ObjectiveTo compare prevalent and incident morbidity and mortality between those with the HFE p.C282Y genetic variant (responsible for most hereditary haemochromatosis type 1) and those with no p.C282Y mutations, in a large UK community sample of European descent.DesignCohort study.Setting22 centres across England, Scotland, and Wales in UK Biobank (2006-10).Participants451 243 volunteers of European descent aged 40 to 70 years, with a mean follow-up of seven years (maximum 9.4 years) through hospital inpatient diagnoses and death certification.Main outcome measureOdds ratios and Cox hazard ratios of disease rates between participants with and without the haemochromatosis mutations, adjusted for age, genotyping array type, and genetic principal components. The sexes were analysed separately as morbidity due to iron excess occurs later in women.ResultsOf 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), haemochromatosis was diagnosed in 21.7% (95% confidence interval 19.5% to 24.1%, 281/1294) of men and 9.8% (8.4% to 11.2%, 156/1596) of women by end of follow-up. p.C282Y homozygous men aged 40 to 70 had a higher prevalence of diagnosed haemochromatosis (odds ratio 411.1, 95% confidence interval 299.0 to 565.3, P<0.001), liver disease (4.30, 2.97 to 6.18, P<0.001), rheumatoid arthritis (2.23, 1.51 to 3.31, P<0.001), osteoarthritis (2.01, 1.71 to 2.36, P<0.001), and diabetes mellitus (1.53, 1.16 to 1.98, P=0.002), versus no p.C282Y mutations (n=175 539). During the seven year follow-up, 15.7% of homozygous men developed at least one incident associated condition versus 5.0% (P<0.001) with no p.C282Y mutations (women 10.1% v 3.4%, P<0.001). Haemochromatosis diagnoses were more common in p.C282Y/p.H63D heterozygotes, but excess morbidity was modest.ConclusionsIn a large community sample, HFE p.C282Y homozygosity was associated with substantial prevalent and incident clinically diagnosed morbidity in both men and women. As p.C282Y associated iron overload is preventable and treatable if intervention starts early, these findings justify re-examination of options for expanded early case ascertainment and screening.

Importance treatment of dementia in individuals with comorbidities is complex, leading to potentially inappropriate prescribing (PIP). The impact of PIP in this population is unknown. Objective to estimate the rate of PIP and its effect on adverse health outcomes (AHO). Design retrospective cohort. Setting primary care electronic health records linked to hospital discharge data from England. Subjects 11,175 individuals with dementia aged over 65 years in 2016 and 43,463 age- and sex-matched controls. Methods Screening Tool of Older Persons’ Prescriptions V2 defined PIP. Logistic regression tested associations with comorbidities at baseline, and survival analyses risk of incident AHO, adjusted for age, gender, deprivation and 14 comorbidities. Results the dementia group had increased risk of PIP (73% prevalence; odds ratio [OR]: 1.92; confidence interval [CI]: 83–103%; P &lt; 0.01) after adjusting for comorbidities. Most frequent PIP criteria were related to anti-cholinergic drugs and therapeutic duplication. Risk of PIP was higher in patients also diagnosed with coronary-heart disease (odds OR: 2.17; CI: 1.91–2.46; P &lt; 0.01), severe mental illness (OR: 2.09; CI: 1.62–2.70; P &lt; 0.01); and depression (OR: 1.81; CI: 1.62–2.01; P &lt; 0.01). During follow-up (1 year), PIP was associated with increased all-cause mortality (hazard ratio: 1.14; CI: 1.02–1.26; P &lt; 0.02), skin ulcer and pressure sores (hazard ratio: 1.66; CI: 1.12–2.46; P &lt; 0.01), falls (hazard ratio: 1.37; CI: 1.15–1.63; P &lt; 0.01), anaemia (hazard ratio: 1.61; CI: 1.10–2.38; P &lt; 0.02) and osteoporosis (hazard ratio: 1.62; CI: 1.02–2.57; P &lt; 0.04). Conclusion patients with dementia frequently receive PIPs, and those who do are more likely to experience AHO. These results highlight the need to optimise medication in dementia patients, especially those with comorbidities.

This study was conducted to assess the predictive utility of self-esteem and dispositional optimism to postpartum depression. Forty-five British women completed standard measures of self-esteem, optimism, and postpartum depression several weeks before childbirth. Depression was again measured at two and six weeks postpartum. Optimism was associated with less depressive symptoms during pregnancy and at two weeks postpartum, while self-esteem was associated with lower depression over all three administrations. After controlling for optimism and earlier levels of depressive symptoms, self-esteem remained associated with lower levels of depressive symptoms two weeks postpartum. This suggests that self-esteem and not optimism appears to be a reliable contributing factor to the differential susceptibility to depression in the early postpartum period.

ObjectiveTo estimate effects of vitamin D levels on incident delirium hospital admissions using inherited genetic variants in mendelian randomization models, which minimize confounding and exclude reverse causation.MethodsLongitudinal analysis using the UK Biobank, community-based, volunteer cohort (2006–2010) with incident hospital-diagnosed delirium (ICD-10 F05) ascertained during ≤9.9 years of follow-up of hospitalization records (to early 2016). We included volunteers of European descent aged 60-plus years by end of follow-up. We used single-nucleotide polymorphisms previously shown to increase circulating vitamin D levels, and APOE variants. Cox competing models accounting for mortality were used.ResultsOf 313,121 participants included, 544 were hospitalized with delirium during follow-up. Vitamin D variants were protective for incident delirium: hazard ratio = 0.74 per 10 nmol/L (95% confidence interval 0.62–0.87, p = 0.0004) increase in genetically instrumented vitamin D, with no evidence for pleiotropy (mendelian randomization–Egger p > 0.05). Participants with ≥1 APOE ε4 allele were more likely to develop delirium (e.g., ε4ε4 hazard ratio = 3.73, 95% confidence interval 2.68–5.21, p = 8.0 × 10−15 compared to ε3ε3), but there was no interaction with vitamin D variants.Conclusions and relevanceIn a large community-based cohort, there is genetic evidence supporting a causal role for vitamin D levels in incident delirium. Trials of correction of low vitamin D levels in the prevention of delirium are needed.