Search

Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an integrative approach, combining data from genome-wide association studies with pathway and gene-set enrichment analyses. Literature review-based and Reactome database-driven approaches were combined to identify synapse-related pathways of interest in TBI outcome and to assess for shared associations with conditions in which synapse-related pathobiological mechanisms have been implicated, including Alzheimer's disease, schizophrenia (SCZ), major depressive disorder, post-traumatic stress disorder, attention-deficit hyperactivity disorder, and autism spectrum disorder. Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian randomization to investigate potential causal associations. Of the 98 pathways tested, 32 were significantly enriched in the included conditions. In TBI outcome, we identified significant enrichment in five pathways: "Serotonin clearance from the synaptic cleft" ( p = 0.0001), "Presynaptic nicotinic acetylcholine receptors" ( p = 0.0003), "Postsynaptic nicotinic acetylcholine receptors" ( p = 0.0003), "Highly sodium permeable postsynaptic acetylcholine nicotinic receptors" ( p = 0.0001), and "Acetylcholine binding and downstream events" pathways ( p = 0.0003). These associations highlight potential involvement of the cholinergic and serotonergic systems in post-TBI recovery. Three of those pathways were shared between TBI and SCZ, suggesting possible pathophysiologic commonalities. In this study, we utilize comparative and integrative genomic approaches across brain conditions that share synaptic mechanisms to explore the pathophysiology of TBI outcomes. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiological overlap with other neuropsychiatric diseases.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health 1 . This is compounded by the limited efficacy of available treatments 1 and high failure rates during drug development 2 , highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis 3-6 -we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures 7 , we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities., (© 2024. The Author(s).)

The development of dementia is a devastating aspect of Parkinson's disease (PD), affecting nearly half of patients within 10 years post-diagnosis. For effective therapies to prevent and slow progression to PD dementia (PDD), the key mechanisms that determine why some people with PD develop early dementia, while others remain cognitively unaffected, need to be understood. Neuroinflammation and tau protein accumulation have been demonstrated in post-mortem PD brains, and in many other neurodegenerative disorders leading to dementia. However, whether these processes mediate dementia risk early on in the PD disease course is not established. To this end, we used PET neuroimaging with 11C-PK11195 to index neuroinflammation and 18F-AV-1451 for misfolded tau in early PD patients, stratified according to dementia risk in our 'Neuroinflammation and Tau Accumulation in Parkinson's Disease Dementia' (NET-PDD) study. The NET-PDD study longitudinally assesses newly-diagnosed PD patients in two subgroups at low and high dementia risk (stratified based on pentagon copying, semantic fluency, MAPT genotype), with comparison to age- and sex-matched controls. Non-displaceable binding potential (BPND) in 43 brain regions (Hammers' parcellation) was compared between groups (pairwise t-tests), and associations between BPND of the tracers tested (linear-mixed-effect models). We hypothesized that people with higher dementia risk have greater inflammation and/or tau accumulation in advance of significant cognitive decline. We found significantly elevated neuroinflammation (11C-PK11195 BPND) in multiple subcortical and restricted cortical regions in the high dementia risk group compared with controls, while in the low-risk group this was limited to two cortical areas. The high dementia risk group also showed significantly greater neuroinflammation than the low-risk group concentrated on subcortical and basal ganglia regions. Neuroinflammation in most of these regions was associated with worse cognitive performance (Addenbrooke's Cognitive Examination-III score). Overall neuroinflammation burden also correlated with serum levels of pro-inflammatory cytokines. In contrast, increases in 18F-AV-1451 (tau) BPND in PD versus controls were restricted to subcortical regions where off-target binding is typically seen, with no relationship to cognition found. Whole-brain 18F-AV-1451 burden correlated with serum phosphorylated tau181 levels. Although there was minimal regional tau accumulation in PD, regional neuroinflammation and tau burden correlated in PD participants, with the strongest association in the high dementia risk group, suggesting possible co-localization of these pathologies. In conclusion, our findings suggest that significant regional neuroinflammation in early PD might underpin higher risk for PDD development, indicating neuroinflammation as a putative early modifiable aetiopathological disease factor to prevent or slow dementia development using immunomodulatory strategies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Genome-wide association studies have reported a genetic overlap between borderline personality disorder (BPD) and schizophrenia (SCZ). Epidemiologically, the direction and causality of the association between thyroid function and risk of BPD and SCZ are unclear. We aim to test whether genetically predicted variations in TSH and FT4 levels or hypothyroidism are associated with the risk of BPD and SCZ., Methods: We employed Mendelian Randomisation (MR) analyses using genetic instruments associated with TSH and FT4 levels as well as hypothyroidism to examine the effects of genetically predicted thyroid function on BPD and SCZ risk. Bidirectional MR analyses were employed to investigate a potential reverse causal association., Results: Genetically predicted higher FT4 was not associated with the risk of BPD (OR: 1.18; P = 0.60, IVW) or the risk of SCZ (OR: 0.93; P = 0.19, IVW). Genetically predicted higher TSH was not associated with the risk of BPD (OR: 1.11; P = 0.51, IVW) or SCZ (OR: 0.98, P = 0.55, IVW). Genetically predicted hypothyroidism was not associated with BPD or SCZ. We found no evidence for a reverse causal effect between BPD or SCZ on thyroid function., Conclusions: We report evidence for a null association between genetically predicted FT4, TSH or hypothyroidism with BPD or SCZ risk. There was no evidence for reverse causality., (© 2024. The Author(s).)

Background: The relationship between multimorbidity (i.e. ≥ 2 chronic conditions) and incontinence (i.e. urinary and/or faecal incontinence) is underexplored. This study investigated the association between multimorbidity and incident incontinence in Chinese adults aged ≥50 years., Methods: Data from the 2011 and 2015 waves of the China Health and Retirement Longitudinal Study were used. The association between 12 chronic conditions, multimorbidity and new-onset incontinence was analysed using weighted logistic regression models. Mediation analysis was conducted to explore the potential mediators (self-reported health, subjective memory, depressive symptoms, disability, cognitive function, handgrip strength, mobility limitations, medications and frailty status) between multimorbidity and incontinence., Findings: Among 9,986 individuals aged ≥50 years who were continent at baseline, 5.3% (n = 521) were newly incontinent 4 years later (incident cases). The risk of incident incontinence increased with physical multimorbidity (OR 2.04, 95% CI 1.62-2.57). Compared to no chronic condition, having 1, 2, 3 and ≥ 4 chronic conditions were associated with incident incontinence with OR (95% CI): 1.41 (1.01-1.97), 1.74 (1.24-2.44), 2.82 (1.93-4.12) and 3.99 (2.29-6.95), respectively. The association between multimorbidity and incontinence was mediated by self-reported health (41.2%), medications (26.6%), mobility limitations (20.9%), depressive symptoms (12.8%), disability (11.6%), subjective memory (8.7%) and frailty status (8.3%)., Conclusion: This longitudinal study found that physical multimorbidity and specific chronic conditions may increase the risk of new-onset incontinence among Chinese adults aged ≥50 years. Self-reported health, medications and mobility limitations seemed to be important intermediate conditions between multimorbidity and incident incontinence., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Third doses of COVID-19 vaccines were widely deployed following the primary vaccine course waning and the emergence of the Omicron-variant. We investigated protection from third-dose vaccines and previous infection against SARS-CoV-2 infection during Delta-variant and Omicron-variant (BA.1 & BA.2) waves in our frequently PCR-tested cohort of healthcare-workers. Relative effectiveness of BNT162b2 third doses and infection-acquired immunity was assessed by comparing the time to PCR-confirmed infection in boosted participants with those with waned dose-2 protection (≥254 days after dose-2), by primary series vaccination type. Follow-up time was divided by dominant circulating variant: Delta 07 September 2021 to 30 November 2021, Omicron 13 December 2021t o 28 February 2022. We used a Cox regression model with adjustment/stratification for demographic characteristics and staff-type. We explored protection associated with vaccination, infection and both. We included 19,614 participants, 29% previously infected. There were 278 primary infections (4 per 10,000 person-days of follow-up) and 85 reinfections (0.8/10,000 person-days) during the Delta period and 2467 primary infections (43/10,000 person-days) and 881 reinfections (33/10,000) during the Omicron period. Relative Vaccine Effectiveness (VE) 0-2 months post-3rd dose (3rd dose) (3-doses BNT162b2) in the previously uninfected cohort against Delta infections was 63% (95% Confidence Interval (CI) 40%-77%) and was lower (35%) against Omicron infection (95% CI 21%-47%). The relative VE of 3rd dose (heterologous BNT162b2) was greater for primary course ChAdOX1 recipients, with VE 0-2 months post-3rd dose over ≥68% higher for both variants. Third-dose protection waned rapidly against Omicron, with no significant difference between two and three BNT162b2 doses observed after 4-months. Previous infection continued to provide additional protection against Omicron (67% (CI 56%-75%) 3-6 months post-infection), but this waned to about 25% after 9-months, approximately three times lower than against Delta. Infection rates surged with Omicron emergence. Third doses of BNT162b2 vaccine provided short-term protection, with rapid waning against Omicron infections. Protection associated with infections incurred before Omicron was markedly diminished against the Omicron wave. Our findings demonstrate the complexity of an evolving pandemic with the potential emergence of immune-escape variants and the importance of continued monitoring., Competing Interests: Declaration of Competing Interest We declare no competing interests., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Metformin shows beneficial effects on cardiometabolic health in diabetic individuals. However, the beneficial effects in the general population, especially in non-diabetic individuals are unclear. We aim to estimate the effects of perturbation of seven metformin targets on cardiometabolic health using Mendelian randomization (MR)., Methods: Genetic variants close to metformin-targeted genes associated with expression of the corresponding genes and glycated haemoglobin (HbA 1c ) level were used to proxy therapeutic effects of seven metformin-related drug targets. Eight cardiometabolic phenotypes under metformin trials were selected as outcomes (average N = 466,947). MR estimates representing the weighted average effects of the seven effects of metformin targets on the eight outcomes were generated. One-sample MR was applied to estimate the averaged and target-specific effects in 338,425 non-diabetic individuals in UK Biobank., Findings: Genetically proxied averaged effects of five metformin targets, equivalent to a 0.62% reduction of HbA 1c level, was associated with 37.8% lower risk of coronary artery disease (CAD) (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.46-0.84), lower levels of body mass index (BMI) (β = -0.22, 95% CI = -0.35 to -0.09), systolic blood pressure (SBP) (β = -0.19, 95% CI = -0.28 to -0.09) and diastolic blood pressure (DBP) levels (β = -0.29, 95% CI = -0.39 to -0.19). One-sample MR suggested that the seven metformin targets showed averaged and target-specific beneficial effects on BMI, SBP and DBP in non-diabetic individuals., Interpretation: This study showed that perturbation of seven metformin targets has beneficial effects on BMI and blood pressure in non-diabetic individuals. Clinical trials are needed to investigate whether similar effects can be achieved with metformin medications., Funding: Funding information is provided in the Acknowledgements., Competing Interests: Declaration of interests T.R.G, J.Z. and G.D.S have received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. G.D.S. reports Scientific Advisory Board Membership for Relation Therapeutics and Insitro. M.V.H. is presently employed by 23andMe and holds stock in the company, and has previously consulted for Boehringer Ingelheim. The remaining authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The aim of this patient and public involvement and engagement (PPIE) work was to explore improvised theatre as a tool for facilitating bi-directional dialogue between researchers and patients/members of the public on the topic of polygenic risk scores (PRS) use within primary or secondary care. PRS are a tool to quantify genetic risk for a heritable disease or trait and may be used to predict future health outcomes. In the United Kingdom (UK), they are often cited as a next-in-line public health tool to be implemented, and their use in consumer genetic testing as well as patient-facing settings is increasing. Despite their potential clinical utility, broader themes about how they might influence an individual's perception of disease risk and decision-making are an active area of research; however, this has mostly been in the setting of return of results to patients. We worked with a youth theatre group and patients involved in a PPIE group to develop two short plays about public perceptions of genetic risk information that could be captured by PRS. These plays were shared in a workshop with patients/members of the public to facilitate discussions about PRS and their perceived benefits, concerns and emotional reactions. Discussions with both performers and patients/public raised three key questions: (1) can the data be trusted?; (2) does knowing genetic risk actually help the patient?; and (3) what makes a life worthwhile? Creating and watching fictional narratives helped all participants explore the potential use of PRS in a clinical setting, informing future research considerations and improving communication between the researchers and lay members of the PPIE group., (© 2023. The Author(s).)

This retrospective cohort study investigated the incidence and risk factors of major adverse cardiovascular events (MACE) after 1 year of first-documented myocardial infarctions (MIs) in a multi-ethnic Asian population. Secondary MACE were observed in 231 (14.3%) individuals, including 92 (5.7%) cardiovascular-related deaths. Both histories of hypertension and diabetes were associated with secondary MACE after adjustment for age, sex, and ethnicity (HR 1.60 [95%CI 1.22-2.12] and 1.46 [95%CI 1.09-1.97], respectively). With further adjustments for traditional risk factors, individuals with conduction disturbances demonstrated higher risks of MACE: new left-bundle branch block (HR 2.86 [95%CI 1.15-6.55]), right-bundle branch block (HR 2.09 [95%CI 1.02-4.29]), and second-degree heart block (HR 2.45 [95%CI 0.59-10.16]). These associations were broadly similar across different age, sex, and ethnicity groups, although somewhat greater for history of hypertension and BMI among women versus men, for HbA1c control in individuals aged >50 years, and for LVEF ≤ 40% in those with Indian versus Chinese or Bumiputera ethnicities. Several traditional and cardiac risk factors are associated with a higher risk of secondary major adverse cardiovascular events. In addition to hypertension and diabetes, the identification of conduction disturbances in individuals with first-onset MI may be useful for the risk stratification of high-risk individuals.

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension., Methods: We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival., Results: In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality., Conclusions: We hypothesize that CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity)., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Mobile health interventions are promising behavior change tools. However, there is a concern that they may benefit some populations less than others and thus widen inequalities in health. This systematic review investigated differences in uptake of, engagement with, and effectiveness of mobile interventions for weight-related behaviors (i.e., diet, physical activity, and sedentary behavior) based on a range of inequality indicators including age, gender, race/ethnicity, and socioeconomic status. The protocol was registered on PROSPERO (CRD42020192473). Six databases (CINAHL, EMBASE, ProQuest, PsycINFO, Pubmed, and Web of Science) were searched from inception to July 2021. Publications were eligible for inclusion if they reported the results of an exclusively mobile intervention and examined outcomes by at least one inequality indicator. Sixteen publications reporting on 13 studies were included with most reporting on multiple behaviors and inequality indicators. Uptake was investigated in one study with no differences reported by the inequality indicators studied. Studies investigating engagement (n = 7) reported differences by age (n = 1), gender (n = 3), ethnicity (n = 2), and education (n = 2), while those investigating effectiveness (n = 9) reported differences by age (n = 3), gender (n = 5), education (n = 2), occupation (n = 1), and geographical location (n = 1). Given the limited number of studies and their inconsistent findings, evidence of the presence of a digital divide in mobile interventions targeting weight-related behaviors is inconclusive. Therefore, we recommend that inequality indicators are specifically addressed, analyzed, and reported when evaluating mobile interventions., (© 2023 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing opportunities, adverse effects, and biomarkers of efficacy., Methods: The loss-of-function missense variant rs34536443 in TYK2 gene was used as a genetic instrument to proxy the effect of TYK2 inhibition. A phenome-wide Mendelian randomization (MR) study was conducted to explore the associations of genetically-proxied TYK2 inhibition with 1473 disease outcomes in UK Biobank (N = 339,197). Identified associations were examined for replication in FinnGen (N = 260,405). We further performed tissue-specific gene expression MR, colocalization analyses, and MR with 247 blood biomarkers. A systematic review of randomized controlled trials (RCTs) on TYK2 inhibitor was performed to complement the genetic evidence., Findings: PheWAS-MR found that genetically-proxied TYK2 inhibition was associated with lower risk of a wide range of autoimmune diseases. The associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression and the associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There were nominal associations of genetically-proxied TYK2 inhibition with increased risk of prostate and breast cancer but not in tissue-specific expression MR or colocalization analyses. Thirty-seven blood biomarkers were associated with the TYK2 loss-of-function mutation. Evidence from RCTs confirmed the effectiveness of TYK2 inhibitors on plaque psoriasis and reported several adverse effects., Interpretation: This study supports TYK2 inhibitor as a potential treatment for psoriasis and several other autoimmune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects., Funding: None., Competing Interests: Declaration of interests DG is employed part-time by Novo Nordisk. The other authors declare no competing interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Few genome-wide association studies (GWAS) analyzing genetic regulation of morphological traits of white blood cells have been reported. We carried out a GWAS of 12 morphological traits in 869 individuals from the general population of Sardinia, Italy. These traits, included measures of cell volume, conductivity and light scatter in four white-cell populations (eosinophils, lymphocytes, monocytes, neutrophils). This analysis yielded seven statistically significant signals, four of which were novel (four novel, PRG2, P2RX3, two of CDK6). Five signals were replicated in the independent INTERVAL cohort of 11 822 individuals. The most interesting signal with large effect size on eosinophil scatter (P-value = 8.33 x 10-32, beta = -1.651, se = 0.1351) falls within the innate immunity cluster on chromosome 11, and is located in the PRG2 gene. Computational analyses revealed that a rare, Sardinian-specific PRG2:p.Ser148Pro mutation modifies PRG2 amino acid contacts and protein dynamics in a manner that could possibly explain the changes observed in eosinophil morphology. Our discoveries shed light on genetics of morphological traits. For the first time, we describe such large effect size on eosinophils morphology that is relatively frequent in Sardinian population., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: The effect of long-term exposure to antiretroviral therapy (ART) on hypertension in sub-Saharan Africa remains unclear. We aimed to determine the prevalence and incidence of hypertension in people living with HIV (PLWH) with more than 10 years of ART in Uganda., Methods: The analysis was performed within a cohort of adult PLWH with more than 10 years of ART at an HIV clinic in Kampala, Uganda. Participants were eligible for this analysis if they had ≥2 follow-up visits. Hypertension was defined as two consecutive systolic blood pressure (SBP) measures greater than 140 mmHg and/or diastolic blood pressure (DBP) greater than 90 mmHg, and/or documented diagnosis and/or the initiation of antihypertensives. We determined the proportion of PLWH with hypertension at baseline and used multivariable logistic regression to determine the factors associated with prevalent hypertension. To determine the incidence of hypertension, follow-up began from the cohort baseline date and was censored at the last clinic visit or date of the event, whichever occurred earlier. Multivariable Poisson regression was used to determine the adjusted incidence rate ratios (aIRR) of hypertension according to demographic, ART, and clinical characteristics., Results: Of the 1000 ALT participants, 970 (97%) had ≥2 follow-up visits, and 237 (24.4%) had hypertension at baseline. The odds of prevalent hypertension were 1.18 for every 5-year increase in age (adjusted odds ratio (aOR) 1.18, 95% CI 1.10-1.34) and were higher among males (aOR 1.70, 95% CI 1.20-2.34), participants with diabetes mellitus (aOR 2.37, 95% CI 1.10-4.01), obesity (aOR 1.99, 95% CI 1.08-3.60), high cholesterol (aOR 1.47, 95% CI 1.16-2.01), and those with prior exposure to stavudine (aOR 2.10, 95% CI 1.35-3.52), or nevirapine (aOR 1.90, 95% CI 1.25-3.01). Of the 733 participants without hypertension at baseline, 116 (15.83%) developed hypertension during 4671.3 person-years of follow-up (incidence rate 24.8 per 1000 person-years; 95% CI 20.7-29.8). The factors associated with incident hypertension were obesity (adjusted incidence rate ratio (aIRR) 1.80, 95% CI 1.40-2.81), older age (aIRR 1.12 per 5-year increase in age, 95% CI 1.10,1.25), and renal insufficiency (aIRR1.80, 95% CI 1.40-2.81)., Conclusion: The prevalence and incidence of hypertension were high in this heavily treated PLWH cohort. Therefore, with increasing ART coverage, HIV programs in SSA should strengthen the screening for hypertension in heavily treated PLWH., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Byonanebye et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Previous Mendelian randomization (MR) studies on obesity and risk of breast cancer adopted a small number of instrumental variables and focused mainly on the crude total effect. We aim to investigate the independent causal effect of obesity on breast cancer susceptibility, considering the distribution of fat, covering both early and late life., Methods: Using an enlarged set of female-specific genetic variants associated with adult general [body mass index (BMI)] and abdominal obesity [waist-to-hip ratio (WHR) with and without adjustment for BMI, WHR and WHRadjBMI] as well as using sex-combined genetic variants of childhood obesity (childhood BMI), we performed a two-sample univariable MR to re-evaluate the total effect of each obesity-related exposure on overall breast cancer (Ncase = 133 384, Ncontrol = 113 789). We further looked into its oestrogen receptor (ER)-defined subtypes (NER+ = 69 501, NER- = 21 468, Ncontrol = 105 974). Multivariable MR was applied to estimate the independent causal effect of each obesity-related exposure on breast cancer taking into account confounders as well as to investigate the independent effect of adult and childhood obesity considering their inter-correlation., Results: In univariable MR, the protective effects of both adult BMI [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P = 2.06 × 10-3] and childhood BMI (OR = 0.78, 95% CI = 0.70-0.87, P = 4.58 × 10-6) were observed for breast cancer overall. Comparable effects were found in ER+ and ER- subtypes. Similarly, genetically predicted adult WHR was also associated with a decreased risk of breast cancer overall (OR = 0.87, 95% CI = 0.80-0.96, P = 3.77 × 10-3), restricting to ER+ subtype (OR = 0.88, 95% CI = 0.80-0.98, P = 1.84 × 10-2). Conditional on childhood BMI, the effect of adult general obesity on breast cancer overall attenuated to null (BMI: OR = 1.00, 95% CI = 0.90-1.10, P = 0.96), whereas the effect of adult abdominal obesity attenuated to some extent (WHR: OR = 0.90, 95% CI = 0.82-0.98, P = 1.49 × 10-2; WHRadjBMI: OR = 0.92, 95% CI = 0.86-0.99, P = 1.98 × 10-2). On the contrary, an independent protective effect of childhood BMI was observed in breast cancer overall, irrespective of adult measures (adjusted for adult BMI: OR = 0.84, 95% CI = 0.77-0.93, P = 3.93 × 10-4; adjusted for adult WHR: OR = 0.84, 95% CI = 0.76-0.91, P = 6.57 × 10-5; adjusted for adult WHRadjBMI: OR = 0.80, 95% CI = 0.74-0.87, P = 1.24 × 10-7)., Conclusion: Although successfully replicating the inverse causal relationship between adult obesity-related exposures and risk of breast cancer, our study demonstrated such effects to be largely (adult BMI) or partly (adult WHR or WHRadjBMI) attributed to childhood obesity. Our findings highlighted an independent role of childhood obesity in affecting the risk of breast cancer as well as the importance of taking into account the complex interplay underlying correlated exposures., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objective: To investigate the effects of metabolic traits, lifestyle factors, and drug interventions on liver fat using the mendelian randomisation paradigm., Design: Mendelian randomisation study., Setting: Publicly available summary level data from genome-wide association studies., Participants: Genome-wide association studies of 32 974 to 1 407 282 individuals who were predominantly of European descent., Exposures: Genetic variants predicting nine metabolic traits, six lifestyle factors, four lipid lowering drug targets, three antihypertensive drug targets, and genetic association estimates formagnetic resonance imaging measured liver fat., Main Outcome Measures: Mendelian randomisation analysis was used to investigate the effects of these exposures on liver fat, incorporating sensitivity analyses that relaxed the requisite modelling assumptions., Results: Genetically predicted liability to obesity, type 2 diabetes, elevated blood pressure, elevated triglyceride levels, cigarette smoking, and sedentary time watching television were associated with higher levels of liver fat. Genetically predicted lipid lowering drug effects were not associated with liver fat; however, β blocker and calcium channel blocker antihypertensive drug effects were associated with lower levels of liver fat., Conclusion: These analyses provide evidence of a causal effect of various metabolic traits, lifestyle factors, and drug targets on liver fat. The findings complement existing epidemiological associations, further provide mechanistic insight, and potentially supports a role for drug interventions in reducing the burden of hepatic steatosis and related disease. Further clinical study is now warranted to investigate the relevance of these genetic analyses for patient care., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Swedish Heart-Lung Foundation, the Swedish Research Council for Health, Working Life and Welfare, the Swedish Research Council, the Swedish Cancer Society, the British Heart Foundation Centre of Research Excellence at Imperial College London, and the United Kingdom Research and Innovation Medical Research Council. DG is employed part-time by Novo Nordisk and has received consultancy fees from Policy Wisdom. The remaining authors report no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Providing care for the dependent older person is complex and there have been persistent concerns about care quality as well as a growing recognition of the need for systems approaches to improvement. The I-SCOPE (Improving Systems of Care for the Older person) project employed Resilient Healthcare (RHC) theory and the CARE (Concepts for Applying Resilience) Model to study how care organisations adapt to complexity in everyday work, with the aim of exploring how to support resilient performance. The project was an in-depth qualitative study across multiple sites over 24 months. There were: 68 hours of non-participant observation, shadowing care staff at work and starting broad before narrowing to observe care domains of interest; n = 33 recorded one-to-one interviews (32 care staff and one senior inspector); three focus groups (n = 19; two with inspectors and one multi-disciplinary group); and five round table discussions on emergent results at a final project workshop (n = 31). All interviews and discussion groups were recorded and transcribed verbatim. Resident and family interviews (n = 8) were facilitated through use of emotional touchpoints. Analysis using QSR NVivo 12.0 focused on a) capturing everyday work in terms of the interplay between demand and capacity, adaptations and intended and unintended outcomes and b) a higher-level thematic description (care planning and use of information; coordination of everyday care activity; providing person-centred care) which gives an overview of resilient performance and how it might be enhanced. This gives important new insight for improvement. Conclusions are that resilience can be supported through more efficient use of information, supporting flexible adaptation, coordination across care domains, design of the physical environment, and family involvement based on realistic conversations about quality of life., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Ross et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Sex hormone-binding globulin (SHBG), testosterone and oestradiol have been associated with many diseases in observational studies; however, the causality of associations remains unestablished., Methods: A phenome-wide Mendelian randomization (MR) association study was performed to explore disease outcomes associated with genetically proxied circulating SHBG, testosterone and oestradiol levels by using updated genetic instruments in 339 197 unrelated White British individuals (54% female) in the UK Biobank. Two-sample MR analyses with data from large genetic studies were conducted to replicate identified associations in phenome-wide MR analyses. Multivariable MR analyses were performed to investigate mediation effects of hormone-related biomarkers in observed associations with diseases., Results: Phenome-wide MR analyses examined associations of genetically predicted SHBG, testosterone and oestradiol levels with 1211 disease outcomes, and identified 28 and 13 distinct phenotypes associated with genetically predicted SHBG and testosterone, respectively; 22 out of 28 associations for SHBG and 10 out of 13 associations for testosterone were replicated in two-sample MR analyses. Higher genetically predicted SHBG levels were associated with a reduced risk of hypertension, type 2 diabetes, diabetic complications, coronary atherosclerotic outcomes, gout and benign and malignant neoplasm of uterus, but an increased risk of varicose veins and fracture (mainly in females). Higher genetically predicted testosterone levels were associated with a lower risk of type 2 diabetes, coronary atherosclerotic outcomes, gout and coeliac disease mainly in males, but an increased risk of cholelithiasis in females., Conclusions: These findings suggest that sex hormones may causally affect risk of several health outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Cardiovascular disease (CVD) risk prediction models for individuals with type 2 diabetes are important tools to guide intensification of interventions for CVD prevention. We aimed to assess the added value of incorporating risk factors variability in CVD risk prediction for people with type 2 diabetes., Methods: We used electronic health records (EHRs) data from 83 910 adults with type 2 diabetes but without pre-existing CVD from the UK Clinical Practice Research Datalink for 2004-2017. Using a landmark-modelling approach, we developed and validated sex-specific Cox models, incorporating conventional predictors and trajectories plus variability of systolic blood pressure (SBP), total and high-density lipoprotein (HDL) cholesterol, and glycated haemoglobin (HbA1c). Such models were compared against simpler models using single last observed values or means., Results: The standard deviations (SDs) of SBP, HDL cholesterol and HbA1c were associated with higher CVD risk (P < 0.05). Models incorporating trajectories and variability of continuous predictors demonstrated improvement in risk discrimination (C-index = 0.659, 95% CI: 0.654-0.663) as compared with using last observed values (C-index = 0.651, 95% CI: 0.646-0.656) or means (C-index = 0.650, 95% CI: 0.645-0.655). Inclusion of SDs of SBP yielded the greatest improvement in discrimination (C-index increase = 0.005, 95% CI: 0.004-0.007) in comparison to incorporating SDs of total cholesterol (C-index increase = 0.002, 95% CI: 0.000-0.003), HbA1c (C-index increase = 0.002, 95% CI: 0.000-0.003) or HDL cholesterol (C-index increase= 0.003, 95% CI: 0.002-0.005)., Conclusion: Incorporating variability of predictors from EHRs provides a modest improvement in CVD risk discrimination for individuals with type 2 diabetes. Given that repeat measures are readily available in EHRs especially for regularly monitored patients with diabetes, this improvement could easily be achieved., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objectives: Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) is a rare life-threatening complication that typically occurs several weeks after SARS-CoV-2 infection in children and young people (CYP). We used national and regional-level data from the COVID-19 pandemic waves in England to develop a model to predict PIMS-TS cases., Methods: SARS-CoV-2 infections in CYP aged 0-15 years in England were estimated using the PHE-Cambridge real-time model. PIMS-TS cases were identified through the British Paediatric Surveillance Unit during (March-June 2020) and through Secondary Uses Services (SUS) from November 2020. A predictive model was developed to estimate PIMS-TS risk and lag times after SARS-CoV-2 infections., Results: During the Alpha wave, the model accurately predicted PIMS-TS cases (506 vs. 502 observed cases), with a median estimated risk of 0.038% (IQR, 0.037-0.041%) of paediatric SARS-CoV-2 infections. For the Delta wave, the median risk of PIMS-TS was significantly lower at 0.026% (IQR, 0.025-0.029%), with 212 observed PIMS-TS cases compared to 450 predicted by the model., Conclusions: The model accurately predicted national and regional PIMS-TS cases in CYP during the Alpha wave. PIMS-TS cases were 53% lower than predicted during the Delta wave. Further studies are needed to understand the mechanisms of the observed lower risk with the Delta variant., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Shingleton, Burton, Williams, Finnie, Bennett, Birrell, Kenny, Watson- Koszel, Viner, Arditi, DeAngelis, Gent and Ladhani.)

The objectives of this study were to define risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in University of Cambridge (UoC) students during a period of increased incidence in October and November 2020. The study design was a survey.Routine public health surveillance identified an increase in the numbers of UoC students with confirmed SARS-CoV-2 positivity in the 10 days after a national lockdown was announced in the UK on 5th November 2020. Cases were identified both through symptom-triggered testing and a universal asymptomatic testing programme. An online questionnaire was sent to all UoC students on 25 November to investigate risk factors for testing positive in the period after 30th October 2020. This asked about symptoms, SARS-CoV-2 test results, aspects of university life, and attendance at social events in the week prior to lockdown. Univariate and multivariable analyses were undertaken evaluating potential risk factors for SARS-CoV-2 positivity.Among 3980 students responding to the questionnaire, 99 (2.5%) reported testing SARS-CoV-2 positive in the period studied; 28 (28%) were asymptomatic. We found strong independent associations with SARS-CoV-2 positivity and attendance at two social settings in the City of Cambridge (adjusted odds ratio favouring disease 13.0 (95% CI 6.2-26.9) and 14.2 (95% CI 2.9-70)), with weaker evidence of association with three further social settings. By contrast, we did not observe strong independent associations between disease risk and accommodation type or attendance at a range of activities associated with the university curriculum.To conclude attendance at social settings can facilitate widespread SARS-CoV-2 transmission in university students. Constraint of transmission in higher education settings needs to emphasise risks outside university premises, as well as a COVID-safe environment within university premises.

Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10 -11 ) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships., (© 2022. The Author(s).)

To develop healthy ageing interventions, longitudinal associations between objectively assessed physical behaviours and physical function need to be better understood. We assessed associations between accelerometer-assessed total physical activity (PA), moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), sedentary time and prolonged sedentary bout time, and clinically assessed physical function (grip strength, usual walking speed (UWS), chair stand speed) at two time-points in 3188 participants (≥ 60 years) of the EPIC-Norfolk study. Bidirectional associations were assessed using multivariable linear regression. Over an average of 6.1 years, baseline physical behaviours (greater total PA, MVPA and LPA, and less sedentary time) were associated with better subsequent walking and chair stand speed. Better baseline physical function was associated with better follow-up physical behaviours. There were no bidirectional associations between changes in physical behaviours and grip strength. Improvements in UWS were associated with improvements in all physical behaviours. Improvements in chair stand speed were associated with improvements in total PA, MVPA, and sedentary bout time. Improvements in physical behaviours were associated with improvements in UWS (3.1 cm/s/yr per 100 cpm/yr  total PA, 3.6 cm/s/yr per hr/day/yr MVPA, 2.5 cm/s/yr per hr/day/yr LPA, - 2.9 cm/s/yr per hour/day/yr sedentary time, and - 1.6 cm/s/yr per hr/day/yr prolonged sedentary bout time). Only improvements in total PA, MVPA and sedentary bout time were associated with improvements in chair stand speed. In conclusion, we found bidirectional associations between changes in some physical behaviours and physical function and between baseline physical behaviours and subsequent physical function, highlighting the importance of considering the full range of physical behaviours to promote healthy ageing., Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-022-00733-y., Competing Interests: Conflicts of interestThere are no conflicts of interest declared. Ethical approval Ethical procedures in this study were approved by the Norfolk Local Research Ethics and East Norfolk and Waveney NHS Research Governance Committee. EPIC was closely monitored both internally by the University of Cambridge and externally by various governing committees such as the Local Research Ethics Committee and Confidentiality Advisory Group (CAG) of the Health Research Authority. The EPIC-Norfolk Approval Board approved access to data from the study, with all released data already anonymised., (© The Author(s) 2022.)

Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10 -4 ). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke., (© 2022. The Author(s).)

Aims/hypothesis: Metformin use has been associated with reduced incidence of dementia in diabetic individuals in observational studies. However, the causality between the two in the general population is unclear. This study uses Mendelian randomisation (MR) to investigate the causal effect of metformin targets on Alzheimer's disease and potential causal mechanisms in the brain linking the two., Methods: Genetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that associated with HbA 1c level (N=344,182) and expression level of the corresponding gene (N≤31,684). The cognitive outcomes were derived from genome-wide association studies comprising 527,138 middle-aged Europeans, including 71,880 with Alzheimer's disease or Alzheimer's disease-by-proxy. MR estimates representing lifelong metformin use on Alzheimer's disease and cognitive function in the general population were generated. Effect of expression level of 22 metformin-related genes in brain cortex (N=6601 donors) on Alzheimer's disease was further estimated., Results: Genetically proxied metformin use, equivalent to a 6.75 mmol/mol (1.09%) reduction on HbA 1c , was associated with 4% lower odds of Alzheimer's disease (OR 0.96 [95% CI 0.95, 0.98], p=1.06×10 -4 ) in non-diabetic individuals. One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on Alzheimer's disease (OR 0.88, p=4.73×10 -4 ) that was independent of AMP-activated protein kinase. MR of expression in brain cortex tissue showed that decreased MCI-related gene (NDUFA2) expression was associated with lower Alzheimer's disease risk (OR 0.95, p=4.64×10 -4 ) and favourable cognitive function., Conclusions/interpretation: Metformin use may cause reduced Alzheimer's disease risk in the general population. Mitochondrial function and the NDUFA2 gene are plausible mechanisms of action in dementia protection., (© 2022. The Author(s).)

The features in a high-dimensional biomedical prediction problem are often well described by low-dimensional latent variables (or factors). We use this to include unlabeled features and additional information on the features when building a prediction model. Such additional feature information is often available in biomedical applications. Examples are annotation of genes, metabolites, or p-values from a previous study. We employ a Bayesian factor regression model that jointly models the features and the outcome using Gaussian latent variables. We fit the model using a computationally efficient variational Bayes method, which scales to high dimensions. We use the extra information to set up a prior model for the features in terms of hyperparameters, which are then estimated through empirical Bayes. The method is demonstrated in simulations and two applications. One application considers influenza vaccine efficacy prediction based on microarray data. The second application predicts oral cancer metastasis from RNAseq data., (© 2022 The Authors. Biometrical Journal published by Wiley-VCH GmbH.)

While there is growing evidence of associations between infections and dementia risk, associations with cognitive impairment and potential structural correlates of cognitive decline remain underexplored. Here we aimed to investigate the presence and nature of any associations between common infections, cognitive decline and neuroimaging parameters. The UK Biobank is a large volunteer cohort (over 500,000 participants recruited aged 40-69) with linkage to primary and secondary care records. Using linear mixed effects models, we compared participants with and without a history of infections for changes in cognitive function during follow-up. Linear regression models were used to investigate the association of infections with hippocampal and white matter hyperintensity (WMH) volume. 16,728 participants (median age 56.0 years [IQR 50.0-61.0]; 51.3% women) had baseline and follow-up cognitive measures. We found no evidence of an association between the presence of infection diagnoses and cognitive decline for mean correct response time (slope difference [infections versus no infections] = 0.40 ms, 95% CI: -0.17-0.96 per year), visual memory (slope difference 0.0004 log errors per year, 95% CI: -0.003-0.004, fluid intelligence (slope difference 0.007, 95% CI: -0.010-0.023) and prospective memory (OR 0.88, 95% CI: 0.68-1.14). No evidence of an association was found between infection site, setting or frequency and cognitive decline except for small associations on the visual memory test. We found no association between infections and hippocampal or WMH volume. Limitations of our study include selection bias, potential practice effects and the relatively young age of our cohort. Our findings do not support a major role for common midlife infections in contributing to cognitive decline for this cohort. Further research is warranted in individuals with more severe infections, for infections occurring later in life., (© 2022. The Author(s).)

The objective of this study was to determine the effectiveness of MRP8/14 as a predictor of disease flare in patients with juvenile idiopathic arthritis (JIA) following the withdrawal of methotrexate (MTX) in a routine clinical setting. All MRP8/14 tests performed at a single centre in a 27-month period were considered for analysis. Patients were assessed against criteria for inactive disease and subsequent disease flare. Decisions on whether or not to stop treatment were recorded. MRP8/14 results were assessed in conjunction with clinical information. Clinicians were also surveyed to investigate if MRP8/14 influenced their decision to discontinue MTX where this was available at that time point. One hundred four cases met the inclusion criteria during the study period. Although there was no significant difference in flares between patients with an elevated or low MRP8/14 value, in those who stopped MTX (n = 22), no patients with a low MRP8/14 (≤ 4000 ng/ml) result flared (follow-up time 12 months). Clinicians reported that for patients with clinically inactive disease and an elevated MRP8/14 result (> 4000 ng/ml), none would advise withdrawal of MTX. Low MRP8/14 was interpreted favourably when considering stopping MTX treatment in patients with JIA. Implementation of MRP8/14 testing has changed clinical practice at this centre. However, the observation that some patients in our cohort who had an elevated MRP8/14 value did not flare after stopping MTX for non-disease-related reasons highlights the need for further biomarkers to predict the risk of flare off medication in JIA and aid clinicians in treatment decisions. Key Points • First study of serum MRP8/14 measurement in clinical practice to inform treatment decisions in patients with JIA. • No patients with a low MRP8/14 test result went on to suffer a disease flare in 12 months of follow follow-up. • Further biomarkers are needed to predict the risk of flare off medication in JIA and treatment decisions., (© 2022. The Author(s).)

Background and Objectives: Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed class of medication used to treat heart failure, hypertension, and chronic kidney disease. However, previous observational studies have shown conflicting directions of associations between ACE inhibitors and risk of Alzheimer disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer disease (AD). However, it is unclear whether this effect is mediated through blood pressure and extends to other neurodegenerative diseases., Methods: We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk in people of European ancestry. We further investigated whether any effect of ACE expression on AD risk is mediated through changes in blood pressure and whether effects extend to Parkinson disease, small-vessel disease, or cognitive function in a Mendelian randomization paradigm., Results: There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk in people of European ancestry. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure nor that ACE expression affected risk of other neurodegenerative traits., Discussion: Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes in people of European ancestry. Further work is required to investigate whether therapeutic inhibition of ACE increases risk of Alzheimer disease., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: To generate a prognostic model to predict keratoconus progression to corneal crosslinking (CXL)., Design: Retrospective cohort study., Methods: We recruited 5025 patients (9341 eyes) with early keratoconus between January 2011 and November 2020. Genetic data from 926 patients were available. We investigated both keratometry or CXL as end points for progression and used the Royston-Parmar method on the proportional hazards scale to generate a prognostic model. We calculated hazard ratios (HRs) for each significant covariate, with explained variation and discrimination, and performed internal-external cross validation by geographic regions., Results: After exclusions, model fitting comprised 8701 eyes, of which 3232 underwent CXL. For early keratoconus, CXL provided a more robust prognostic model than keratometric progression. The final model explained 33% of the variation in time to event: age HR (95% CI) 0.9 (0.90-0.91), maximum anterior keratometry 1.08 (1.07-1.09), and minimum corneal thickness 0.95 (0.93-0.96) as significant covariates. Single-nucleotide polymorphisms (SNPs) associated with keratoconus (n=28) did not significantly contribute to the model. The predicted time-to-event curves closely followed the observed curves during internal-external validation. Differences in discrimination between geographic regions was low, suggesting the model maintained its predictive ability., Conclusions: A prognostic model to predict keratoconus progression could aid patient empowerment, triage, and service provision. Age at presentation is the most significant predictor of progression risk. Candidate SNPs associated with keratoconus do not contribute to progression risk., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Policies to reduce meat consumption are needed to help achieve climate change targets, and could also improve population health. Public acceptability can affect the likelihood of policy implementation. This study estimated the acceptability of policies to reduce red and processed meat consumption, and whether acceptability differed when policies were framed as benefitting health or the environment. In an online experiment, 2215 UK adults rated the acceptability of six policies, presented in a randomised order. Prior to rating policies, participants were randomised to one of two framing conditions, with policy outcomes described either as benefitting health or the environment. Regression models examined differences in the primary outcome - policy acceptability (rated on a 7-point scale) - by framing. Labels were the most accepted policy (48% support), followed by a media campaign (45%), reduced availability (40%) and providing incentives (38%). Increasing price (27%) and banning advertising (26%) were the least accepted. A substantial proportion of participants neither supported nor opposed most policies (26-33%), although this fell to 16% for increasing price. There was no evidence that framing policy benefits from a health or environment perspective influenced acceptability (-0.06, 95%CIs: 0.18,0.07). Fewer than half of the UK sample expressed support for any of six policies to reduce meat consumption, regardless of framing measures as benefitting health or the environment. Conversely, fewer than half expressed opposition, with the exception of price, suggesting considerable scope to influence public opinion in support of meat reduction measures to meet environmental and health goals., Competing Interests: None, (© 2022 The Authors.)

Importance: Previous in vitro and postmortem research suggests that inflammation may lead to structural brain changes via activation of microglia and/or astrocytic dysfunction in a range of neuropsychiatric disorders., Objective: To investigate the relationship between inflammation and changes in brain structures in vivo and to explore a transcriptome-driven functional basis with relevance to mental illness., Design, Setting, and Participants: This study used multistage linked analyses, including mendelian randomization (MR), gene expression correlation, and connectivity analyses. A total of 20 688 participants in the UK Biobank, which includes clinical, genomic, and neuroimaging data, and 6 postmortem brains from neurotypical individuals in the Allen Human Brain Atlas (AHBA), including RNA microarray data. Data were extracted in February 2021 and analyzed between March and October 2021., Exposures: Genetic variants regulating levels and activity of circulating interleukin 1 (IL-1), IL-2, IL-6, C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were used as exposures in MR analyses., Main Outcomes and Measures: Brain imaging measures, including gray matter volume (GMV) and cortical thickness (CT), were used as outcomes. Associations were considered significant at a multiple testing-corrected threshold of P < 1.1 × 10-4. Differential gene expression in AHBA data was modeled in brain regions mapped to areas significant in MR analyses; genes were tested for biological and disease overrepresentation in annotation databases and for connectivity in protein-protein interaction networks., Results: Of 20 688 participants in the UK Biobank sample, 10 828 (52.3%) were female, and the mean (SD) age was 55.5 (7.5) years. In the UK Biobank sample, genetically predicted levels of IL-6 were associated with GMV in the middle temporal cortex (z score, 5.76; P = 8.39 × 10-9), inferior temporal (z score, 3.38; P = 7.20 × 10-5), fusiform (z score, 4.70; P = 2.60 × 10-7), and frontal (z score, -3.59; P = 3.30 × 10-5) cortex together with CT in the superior frontal region (z score, -5.11; P = 3.22 × 10-7). No significant associations were found for IL-1, IL-2, CRP, or BDNF after correction for multiple comparison. In the AHBA sample, 5 of 6 participants (83%) were male, and the mean (SD) age was 42.5 (13.4) years. Brain-wide coexpression analysis showed a highly interconnected network of genes preferentially expressed in the middle temporal gyrus (MTG), which further formed a highly connected protein-protein interaction network with IL-6 (enrichment test of expected vs observed network given the prevalence and degree of interactions in the STRING database: 43 nodes/30 edges observed vs 8 edges expected; mean node degree, 1.4; genome-wide significance, P = 4.54 × 10-9). MTG differentially expressed genes that were functionally enriched for biological processes in schizophrenia, autism spectrum disorder, and epilepsy., Conclusions and Relevance: In this study, genetically determined IL-6 was associated with brain structure and potentially affects areas implicated in developmental neuropsychiatric disorders, including schizophrenia and autism.

Objective: To optimise dementia prevention strategies, we must understand the complex relationships between lifestyle behaviours, frailty and genetics., Methods: We explored relationships between frailty index, healthy lifestyle and polygenic risk scores (all assessed at study entry) and incident all-cause dementia as recorded on hospital admission records and death register data., Results: The analytical sample had a mean age of 64.1 years at baseline (SD=2.9) and 53% were women. Incident dementia was detected in 1762 participants (median follow-up time=8.0 years). High frailty was associated with increased dementia risk independently of genetic risk (HR 3.68, 95% CI 3.11 to 4.35). Frailty mediated 44% of the relationship between healthy lifestyle behaviours and dementia risk (indirect effect HR 0.95, 95% CI 0.95 to 0.96). Participants at high genetic risk and with high frailty had 5.8 times greater risk of incident dementia compared with those at low genetic risk and with low frailty (HR 5.81, 95% CI 4.01 to 8.42). Higher genetic risk was most influential in those with low frailty (HR 1.31, 95% CI 1.22 to 1.40) but not influential in those with high frailty (HR 1.09, 95% CI 0.92 to 1.28)., Conclusion: Frailty is strongly associated with dementia risk and affects the risk attributable to genetic factors. Frailty should be considered an important modifiable risk factor for dementia and a target for dementia prevention strategies, even among people at high genetic risk., Competing Interests: Competing interests: DDW, JMR, LMKW and DJL have nothing to report. KR has asserted copyright of the Clinical Frailty Scale through Dalhousie University’s Industry, Liaison and Innovation Office. Use is free for education, research, and not-for-profit health care. Users agree not to change or commercialise the scale. In addition to academic and hospital appointments, KR is cofounder of DGI Clinical, which in the last five years has contracts with pharma and device manufacturers (Biogen, Shire, Hollister, Novartis, Nutricia, Roche, Takeda) on individualiSed outcome measurement. In 2017, he attended an advisory board meeting with Lundbeck on dementia, and in 2020 chaired a Scientific Workshop & Technical Review Panel on frailty for the Singapore National Research Foundation. Otherwise any personal fees are for invited guest lectures, rounds and academic symposia, received directly from event organiSers, for presentations on frailty. He is Associate Director of the Canadian Consortium on Neurodegeneration in Aging, which is funded by the Canadian Institutes for Health Research, the Alzheimer Society of Canada and several other funding partners., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Identifying linked cases of infection is a critical component of the public health response to viral infectious diseases. In a clinical context, there is a need to make rapid assessments of whether cases of infection have arrived independently onto a ward, or are potentially linked via direct transmission. Viral genome sequence data are of great value in making these assessments, but are often not the only form of data available. Here, we describe A2B-COVID, a method for the rapid identification of potentially linked cases of COVID-19 infection designed for clinical settings. Our method combines knowledge about infection dynamics, data describing the movements of individuals, and evolutionary analysis of genome sequences to assess whether data collected from cases of infection are consistent or inconsistent with linkage via direct transmission. A retrospective analysis of data from two wards at Cambridge University Hospitals NHS Foundation Trust during the first wave of the pandemic showed qualitatively different patterns of linkage between cases on designated COVID-19 and non-COVID-19 wards. The subsequent real-time application of our method to data from the second epidemic wave highlights its value for monitoring cases of infection in a clinical context., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Background: Factors such as age, pre-injury health, and injury severity, account for less than 35% of outcome variability in traumatic brain injury (TBI). While some residual outcome variability may be attributable to genetic factors, published candidate gene association studies have often been underpowered and subject to publication bias., Methods: We performed the first genome- and transcriptome-wide association studies (GWAS, TWAS) of genetic effects on outcome in TBI. The study population consisted of 5268 patients from prospective European and US studies, who attended hospital within 24 h of TBI, and satisfied local protocols for computed tomography., Findings: The estimated heritability of TBI outcome was 0·26. GWAS revealed no genetic variants with genome-wide significance (p < 5 × 10 -8 ), but identified 83 variants in 13 independent loci which met a lower pre-specified sub-genomic statistical threshold (p < 10 -5 ). Similarly, none of the genes tested in TWAS met tissue-wide significance. An exploratory analysis of 75 published candidate variants associated with 28 genes revealed one replicable variant (rs1800450 in the MBL2 gene) which retained significance after correction for multiple comparison (p = 5·24 × 10 -4 )., Interpretation: While multiple novel loci reached less stringent thresholds, none achieved genome-wide significance. The overall heritability estimate, however, is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome. The meta-analytic approach to the GWAS and the availability of summary data allows for a continuous extension with additional cohorts as data becomes available., Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section., Competing Interests: Declaration of interests K.K. is now an employee of Boehringer Ingelheim. S.I. declares royalties or licenses with McGraw Hill education. L.W. reports receiving consultancy fees from Vasopharm and Novartis outside the submitted work. C.D.A. declares sponsored research support from Bayer AG and consulting fees from ApoPharma. R.DA. declares consultation for MesoScale Discoveries and Ischemix, Inc.; stocks/stock options in BrainBox Solutions, Inc. and NovaSignal, Inc.; and has received equipment, materials, drugs, medical writing, gifts or other services from MesoScale Discoveries. M.B.S. declares advisory work and stock options with Oxeia Biopharmaceuticals. A.I.R.M. serves as an advisory board member for PressuraNeuro. D.K.M. declares the following conflicts of interest outside the scope of the submitted work: collaborative grant funding, consultancy fees, or educational grants from Lantmannen AB, GlaxoSmithKline Ltd., PressuraNeuro Ltd., Calico LLC, NeuroTrauma Sciences LLC, and Integra Neurosciences. He acts as a Trustee for Queens’ College (Cambridge, UK), the Intensive Care National Audit and Research Centre (London, UK), and is Chair and Trustee of the European Brain Injury Consortium. J.R. declares participation on advisory boards for Takeda Pharmaceuticals, Pfizer and Boehringer Ingelheim, outside the scope of the submitted work. The remaining authors declare no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in 'biological age' than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Brain health as expressed in our mental health and occurrence of specific disorders such as dementia and stroke is vitally important to quality of life, functional independence, and risk of institutionalization. Maintaining brain health is, therefore, a societal imperative, and public health challenge, from prevention of acquisition of brain disorders, through protection and risk reduction to supporting those with such disorders through effective societal and system approaches. To identify possible mechanisms that explain the differential effect of potentially modifiable risk factors, and factors that may mitigate risk, a life course approach is needed. This is key to understanding how poor health can accumulate from the earliest life stages. It also allows us to integrate and investigate key material, behavioral, and psychological factors that generate health inequalities within and across communities and societies. This review provides a narrative on how brain health is intimately linked to wider health determinants, thus importance for clinicians and societies alike. There is compelling evidence accumulated from research over decades that socioeconomic status, higher education, and healthy lifestyle extend life and compress major morbidities into later life. Brain health is part of this, but collective action has been limited, partly because of the separation of disciplines and focus on highly reductionist approaches in that clinicians and associated research have focused more on mitigation and early detection of specific diseases. However, clinicians could be part of the drive for better brain health for all society to support life courses that have more protection and less risk. There is evidence of change in such risks for conditions such as stroke and dementia across generations. The evidence points to the importance of starting with parental health and life course inequalities as a central focus.

Background: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization., Methods: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included., Results: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2., Conclusions: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)