. Following the initiation of the first lockdown (23/03/2020), there was a large reduction of 29-61 contacts per 1000 patients per week among vulnerable and general population groups. For patients with alcohol misuse, aged ≥14 years with intellectual disability, and children with safeguarding concerns, this reduction was significantly more extreme than corresponding general populations (relative rate difference -23.8 [95% confidence interval -39.8,-7.7], -24.6 [-38.8,-10.5], and -15.4 [-26.9,-3.8], respectively). Following the final lockdown (29/03/2021), all groups had consulting rates exceeding pre-pandemic rates (with increases more marked in vulnerable populations), except those only including children. Conclusion Analyses suggested a larger short-term impact of the first COVID-19 lockdown on primary care contact for some vulnerable groups, compared to the general population; differential impacts persisted through subsequent lockdowns and beyond for some vulnerable groups. There is a need to examine drivers of these differences to enable more equitable primary care access and provision.

The neuropathological process in Parkinson’s disease (PD) and Lewy body disorders has been shown to extend well beyond the degeneration of the dopaminergic system, affecting other neuromodulatory systems in the brain which play crucial roles in the clinical expression and progression of these disorders. Here, we investigate the role of the macrostructural integrity of the nucleus basalis of Meynert (NbM), the main source of cholinergic input to the cerebral cortex, in cognitive function, clinical manifestation, and disease progression in non-demented subjects with PD and individuals with isolated REM sleep behaviour disorder (iRBD). Using structural MRI data from 393 early PD patients, 128 iRBD patients, and 186 controls from two longitudinal cohorts, we found significantly lower NbM grey matter volume in both PD (β=-12.56, p=0.003) and iRBD (β=-16.41, p=0.004) compared to controls. In PD, higher NbM volume was associated with better higher-order cognitive function (β=0.10, p=0.045), decreased non-motor (β=-0.66, p=0.026) and motor (β=-1.44, p=0.023) symptom burden, and lower risk of future conversion to dementia (Hazard ratio (HR)<0.400, p<0.004). Higher NbM volume in iRBD was associated with decreased future risk of phenoconversion to PD or dementia with Lewy bodies (DLB) (HR<0.490, p<0.016). However, despite similar NbM volume deficits to those seen in PD, associations between NbM structural deficits and current disease burden or clinical state were less pronounced in iRBD. These findings identify NbM volume as a potential biomarker with dual utility: predicting cognitive decline and disease progression in early PD, while also serving as an early indicator of phenoconversion risk in prodromal disease. The presence of structural deficits before clear clinical correlates in iRBD suggests complex compensatory mechanisms may initially mask cholinergic dysfunction, with subsequent failure of these mechanisms potentially contributing to clinical conversion.

Background: Lower urinary tract symptoms (LUTS) are common Parkinson's disease (PD), causing great impact. Objective: The goal was to undertake a phase II randomized control trial of transcutaneous tibial nerve stimulation (TTNS) delivered by Geko device for LUTS related to overactive bladder (OAB) in PD, an easy to use of the shelf solution. Methods: Participants were randomized to active/sham stimulation. Primary outcome measure was the International Consultation on Incontinence Questionnaire-Overactive Bladder score (ICIQ-OAB) at 12 weeks. Results: A total of 148 participants were allocated to active (73) and sham arms (75). No difference was seen between arms (coefficient, 0.48; 95% CI, -0.2 to 1.2; P = 0.17), although both active and sham showed improvements over baseline. Pain was the most common adverse event. Conclusion: No difference was seen between active and sham arms. Symptom improvements seen in both groups are consistent with a placebo effect, however, we cannot exclude a biological effect from the sham intervention. Although negative, this result should be taken only in context of Geko use rather TTNS in general. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Increasing numbers of people require evaluation for possible dementia. However, research on the accuracy of informant questionnaires in primary care remains limited. Methods This study assessed the diagnostic accuracy of IQCODE, AD8, and GPCOGi based on the informant’s relationship to the patient. We recruited 240 participants from 21 general practices in South West England. The reference standard for a diagnosis of dementia was made by a specialist clinician using ICD-10 criteria. A threshold of greater than 3.3 on IQCODE, greater or equal to 2 on AD8 and less than 5 on the informant component of GPCOG was used to indicate an abnormal test. Results Of 238 participants with informant data, 131 had dementia, 60 had CIND, and 47 had normal cognition. Median informant age was 70 years (IQR 60 years to 78 years). 71% of informants were female and 56% were spouses. On all three questionnaires, compared to spouses, adult descendants tended to score participants more cognitively impaired, whereas friends scored participants less cognitively impaired. However, there was little evidence of difference by informant type once fully adjusted. Sensitivity by informant type ranged from 91 to 100% for IQCODE, 94–100% for AD8 and 99% to100% for GPCOGi. There was no significant difference in sensitivity by informant type. Specificity by informant type ranged from 25 to 79% for IQCODE, 13–75% for AD8 and 17–38% for GPCOGi. Adult descendants tended to have the lowest specificity at 25% (95% CI 10–47%) for IQCODE, 13% (95% CI 3–32%) for AD8 and 17% (95% CI 5–37%) for GPCOGi. Friends tended to have the highest specificity at 79% (95% CI 49–95%) for IQCODE, 75% (95% CI 48–93%) for AD8 and 38% (95% CI 15–64%) for GPCOGi. Conclusions An informant of any relationship type, using IQCODE, AD8 or GPCOGi may be useful for ruling out dementia but not for ruling it in. We found no evidence of difference between spouse or adult descendants but friends performed significantly better overall on IQCODE and AD8.

Education in the care of older people, beginning at undergraduate-level, will help to meet the needs of our aging population. Thus, we need to understand why and in what ways medical students have difficulty engaging with older people and geriatric medicine. Twenty-two medical students studying at the University of Bristol (UK) participated in focus groups, exploring their attitudes toward older people and toward geriatric medicine. Five themes were derived using reflexive thematic analysis. Relationships with older relatives contribute toward students' perceptions of older patients and can enhance their empathy. However, some compartmentalize personal experiences from professional practice to mitigate moral distress. Students are aware of ageism, and in turn encounter challenging views among the older population, which both present significant challenges. It was clear that career decision-making is multi-faceted; inspiring role models, welcoming learning environments, and undergraduate experience were all important. Critically, undergraduate exposure to the full breadth of geriatric medicine and the spectrum of aging was key to changing students' negative pre-conceptions about caring for older people and geriatric medicine. Undergraduate medical education offers a crucial point during medical training where we can intervene to improve the attitudes of and inspire career interest in tomorrow's doctors.

Background Parkinson's disease (PD) has marked phenotypic variability. Increased lipids have been suggested as being neuroprotective whilst hyperglycemia may increase α-synuclein aggregation. Objective We have tested whether high total cholesterol and high-density lipoprotein cholesterol (HDL-C) and low levels of fructosamine are associated with better PD phenotypes and predict less rapid progression Methods Non-fasting serum HDL-C, total cholesterol, and fructosamine were measured at baseline in 866 patients with early PD (median duration, 0.96; IQR, 0.43–1.98 years) from the Oxford Discovery cohort. These biomarkers were compared against our data-derived PD subtypes using multinomial logistic regression. We used multilevel models to predict longitudinal motor and non-motor outcomes (e.g., cognition, mood). Results HDL-C and total cholesterol differed across baseline PD phenotype clusters, with reduced levels associated with the most severe motor and non-motor phenotypes (psychological well-being, cognitive impairment, REM sleep behavior disorder, and daytime sleepiness). Higher HDL-C and total cholesterol, although the latter was attenuated after adjustment for statin use, were associated with better baseline activities of daily living (e.g., UPDRS-II score with 1 SD increase in HDL-C −0.74, 95%CI −1.22 to −0.26, p = 0.002) and non-motor features. Neither predicted the rate of motor or non-motor progression. Fructosamine levels were not associated with phenotypic variability or rate of disease progression. Conclusions Hypercholesterolemia was associated with a better motor/non-motor disease subtype and daily living impairment at presentation, but did not predict longitudinal change. Future research needs to determine if these associations are causally related or secondary to disease onset by examining prodromal subjects.

Importance: Vascular dementia (VaD) is a devastating cerebrovascular disease with no disease-modifying treatments available. Repurposing existing drugs for VaD risk factors could have an important clinical impact. Objective: To determine whether lipid-lowering, anti-hypertensive, or anti-inflammatory drug targets affect the risk of vascular dementia using Mendelian randomization. Design: Evidence suggests that higher cholesterol and blood pressure are associated with increased VaD risk, and inflammation is thought to play a key role in pathogenesis. Two-sample MR was conducted using cis-acting genetic variants in genes encoding each drug target, and data on five VaD-related outcomes. Instrument performance was assessed with positive controls (coronary artery disease, heart failure, stroke and rheumatoid arthritis). Setting: Summary-level genetic data Participants: Publicly available genetic association data from large cohorts of European ancestry. To maximize the sample size for vascular dementia risk as an outcome, we conducted a meta-analysis of case-control data from FinnGen & MEGAVCID. Exposures: Genetically proxied drug effects for 46 lipid-lowering (n=17), antihypertensive (n=18), and anti-inflammatory (n=11) targets. Main Outcomes and Measures: Odds ratios/betas and 95% CIs for VaD outcomes (clinical diagnosis, white matter hyperintensity volume, fractional anisotropy, mean diffusivity and lacunar stroke diagnosis) were estimated per 1-unit change in the exposure. Results: For VaD risk, N=7,009 cases and N=899,672 controls were used. Neuroimaging outcome datasets included a maximum of N=50,559 participants. Beta-1 adrenergic receptor (ADRB1) was the only target for which there was consistent, albeit modest, evidence of benefit for four out of the five outcomes (clinical diagnosis: OR= 0.90, 95%CI 0.80 to 1.01, white matter hyperintensities: β= -0.03, 95%CI -0.07 to 0.00, mean diffusivity: β= -0.18, 95%CI -0.37 to 0.00, lacunar stroke: OR= 0.91, 95%CI 0.80 to 1.03). Angiotensin-converting enzyme (ACE) inhibition was suggested to increased VaD risk (OR= 1.12, 95%CI 1.01 to 1.24). There was little evidence to suggest other targets affect the outcomes. Conclusions and relevance: ARDB1 antagonism may be a promising repurposing candidate for VaD. Pharmacovigilance studies are required to further examine the potential of ACE inhibitors to increase VaD risk. There is little evidence to support repurposing of many licensed lipid-lowering, antihypertensive and anti-inflammatory drugs for VaD prevention or treatment.

Background Nocturia is the most common lower urinary tract symptom (LUTS) in Parkinson’s disease (PD) and impacts sleep and subsequent daytime function. Often nocturia in PD is attributed to overactive bladder, however we explored the contribution of the over-production of urine at night, nocturnal polyuria (NP), as another factor. Objectives To assess the prevalence and severity of NP in a PD cohort with LUTS and explore associations with autonomic and other patient characteristics. Methods Sub-study nested within a trial for LUTS in PD. All participants performed 72-hour bladder diaries. Nocturnal polyuria index (NPi) was calculated from diaries and key associations were explored. Results 62.6 % of participants had NP based on the NPi33 threshold (producing > 33 % urine at night). Increasing NPi was strongly significantly associated with greater nocturia (OR 1.7 per 5 % NPi unit; 1.5–2.0; P < 0.001). A significant association was observed between NPi and orthostatic hypotension (OR 1.2 per 5 % NPi unit increase; 1.0–1.4; P = 0.03) and reported cardiovascular symptoms (coefficient 0.07; 0.03–0.11; P = 0.002). A marked association was seen with severe NP and orthostatic hypotension (OR 4.9; 1.56–15.57; P = 0.006). Conclusion NP is very common in this PD cohort symptomatic for LUTS, and is closely associated with increasing rate of nocturia. NP is linked to cardiovascular symptoms and autonomic dysfunction, particularly blood pressure lability which may be causal or simply reflect advanced disease state.

Background Ecological studies hypothesise a ‘safety in numbers’ (SiN) effect whereby road safety for bicycles and other micromobility users improves as their numbers increase, due to behavioural changes of motorists. Causal interpretation of these studies is difficult due to confounding and reverse causation. The introduction of electric scooter (e-scooter) rental schemes in selected districts in England meant an increase in micromobility users in these areas, which presented an opportunity to test the SiN hypothesis using a natural experiment. Methods Time-series analysis of police data on road collisions in local authorities (LAs) in Great Britain, 2015–2023. Random-effects Poisson regression time-series models compared collision rates in LA districts with an e-scooter trial (n=41) versus matched control districts (n=41). Primary outcomes were all road collisions and bicycle collisions. Models adjusted for time; seasonality; baseline collision rate; COVID-19 period; and preintervention/postintervention period (proxied by intervention group/COVID-19 period interaction). Results The rate of bicycle collisions reduced following the introduction of the schemes, compared with control districts (incidence rate ratio (IRR) 0.78, 95% CI 0.68 to 0.89 during peak COVID-19; IRR 0.87, 95% CI 0.77 to 0.99 in the post-COVID-19 period). This effect was specific to bicycle collisions and strongest in the subgroup of serious/fatal collisions. Conclusions Findings suggest that the increase of a new and sustainable mode of transport, e-scooters, may have reduced bicycle collisions. This could have far-reaching benefits including reduced injuries, safer environments, and public health and environmental benefits if more people choose bicycles and micromobility over car transport. Findings should be verified in further work.

Background Cardiovascular disease and chronic kidney disease progression pathophysiology are similar. We investigated associations of cardiometabolic protein expression and pathways with kidney function decline in older adults with advanced chronic kidney disease (CKD) referred for nephrology assessment. Methods Two plasma proteomic panels analysed at baseline (Olink® cardiometabolic T96 and cardiovascular II T96, Uppsala, Sweden) and longitudinal estimated glomerular filtration rate (eGFR) data from European adults aged > 65 years with a single eGFR of <20 mL/min/1.73m2 (The EQUAL Study) were used to explore mechanisms of CKD progression. Protein-slope associations were estimated using generalised linear mixed-effects models and with a false discovery rate P < 0.05 taken to validation to verify the effect size of the association. Proteins were further modularised into biological pathways using pathway enrichment analysis. Results A discovery sub-cohort of 238 complete-case participants from Germany, United Kingdom and Poland (median age 76 years, 41% female sex, median baseline eGFR 17.8 mL/min/1.73m2) were included and 246 participants from Sweden formed the validation sub-cohort (median age 75 years, 28% female, median baseline eGFR 17.5 mL/min/1.73m2). Of the 175 analysed proteins, higher expression levels of Receptor-type tyrosine-protein phosphatase S (-15.4% change in eGFR per year per doubling of protein expression; 95%CI -23.5%, -7.6%), Insulin-like growth factor binding protein 6 (-7.9%; 95%CI -12.3%, -3.5%) and Ficolin 2 (-7.4%; 95%CI -12.0%, -2.8%) showed a validated association with eGFR decline. Conclusions Higher expression levels of proteins and biological pathways involving fibrogenesis and the complement cascade were found to be associated with kidney function loss. However, study limitations and unavailability of concurrent kidney cellular proteomic signatures necessitate further study.