Impact of co-resident health and living alone on risk of hospital admission for people with Parkinson's disease.

BACKGROUND: People with Parkinson's Disease (PwP) have a higher rate of hospitalisation compared to the general population. Little is known about the impact of having a co-resident and their health on hospitalisation rates of PwP. METHODS: We utilised Clinical Practice Research Datalink (CPRD) GOLD data (2010-2015) to identify PwP and co-residents. We classed either the fittest or youngest adult as the primary caregiver in each household. Caregiver health was classified by the Cambridge Multimorbidity Score (CMS), primary care utilisation and prescriptions. We calculated the hospitalisation (elective, emergency) incidence rate ratios (IRRs) for PwP who lived alone compared to those with a caregiver using negative binomial regression, and whether worse caregiver health predicted higher risk of admissions. RESULTS: We identified 3254 PwP and 4007 family members. PwP who lived alone were less likely to have an elective admission (0.79; 95 % CI 0.69-0.91) and more likely to have an emergency admission (1.40; 95 % CI 1.70-1.54). Worse caregiver health, as measured by the CMS, was associated with an increased risk of emergency admission (IRR 1.35; 95 % CI 1.17-1.57), but this attenuated and was consistent with chance in the fully adjusted model (1.04; 95 % CI 0.95-1.13). No strong associations were seen between caregiver health and elective admissions. CONCLUSION: PwP who live alone are at increased risk of emergency and less likely to have elective hospital admissions. It is important that health care providers support such people and ensure they receive equitable access to the potential benefits of elective procedures.

The impact of targeted local outreach clinics to improve COVID-19 vaccine uptake: controlled interrupted time series in South West England.

BACKGROUND: Outreach clinics were part of efforts to maximise uptake in COVID-19 vaccination. METHODS: We used controlled interrupted time series, matching on age, sex, deprivation and vaccination eligibility date, to determine the effect of outreach clinics on time to first COVID-19 vaccine, using a population-based electronic health record database of 914,478 people, from December 2020 to December 2021; people living within 1 mile of each outreach clinics were exposed. RESULTS: 50% of 288,473 exposed citizens were white British, and 71% were aged 0-49 years. There was no evidence for an overall statistically significant increase in cumulative percentage vaccinated due to the outreach clinic at 6 weeks, with an overall pooled effect estimate of -0.07% (95% CI: -1.15%, 1.02%). The pooled estimate for increased cumulative vaccine uptake varied slightly depending on how the analysis was stratified; by ethnic group it was - 0.12% (95% CI: -0.90%, 0.66%); by age group it was - 0.06% (95% CI: -0.41%, 0.28%); and by deprivation it was 0.03% (95% CI: -0.74%, 0.79%). CONCLUSIONS: Living within a mile of an outreach clinic was not associated with higher vaccine uptake. Evaluation of future outreach clinics should consider the relative importance of travel amongst other barriers to accessing vaccines.

The PRIME-NL study: evaluating a complex healthcare intervention for people with Parkinson's disease in a dynamic environment.

BACKGROUND: An innovative, integrative care model for people with Parkinson (PRIME Parkinson) has gradually been implemented in a selected region of the Netherlands since 2021. A prospective evaluation of this model (PRIME-NL study) was initiated in parallel, spanning the year prior to implementation (baseline) and the implementation period. Following publication of the original study protocol, the COVID-19 crisis delayed implementation of the full PRIME Parkinson care model by two years and hampered the recruitment of study participants. OBJECTIVE: To describe which methodological adjustments were made to the study protocol because of these developments. METHODS: We compare various outcomes between a region where PRIME Parkinson care was implemented (innovation region) versus the rest of the Netherlands (usual care region). We use healthcare claims data of virtually all people with Parkinson in the Netherlands and annual questionnaires in a representative subsample of 984 people with Parkinson, 566 caregivers and 192 healthcare professionals. Four major methodological adjustments had to be made since publication of the original protocol. First, we extended the evaluation period by two years. Second, we incorporated annual process measures of the stage of implementation of the new care model. Third, we introduced a real-time iterative feedback loop of interim results to relevant stakeholders. Fourth, we updated the statistical analysis plan. DISCUSSION: This manuscript provides transparency in how the design and analyses of the evaluation study had to be adapted to control for external influences in a dynamic environment, including eruption of the COVID-19 crisis. Our solutions could serve as a template for evaluating other complex healthcare interventions in a dynamic environment.

Consistency of alerts generated by, and implementation of, the NHS England acute kidney injury detection algorithm in English laboratories.

BACKGROUND: National Health Services (NHS) England mandates that an acute kidney injury (AKI) detection algorithm be embedded in laboratories. We evaluated the implementation of the algorithm and the consistency of alerts submitted to the United Kingdom Renal Registry (UKRR). METHODS: Code was developed to simulate the syntax of the AKI detection algorithm, executed on data from local laboratories submitted to the UKRR, including alerts and serum creatinine (SCr) results spanning 15 months before and after the alert submission. Acute kidney injury alerts were categorized into stages 0/1/2/3. Inter-rater agreement (Gwet's AC1) was used to compare local and centrally derived alerts at individual laboratory and commercial laboratory information management system (LIMS) levels, penalizing extreme disagreements. RESULTS: The analysis included 9,096,667 SCr results from 29 labs (475,634 patients; median age 72 years, 47% female) between algorithm activation and data extraction (September 30, 2020). Laboratories and the central simulation generated 1,579,633 and 1,646,850 non-zero AKI alerts, respectively. Agreement was high within known laboratory information management system providers (0.97-0.98) but varied across individual laboratories (overall range 0.17-0.98, 0.17-0.23 in three). Agreement tended to be lower (Gwet's AC1 0.88) with the highest baseline SCr quartile (median 164 µmol/L). CONCLUSIONS: Overall, alerts submitted to the UKRR are a valid source of AKI surveillance but there are concerns about inconsistent laboratory practices, incomplete adoption of the NHSE algorithm code, alert suppression, and variable interpretation of guidelines. Future efforts should audit and support laboratories with low agreement rates, and explore reasons for lower agreement in individuals with pre-existing CKD.

Following hip fracture, hospital organizational factors associated with prescription of anti-osteoporosis medication on discharge, to address imminent refracture risk: a record-linkage study.

Patients who sustain a hip fracture are known to be at imminent refracture risk. Their complex multidisciplinary rehabilitation needs to include falls prevention and anti-osteoporosis medication (AOM) to prevent such fractures. This study aimed to determine which hospital-level organizational factors predict prescription of post-hip fracture AOM and refracture risk. A cohort of 178 757 patients aged ≥60 yr who sustained a hip fracture in England and Wales (2016-2019) was examined and followed for 1 yr. Patient-level hospital admission datasets from 172 hospitals, the National Hip Fracture Database, and mortality data were linked to 71 metrics extracted from 18 hospital-level organizational reports. Multilevel models determined organizational factors, independent of patient case-mix, associated with (1) AOM prescription and (2) refracture (by ICD10 coding). Patients were mean (SD) 82.7 (8.6) yr old, 71% female, with 18% admitted from care homes. Overall, 101 735 (57%) were prescribed AOM during admission, while 50 354 (28%) died during 1-yr follow-up, 12 240 (7%) refractured. Twelve organizational factors were associated with AOM prescription, for example, orthogeriatrician-led care compared to traditional care models (odds ratio [OR] 4.65 [95% CI, 2.25-9.59]); AOM was 9% (95% CI, 6%-13%) more likely to be prescribed in hospitals providing routine bone health assessment to all patients. Refracture occurred at median 126 d (IQR 59-234). Eight organizational factors were associated with refracture risk; hospitals providing orthogeriatrician assessment to all patients within 72 h of admission had an 18% (95% CI, 2%-31%) lower refracture risk, weekend physiotherapy provision had an 8% (95% CI, 3%-14%) lower risk, and where occupational therapists attended clinical governance meetings, a 7% (95% CI, 2%-12%) lower risk. Delays initiating post-discharge community rehabilitation were associated with a 15% (95% CI, 3%-29%) greater refracture risk. These novel, national findings highlight the importance of orthogeriatrician, physiotherapist, and occupational therapist involvement in secondary fracture prevention post hip fracture; notably, fracture risk reductions were seen within 12 mo of hip fracture.

Patients who have broken (fractured) a hip are at risk of having another fracture soon after. They have complex needs to avoid more fractures, which include being prescribed bone-strengthening medicines and taking measures to prevent falls. This study looked at which of the measurements, that describe how well a hospital is organized, are associated with whether bone-strengthening medicine is prescribed and the chance of having another fracture. We used data from 178 757 patients aged over 60 yr who had a hip fracture at 172 English and Welsh hospitals, linked to their hospital records, and other datasets that describe hospital services. Overall, 57% of patients were prescribed bone-strengthening medicines, and 7% went on to have another fracture. Bone-strengthening medicines were more likely to be prescribed in hospitals where patient care was led by a consultant specializing in the care of older people with fractures (called orthogeriatricians) and in hospitals which routinely checked patients' bone health. Patients attending hospitals that provided orthogeriatrician assessment to all patients within 72 h of being admitted, physiotherapy services at the weekend, or where occupational therapists attended meetings aimed at improving hospital services had a lower chance of having another fracture.

Investigation of the genetic aetiology of Lewy body diseases with and without dementia.

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

Genome-wide determinants of mortality and motor progression in Parkinson's disease.

There are 90 independent genome-wide significant genetic risk variants for Parkinson's disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

Dopa Responsiveness in Parkinson's Disease.

BACKGROUND: Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time. OBJECTIVES: To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these. METHODS: We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥24.5% defined as a definite response). Growth-mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters. RESULTS: 1525 dopaminergic challenge tests were performed in 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer disease duration (51.1-74.3%). We identified 3 response groups: "Striking" (n = 29, 8.7%); "Excellent" (n = 110; 32.7%) and "Modest" (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01). CONCLUSION: Three distinct patterns of the dopaminergic response were observed. As the proportion of PD cases with definite dopa responsiveness increased over time, the initial treatment response may be an unreliable diagnostic aid.

Guide to Decomposition of Causal Effects Into Mediation, Interaction, and Direct Effects: Case Study on Aerobic Exercise and Parkinson Disease.

Mediation analysis can be applied in medical research with the aim of understanding the pathways that operate between an exposure and its effects on an outcome. This method can help to improve our understanding of pathophysiologic mechanisms and may guide the choice of potential treatment strategies. Traditional mediation analysis decomposes the total effect of an intervention on the outcome into 2 effects: (1) an indirect effect, from exposure using a mediator to the outcome, and (2) a direct effect, directly from exposure to outcome. A limitation of this method is that it assumes no interaction between the exposure and the mediator, which can either lead to an over- or underestimation of clinically relevant effects. The "4-way decomposition" method has the advantage of overcoming this limitation. Specifically, the total effect of an exposure on the outcome is decomposed into 4 elements: (1) reference interaction (interaction only), (2) mediated interaction (mediation and interaction), (3) the pure indirect effect (mediation but not interaction), and (4) the direct effect (no mediation and no interaction). We provide a guide to select the most appropriate method to investigate and decompose any causal effect given the research question at hand. We explain the application of the 4-way decomposition and illustrate this with a real-world example of how aerobic exercise may influence motor function in persons with Parkinson disease.

Enhancing recruitment of individuals living with frailty, multimorbidity and cognitive impairment to Parkinson's research: experiences from the PRIME-UK cross-sectional study.

BACKGROUND AND OBJECTIVES: People with parkinsonism who are older, living in a care home, with frailty, multimorbidity or impaired capacity to consent are under-represented in research, limiting its generalisability. We aimed to evaluate more inclusive recruitment strategies. METHODS: From one UK centre, we invited people with parkinsonism to participate in a cross-sectional study. Postal invitations were followed by telephone reminders and additional support to facilitate participation. Personal consultees provided information on the views regarding research participation of adults with impaired capacity. These approaches were evaluated: (i) using external data from the Parkinson's Real World Impact assesSMent (PRISM) study and Clinical Practice Research Datalink (CPRD), a sample of all cases in UK primary care, and (ii) comparing those recruited with or without intensive engagement. RESULTS: We approached 1,032 eligible patients, of whom 542 (53%) consented and 477 (46%) returned questionnaires. The gender ratio in PRIME-UK (65% male) closely matched CPRD (61% male), unlike in the PRISM sample (46%). Mean age of PRIME participants was 75.9 (SD 8.5) years, compared to 75.3 (9.5) and 65.4 (8.9) years for CPRD and PRISM, respectively. More intensive engagement enhanced recruitment of women (13.3%; 95% CI 3.8, 22.9%; P = 0.005), care home residents (6.2%; 1.1, 11.2%; P = 0.004), patients diagnosed with atypical parkinsonism (13.7%; 5.4, 19.9%; P < 0.001), and those with a higher frailty score (mean score 0.2, 0.1, 0.2; P < 0.001). CONCLUSIONS: These recruitment strategies resulted in a less biased and more representative sample, with greater inclusion of older people with more complex parkinsonism.

Assessing the validity of a Parkinson's care evaluation: the PRIME-NL study.

INTRODUCTION: The PRIME-NL study prospectively evaluates a new integrated and personalized care model for people with parkinsonism, including Parkinson's disease, in a selected region (PRIME) in the Netherlands. We address the generalizability and sources of selection and confounding bias of the PRIME-NL study by examining baseline and 1-year compliance data. METHODS: First, we assessed regional baseline differences between the PRIME and the usual care (UC) region using healthcare claims data of almost all people with Parkinson's disease in the Netherlands (the source population). Second, we compared our questionnaire sample to the source population to determine generalizability. Third, we investigated sources of bias by comparing the PRIME and UC questionnaire sample on baseline characteristics and 1-year compliance. RESULTS: Baseline characteristics were similar in the PRIME (n = 1430) and UC (n = 26,250) source populations. The combined questionnaire sample (n = 920) was somewhat younger and had a slightly longer disease duration than the combined source population. Compared to the questionnaire sample in the PRIME region, the UC questionnaire sample was slightly younger, had better cognition, had a longer disease duration, had a higher educational attainment and consumed more alcohol. 1-year compliance of the questionnaire sample was higher in the UC region (96%) than in the PRIME region (92%). CONCLUSION: The generalizability of the PRIME-NL study seems to be good, yet we found evidence of some selection bias. This selection bias necessitates the use of advanced statistical methods for the final evaluation of PRIME-NL, such as inverse probability weighting or propensity score matching. The PRIME-NL study provides a unique window into the validity of a large-scale care evaluation for people with a chronic disease, in this case parkinsonism.

Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life.

BACKGROUND: Alzheimer's disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively. METHODS: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants. RESULTS: Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk. CONCLUSIONS: Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play.

Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial.

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. Trial Registration: isrctn.org Identifier: ISRCTN92187251.

Motor Complications in Parkinson's Disease: Results from 3343 Patients Followed for up to 12 Years.

BACKGROUND: Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. OBJECTIVES: To quantify the presence, severity, impact and associated factors for motor complications in PD. METHODS: Analysis of three large prospective cohort studies of recent-onset PD patients followed for up to 12 years. The MDS-UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms. RESULTS: 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4-6 years and 59.0% (55.6, 62.3) at 8-10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4-6 years and 42.1% (38.7, 45.5) at 8-10 years. Dystonia affected 13.4% (12.1, 14.9) at 4-6 years and 22.8% (20.1, 25.9) at 8-10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2-4 years post-diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years). CONCLUSIONS: Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications.

NMR metabolomic modeling of age and lifespan: A multicohort analysis.

Metabolomic age models have been proposed for the study of biological aging, however, they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. Ninety-eight metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈31,000 individuals, age range 24-86 years). We used nonlinear and penalized regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with aging risk factors and phenotypes. Within the UK Biobank (N ≈102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, and chronic obstructive pulmonary disease), and all-cause mortality. Seven-fold cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47 and 0.65 in the training cohort set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with CA were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06/metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability.

Use of drugs for hyperlipidaemia and diabetes and risk of primary and secondary brain tumours: nested case-control studies using the UK Clinical Practice Research Datalink (CPRD).

OBJECTIVES: Previous studies have suggested that fibrates and glitazones may have a role in brain tumour prevention. We examined if there is support for these observations using primary care records from the UK Clinical Practice Research Datalink (CPRD). DESIGN: We conducted two nested case-control studies using primary and secondary brain tumours identified within CPRD between 2000 and 2016. We selected cases and controls among the population of individuals who had been treated with any anti-diabetic or anti-hyperlipidaemic medication to reduce confounding by indication. SETTING: Adults older than 18 years registered with a general practitioner in the UK contributing data to CPRD. RESULTS: We identified 7496 individuals with any brain tumour (4471 primary; 3025 secondary) in total. After restricting cases and controls to those prescribed any anti-diabetic or anti-hyperlipidaemic medication, there were 1950 cases and 7791 controls in the fibrate and 480 cases with 1920 controls in the glitazone analyses. Longer use of glitazones compared with all other anti-diabetic medications was associated with a reduced risk of primary (adjusted OR (aOR) 0.89 per year, 95% CI 0.80 to 0.98), secondary (aOR 0.87 per year, 95% CI 0.77 to 0.99) or combined brain tumours (aOR 0.88 per year, 95% CI 0.81 to 0.95). There was little evidence that fibrate exposure was associated with risk of either primary or secondary brain tumours. CONCLUSIONS: Longer exposure to glitazones was associated with reduced primary and secondary brain tumour risk. Further basic science and population-based research should explore this finding in greater detail, in terms of replication and mechanistic studies.

Psychosocial Health Among Young Adults With Kidney Failure: A Longitudinal Follow-up of the SPEAK (Surveying Patients Experiencing Young Adult Kidney Failure) Study.

Rationale & Objective: There have been no longitudinal studies examining the evolution of psychosocial health of young adults with kidney failure as they age. We aimed to address this in the Surveying Patients Experiencing Young Adult Kidney Failure-2 (SPEAK-2) study. Study Design: 5-year follow-up longitudinal survey of the original SPEAK cohort. Setting & Participants: 16- to 30-year-olds in the UK receiving kidney replacement therapy (KRT) between 2015 and 2017 who participated in the SPEAK study. Exposure: Kidney failure and KRT modality. Outcomes: Psychosocial health and lifestyle behaviors. Analytical Approach: Within-cohort changes in psychosocial health were analyzed using the paired t test, Wilcoxon signed-rank test and McNemar's test. We compared responses to the age-matched population and examined the impact of changes in KRT modality on psychological health using linear regression for continuous outcome variables as well as logistic, ordered logistic and multinomial logistic regression for binary, ordered categorical and unordered categorical variables, respectively. Results: We obtained 158 survey responses; 129 had previously responded to SPEAK. Of these, 90% had a kidney transplant. Compared to the general population, respondents were less likely to be married or have children and were more likely to be living with their parents. Respondents had nearly 15 times greater odds of being unable to work due to health (odds ratio [OR] = 14.41; 95% confidence interval [CI], 8.0-26.01; P < 0.001). Respondents had poorer quality of life and mental wellbeing and were more likely to report psychological problems (OR = 5.37; 95% CI, 3.45-8.35; P < 0.001). A negative association between remaining on or moving to dialysis and psychosocial health was observed, although this was attenuated when controlling for the psychosocial state in SPEAK. Limitations: Low response rate resulting in imprecise and potentially biased estimates and impact of COVID-19 pandemic while survey was active on psychosocial health. Conclusions: Young adults with kidney failure have persistent poorer psychosocial health compared to their healthy peers as they age. Our findings also suggest a potential causal relationship between KRT modality and psychosocial health.

The psychosocial impact of kidney failure in young adults is implicated in the observed higher risk of transplant loss and death. The Surveying Patients Experiencing Young Adult Kidney Failure (SPEAK) study investigated the psychosocial health of young adults (16-30 years) in the UK receiving kidney replacement therapy and found they had poorer outcomes than the age-matched general population. In this 5-year follow-up study, we observed that as this group matured, they lagged behind their peers in terms of both lifecourse and psychological outcomes. Dialysis recipients had poorer psychosocial health compared to transplant recipients. This emphasizes the lasting impact of kidney failure on young adults' psychosocial health, particularly for those receiving dialysis, highlighting the need for better mental health support and treatment.

Life course plasma metabolomic signatures of genetic liability to Alzheimer's disease.

Mechanisms through which most known Alzheimer's disease (AD) loci operate to increase AD risk remain unclear. Although Apolipoprotein E (APOE) is known to regulate lipid homeostasis, the effects of broader AD genetic liability on non-lipid metabolites remain unknown, and the earliest ages at which metabolic perturbations occur and how these change over time are yet to be elucidated. We examined the effects of AD genetic liability on the plasma metabolome across the life course. Using a reverse Mendelian randomization framework in two population-based cohorts [Avon Longitudinal Study of Parents and Children (ALSPAC, n = 5648) and UK Biobank (n ≤ 118,466)], we estimated the effects of genetic liability to AD on 229 plasma metabolites, at seven different life stages, spanning 8 to 73 years. We also compared the specific effects of APOE ε4 and APOE ε2 carriage on metabolites. In ALSPAC, AD genetic liability demonstrated the strongest positive associations with cholesterol-related traits, with similar magnitudes of association observed across all age groups including in childhood. In UK Biobank, the effect of AD liability on several lipid traits decreased with age. Fatty acid metabolites demonstrated positive associations with AD liability in both cohorts, though with smaller magnitudes than lipid traits. Sensitivity analyses indicated that observed effects are largely driven by the strongest AD instrument, APOE, with many contrasting effects observed on lipids and fatty acids for both ε4 and ε2 carriage. Our findings indicate pronounced effects of the ε4 and ε2 genetic variants on both pro- and anti-atherogenic lipid traits and sphingomyelins, which begin in childhood and either persist into later life or appear to change dynamically.

Prodromal multiple sclerosis: considerations and future utility.

A multiple sclerosis (MS) prodrome has recently been described and is characterised by increased rates of healthcare utilisation and an excess frequency of fatigue, bladder problems, sensory symptoms and pain, in the years leading up to clinical onset of disease. This important observation may have several potential applications including in the identification of risk factors for disease, the potential to delay or prevent disease onset and early opportunities to alter disease course. It may also offer possibilities for the use of risk stratification algorithms and effective population screening. If standardised, clearly defined and disease specific, an MS prodrome is also likely to have a profound influence on research and clinical trials directed at the earliest stages of disease. In order to achieve these goals, it is essential to consider experience already gleaned from other disorders. More specifically, in some chronic neurological disorders the understanding of disease pro-drome is now well advanced and has been successfully applied. However, understanding of the MS prodrome remains at an early stage with key questions including the length of the prodrome, symptom specificity and potential benefits of early intervention as yet unanswered. In this review we will explore the evidence available to date and suggest future research strategies to address unanswered questions. In addition, whilst current understanding of the MS prodrome is not yet sufficient to justify changes in public health policy or MS management, we will consider the practical utility and future application of the MS prodrome in a wider health care setting.