Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants

This is the final version of the article. Available from American Society for Nutrition via the DOI in this record.Background: For older groups, being overweight [body mass index (BMI; in kg/m(2)): 25 to <30] is reportedly associated with a lower or similar risk of mortality than being normal weight (BMI: 18.5 to <25). However, this "risk paradox" is partly explained by smoking and disease-associated weight loss. This paradox may also arise from BMI failing to measure fat redistribution to a centralized position in later life.Objective: This study aimed to estimate associations between combined measurements of BMI and waist-to-hip ratio (WHR) with mortality and incident coronary artery disease (CAD).Design: This study followed 130,473 UK Biobank participants aged 60-69 y (baseline 2006-2010) for ≤8.3 y (n = 2974 deaths). Current smokers and individuals with recent or disease-associated (e.g., from dementia, heart failure, or cancer) weight loss were excluded, yielding a "healthier agers" group. Survival models were adjusted for age, sex, alcohol intake, smoking history, and educational attainment. Population and sex-specific lower and higher WHR tertiles were <0.91 and ≥0.96 for men and <0.79 and ≥0.85 for women, respectively.Results: Ignoring WHR, the risk of mortality for overweight subjects was similar to that for normal-weight subjects (HR: 1.09; 95% CI: 0.99, 1.19; P = 0.066). However, among normal-weight subjects, mortality increased for those with a higher WHR (HR: 1.33; 95% CI: 1.08, 1.65) compared with a lower WHR. Being overweight with a higher WHR was associated with substantial excess mortality (HR: 1.41; 95% CI: 1.25, 1.61) and greatly increased CAD incidence (sub-HR: 1.64; 95% CI: 1.39, 1.93) compared with being normal weight with a lower WHR. There was no interaction between physical activity and BMI plus WHR groups with respect to mortality.Conclusions: For healthier agers (i.e., nonsmokers without disease-associated weight loss), having central adiposity and a BMI corresponding to normal weight or overweight is associated with substantial excess mortality. The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life.AB reported grants from the UK National Institute for Health Research (NIHR) School for Public Health Research (Ageing Well Programme) during the conduct of the study and was an employee of Pfizer Italia until November 2012.Supported by UK Medical Research Council award MR/M023095/1 to DM, the National Institute for Health Research School for Public Health Research Ageing Well Programme (partnership), and the Intramural Research Program of the NIH National Institute on Aging

Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants

This is the final version of the article. Available from American Society for Nutrition via the DOI in this record.Background: For older groups, being overweight [body mass index (BMI; in kg/m(2)): 25 to <30] is reportedly associated with a lower or similar risk of mortality than being normal weight (BMI: 18.5 to <25). However, this "risk paradox" is partly explained by smoking and disease-associated weight loss. This paradox may also arise from BMI failing to measure fat redistribution to a centralized position in later life.Objective: This study aimed to estimate associations between combined measurements of BMI and waist-to-hip ratio (WHR) with mortality and incident coronary artery disease (CAD).Design: This study followed 130,473 UK Biobank participants aged 60-69 y (baseline 2006-2010) for ≤8.3 y (n = 2974 deaths). Current smokers and individuals with recent or disease-associated (e.g., from dementia, heart failure, or cancer) weight loss were excluded, yielding a "healthier agers" group. Survival models were adjusted for age, sex, alcohol intake, smoking history, and educational attainment. Population and sex-specific lower and higher WHR tertiles were <0.91 and ≥0.96 for men and <0.79 and ≥0.85 for women, respectively.Results: Ignoring WHR, the risk of mortality for overweight subjects was similar to that for normal-weight subjects (HR: 1.09; 95% CI: 0.99, 1.19; P = 0.066). However, among normal-weight subjects, mortality increased for those with a higher WHR (HR: 1.33; 95% CI: 1.08, 1.65) compared with a lower WHR. Being overweight with a higher WHR was associated with substantial excess mortality (HR: 1.41; 95% CI: 1.25, 1.61) and greatly increased CAD incidence (sub-HR: 1.64; 95% CI: 1.39, 1.93) compared with being normal weight with a lower WHR. There was no interaction between physical activity and BMI plus WHR groups with respect to mortality.Conclusions: For healthier agers (i.e., nonsmokers without disease-associated weight loss), having central adiposity and a BMI corresponding to normal weight or overweight is associated with substantial excess mortality. The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life.AB reported grants from the UK National Institute for Health Research (NIHR) School for Public Health Research (Ageing Well Programme) during the conduct of the study and was an employee of Pfizer Italia until November 2012.Supported by UK Medical Research Council award MR/M023095/1 to DM, the National Institute for Health Research School for Public Health Research Ageing Well Programme (partnership), and the Intramural Research Program of the NIH National Institute on Aging

Low Vitamin D Levels and Risk of Incident Delirium in 351,000 Older UK Biobank Participants

This is the final version. Available on open access from Wiley via the DOI in this recordBACKGROUND/OBJECTIVES Delirium is common in older adults, especially following hospitalization. Because low vitamin D levels may be associated with increased delirium risk, we aimed to determine the prognostic value of blood vitamin D levels, extending our previous genetic analyses of this relationship. DESIGN Prospective cohort analysis. SETTING Community‐based cohort study of adults from 22 cities across the United Kingdom (the UK Biobank). PARTICIPANTS Adults aged 60 and older by the end of follow‐up in the linked hospital inpatient admissions data, up to 14 years after baseline (n = 351,320). MEASUREMENTS At baseline, serum vitamin D (25‐OH‐D) levels were measured. We used time‐to‐event models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between vitamin D deficiency and incident hospital‐diagnosed delirium, adjusted for age, sex, assessment month, assessment center, and ethnicity. We performed Mendelian randomization genetic analysis in European participants to further investigate vitamin D and delirium risk. RESULTS A total of 3,634 (1.03%) participants had at least one incident hospital‐diagnosed delirium episode. Vitamin D deficiency (50 nmol/L). Increased risk was not limited to the deficient group: insufficient levels (25–50 nmol/L) were also at increased risk (HR = 1.38; 95% CI = 1.28–1.49; P = 4*10−18). The association was independent of calcium levels, hospital‐diagnosed fractures, dementia, and other relevant cofactors. In genetic analysis, participants carrying more vitamin D–increasing variants had a reduced likelihood of incident delirium diagnosis (HR = .80 per standard deviation increase in genetically instrumented vitamin D: .73–.87; P = 2*10−7). CONCLUSION Progressively lower vitamin D levels predicted increased risks of incident hospital‐diagnosed delirium, and genetic evidence supports a shared causal pathway. Because low vitamin D levels are simple to detect and inexpensive and safe to correct, an intervention trial to confirm these results is urgently needed.Alzheimer’s SocietyMedical Research Council (MRC)National Institute on Agin

ApoE e4e4 genotype and mortality with COVID-19 in UK Biobank

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this recor

A highly attenuated recombinant human respiratory syncytial virus lacking the G protein induces long-lasting protection in cotton rats

<p>Abstract</p> <p>Background</p> <p>Respiratory syncytial virus (RSV) is a primary cause of serious lower respiratory tract illness for which there is still no safe and effective vaccine available. Using reverse genetics, recombinant (r)RSV and an rRSV lacking the G gene (ΔG) were constructed based on a clinical RSV isolate (strain 98-25147-X).</p> <p>Results</p> <p>Growth of both recombinant viruses was equivalent to that of wild type virus in Vero cells, but was reduced in human epithelial cells like Hep-2. Replication in cotton rat lungs could not be detected for ΔG, while rRSV was 100-fold attenuated compared to wild type virus. Upon single dose intranasal administration in cotton rats, both recombinant viruses developed high levels of neutralizing antibodies and conferred comparable long-lasting protection against RSV challenge; protection against replication in the lungs lasted at least 147 days and protection against pulmonary inflammation lasted at least 75 days.</p> <p>Conclusion</p> <p>Collectively, the data indicate that a single dose immunization with the highly attenuated ΔG as well as the attenuated rRSV conferred long term protection in the cotton rat against subsequent RSV challenge, without inducing vaccine enhanced pathology. Since ΔG is not likely to revert to a less attenuated phenotype, we plan to evaluate this deletion mutant further and to investigate its potential as a vaccine candidate against RSV infection.</p

Analysis of CYP2C19 genetic variants with ischaemic events in UK patients prescribed clopidogrel in primary care: a retrospective cohort study.

This is the final version. Available from BMJ Publishing Group via the DOI in this record. Data availability statement: Data may be obtained from a third party and are not publicly available. Data are available on application to the UK Biobank ( www.ukbiobank.ac.uk/register-apply). Additional data are available from the corresponding author on reasonable request.OBJECTIVE: To determine whether CYP2C19 loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel. DESIGN: Retrospective cohort analysis. SETTING: Primary care practices in the UK from January 1999 to September 2017. PARTICIPANTS: 7483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36-79 years at time of first clopidogrel prescription. INTERVENTIONS: Clopidogrel prescription in primary care, mean duration 2.6 years (range 2 months to 18 years). MAIN OUTCOME MEASURE: Hospital inpatient-diagnosed ischaemic stroke, MI or angina while treated with clopidogrel. RESULTS: 28.7% of participants carried at least one CYP2C19 LoF variant. LoF carriers had higher rates of incident ischaemic stroke while treated with clopidogrel compared with those without the variants (8 per 1000 person-years vs 5.2 per 1000 person-years; HR 1.53, 95% CIs 1.04 to 2.26, p=0.031). LoF carriers also had increased risk of MI (HR 1.14, 95% CI 1.04 to 1.26, p=0.008). In combined analysis LoF carriers had increased risk of any ischaemic event (stroke or MI) (HR 1.17, 95% CI 1.06 to 1.29, p=0.002). Adjustment for aspirin coprescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischaemic stroke by age 79 (oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers, that is, 7.1% excess stroke incidence in LoF carriers by age 79. CONCLUSIONS: A substantial proportion of the UK population carry genetic variants that reduce metabolism of clopidogrel to its active form. In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischaemic events. Genotype-guided selection of antiplatelet medications may improve outcomes in patients carrying CYP2C19 genetic variants.Medical Research CouncilAlzheimer’s SocietyNational Institute for Health ResearchUniversity of Exeter Medical SchoolUniversity of Connecticut School of MedicineMinistry of National Education, Republic of TurkeyTravelers Chair in Geriatrics and GerontologyNational Institute on Agin

The celiac ganglion modulates LH-induced inhibition of androstenedione release in late pregnant rat ovaries

BACKGROUND: Although the control of ovarian production of steroid hormones is mainly of endocrine nature, there is increasing evidence that the nervous system also influences ovarian steroidogenic output. The purpose of this work was to study whether the celiac ganglion modulates, via the superior ovarian nerve, the anti-steroidogenic effect of LH in the rat ovary. Using mid- and late-pregnant rats, we set up to study: 1) the influence of the noradrenergic stimulation of the celiac ganglion on the ovarian production of the luteotropic hormone androstenedione; 2) the modulatory effect of noradrenaline at the celiac ganglion on the anti-steroidogenic effect of LH in the ovary; and 3) the involvement of catecholaminergic neurotransmitters released in the ovary upon the combination of noradrenergic stimulation of the celiac ganglion and LH treatment of the ovary. METHODS: The ex vivo celiac ganglion-superior ovarian nerve-ovary integrated system was used. This model allows studying in vitro how direct neural connections from the celiac ganglion regulate ovarian steroidogenic output. The system was incubated in buffer solution with the ganglion and the ovary located in different compartments and linked by the superior ovarian nerve. Three experiments were designed with the addition of: 1) noradrenaline in the ganglion compartment; 2) LH in the ovarian compartment; and 3) noradrenaline and LH in the ganglion and ovarian compartments, respectively. Rats of 15, 19, 20 and 21 days of pregnancy were used, and, as an end point, the concentration of the luteotropic hormone androstenedione was measured in the ovarian compartment by RIA at various times of incubation. For some of the experimental paradigms the concentration of various catecholamines (dihydroxyphenylalanine, dopamine, noradrenaline and adrenaline) was also measured in the ovarian compartment by HPLC. RESULTS: The most relevant result concerning the action of noradrenaline in the celiac ganglion was found on day 21 of pregnancy resulting in the inhibition of androstenedione release from the ovarian compartment. In addition on day 15 of pregnancy, LH placed in the ovarian compartment led to an inhibition of the release of androstenedione, and this inhibitory effect was further reinforced by the joint action of noradrenaline in the celiac ganglion and LH in the ovary. The levels of catecholamines in the ovarian compartment showed differences among the experiments; of significance, the joint treatment of noradrenaline in the celiac ganglion and LH in the ovary resulted in a remarkable increase in the ovarian levels of noradrenaline and adrenaline when compared to the effect achieved by either one of the compounds added alone. CONCLUSION: Our results demonstrate that the noradrenergic stimulation of the celiac ganglion reinforces the LH-induced inhibition of androstenedione production by the ovary of late pregnant rats, and that this effect is associated with marked changes in the release of catecholamines in the ovary

Lack of Relationship Between Chronic Upper Abdominal Symptoms and Gastric Function in Functional Dyspepsia

To determine the relationship between gastric function and upper abdominal sensations we studied sixty FD patients (43 female). All patients underwent three gastric function tests: 13C octanoic gastric emptying test, three-dimensional ultrasonography (proximal and distal gastric volume), and the nutrient drink test. Upper abdominal sensations experienced in daily life were scored using questionnaires. Impaired proximal gastric relaxation (23%) and a delayed gastric emptying (33%) are highly prevalent in FD patients; however, only a small overlap exists between the two pathophysiologic disorders (5%). No relationship was found between chronic upper abdominal symptoms and gastric function (proximal gastric relaxation, gastric emptying rate, or drinking capacity) (all P > 0.01). Proximal gastric relaxation or gastric emptying rate had no effect on maximum drinking capacity (P > 0.01). The lack of relationship between chronic upper abdominal sensations and gastric function questions the role of these pathophysiologic mechanisms in the generation of symptoms