Associations of Cardiovascular and Non-Cardiovascular Comorbidities with Dementia Risk in Patients with Diabetes: Results from a Large UK Cohort Study.

BACKGROUND: Type 2 diabetes (T2D) is an established risk factor for dementia. However, it remains unclear whether the presence of comorbidities could further increase dementia risk in diabetes patients. OBJECTIVES: To examine the associations between cardiovascular and non-cardiovascular comorbidities and dementia risk in T2D patients. DESIGN: Population-based cohort study. SETTING: The UK Clinical Practice Research Datalink (CPRD). PARTICIPANTS: 489,205 T2D patients aged over 50 years in the UK CPRD. MEASUREMENTS: Major cardiovascular and non-cardiovascular comorbidities were extracted as time-varying exposure variables. The outcome event was dementia incidence based on dementia diagnosis or dementia-specific drug prescription. RESULTS: During a median of six years follow-up, 33,773 (6.9%) incident dementia cases were observed. Time-varying Cox regressions showed T2D patients with stroke, peripheral vascular disease, atrial fibrillation, heart failure or hypertension were at higher risk of dementia compared to those without such comorbidities (HR [95% CI] = 1.64 [1.59-1.68], 1.37 [1.34-1.41], 1.26 [1.22-1.30], 1.15 [1.11-1.20] or 1.10 [1.03-1.18], respectively). Presence of chronic obstructive pulmonary disease or chronic kidney disease was also associated with increased dementia risk (HR [95% CI] = 1.05 [1.01-1.10] or 1.11 [1.07-1.14]). CONCLUSIONS: A range of cardiovascular and non-cardiovascular comorbidities were associated with further increases of dementia risk in T2D patients. Prevention and effective management of these comorbidities may play a significant role in maintaining cognitive health in T2D patients.

Association of patient characteristics with clinical outcomes in a cohort of hospitalised patients with SARS-CoV-2 infection in a Greek referral centre for COVID-19.

Patient-important outcomes related to coronavirus disease 2019 (COVID-19) continue to drive the pandemic response across the globe. Various prognostic factors for COVID-19 severity have emerged and their replication across different clinical settings providing health services is ongoing. We aimed to describe the clinical characteristics and their association with outcomes in patients hospitalised with COVID-19 in the University Hospital of Ioannina. We assessed a cohort of 681 consecutively hospitalised patients with COVID-19 from January 2020 to December 2021. Demographic data, underlying comorbidities, clinical presentation, biochemical markers, radiologic findings, COVID-19 treatment and outcome data were collected at the first day of hospitalisation and up to 90 days. Multivariable Cox regression analyses were performed to investigate the associations between clinical characteristics (hazard ratios (HRs) per standard deviation (s.d.)) with intubation and/or mortality status. The participants' mean age was 62.8 (s.d., 16.9) years and 57% were males. The most common comorbidities were hypertension (45%), cardiovascular disease (19%) and diabetes mellitus (21%). Patients usually presented with fever (81%), cough (50%) and dyspnoea (27%), while lymphopenia and increased inflammatory markers were the most common laboratory abnormalities. Overall, 55 patients (8%) were intubated, and 86 patients (13%) died. There were statistically significant positive associations between intubation or death with age (HR: 2.59; 95% CI 1.52-4.40), lactate dehydrogenase (HR: 1.44; 95% CI 1.04-1.98), pO2/FiO2 ratio < 100 mmHg (HR: 3.52; 95% CI 1.14-10.84), and inverse association with absolute lymphocyte count (HR: 0.54; 95% CI 0.33-0.87). These data might help to identify points for improvement in the management of COVID-19 patients.

Milk intake and incident stroke and CHD in populations of European descent: a Mendelian randomisation study.

Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (ß = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.

Fetal growth and fetoplacental circulation in pregnancies following bariatric surgery: a prospective study.

OBJECTIVE: To investigate the intrauterine fetal growth pattern and fetoplacental circulation in pregnancies following bariatric surgery. DESIGN: Prospective study. SETTING: Maternity Unit, UK. POPULATION: One hundred and sixty-two pregnant women; 54 with previous bariatric surgery and 108 with no surgery but similar booking body mass index. METHODS: Participants were seen at 11-14, 20-24, 30-33 and 35-37 weeks of gestation and an oral glucose tolerance test (OGTT) was performed at 27-30 weeks. Fetal head and abdominal circumference (AC), femur length (FL), estimated fetal weight (EFW) and fetoplacental Dopplers were measured at three time-points in pregnancy. Birthweight (BW) was recorded. Variables were modelled after adjustment for maternal/pregnancy characteristics. Model estimates are reported as posterior means and quantile-based 90% credible intervals (CrI). MAIN OUTCOME MEASURES: Fetal biometry, fetoplacental Doppler, BW. RESULTS: Compared with the no surgery group, the post-bariatric surgery group had lower EFW during gestation (up to -120 g; [-189 g, -51 g] lighter) at 35-37 weeks, with smaller AC and FL. Similarly, infants of mothers with previous bariatric surgery had lower average BW [-202 g [-330 g, -72 g] lighter). Overall, there was no difference in the fetoplacental Doppler indices between groups but maternal glucose levels at OGTT were positively correlated with third-trimester EFW and BW. CONCLUSIONS: Fetuses of women with previous bariatric surgery are smaller during pregnancy and at birth, compared with those of women without such surgery, and this may be related to the lower maternal glucose levels seen in the former population. The fetoplacental circulation appears not to be altered by maternal weight loss surgery. TWEETABLE ABSTRACT: Offspring of post-bariatric women are smaller during pregnancy and at birth but this is not due to placental insufficiency.

Prevalence of vitamin D deficiency and association with metabolic syndrome in a Qatari population.

OBJECTIVES: Despite long hours of sunlight in Qatar and other regions of the Middle East, vitamin D deficiency has been rising. In parallel, the prevalence of metabolic syndrome has also been increasing in Qatar. Vitamin D levels have been associated with metabolic syndrome but the data are inconsistent and no studies have addressed these inter-relationships in a Middle Eastern population where the prevalence of these conditions is high. The objective is to investigate the prevalence of vitamin D deficiency and its association with metabolic syndrome and its components in the Qatar Biobank population. METHODS: A cross-sectional study of 1205 participants (702 women and 503 men) from the Qatar Biobank, comprising Qataris and non-Qataris between the ages of 18 and 80 years, was used to perform multivariate linear regression analyses to examine the association between metabolic syndrome and prevalence of vitamin D deficiency (defined as <20 ng ml-1 serum vitamin D levels) adjusting for age, sex, ethnicity, season of blood collection, physical activity and education. Odds ratios and 95% confidence intervals were calculated for all analyses. RESULTS: Approximately 64% of participants were vitamin D deficient (<20 ng ml-1) with more men being deficient (68.6%) than women (61.3%). Serum vitamin D was 8% lower in individuals with metabolic syndrome (RR: 0.92, 95%CI: 0.87-0.98, P-value: 0.01) compared to individuals without metabolic syndrome. Waist circumference and HDL as well as high triglyceride levels were also significantly positively associated with vitamin D deficiency. No association was found between the other components of metabolic syndrome or diabetes and the presence of vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency is prevalent in this Qatari population. Presence of metabolic syndrome was associated with presence of vitamin D deficiency. Future prospective studies need to be conducted to investigate the potential for causality.

Investigating nutrition and lifestyle factors as determinants of abdominal obesity: an environment-wide study.

BACKGROUND: The increasing global trends in obesity and its associated burden of disease indicate a need to identify modifiable determinants of obesity. METHODS: A total of 182 nutrition and lifestyles factors were investigated in relation to abdominal obesity among 7,403 male and 8,328 female participants of the Third U.S. National Health and Examination Survey (NHANES III). We used the first phase (1988-1991) of the NHANES III to identify factors with a false discovery rate (FDR) of <5%. Of these, we tentatively replicated our findings in the second phase (1992-1994) of the survey. Principal component analysis was performed to identify unobserved factors underlying the association between validated factors and abdominal obesity, defined as waist circumference >88 cm for women and >102 cm for men. RESULTS: We found five tentatively replicated factors showing significant associations with abdominal obesity in men: serum α-carotene, ß-carotene, serum ß-cryptoxanthin, serum vitamin D and vigorous physical activity. In women, 7 factors were identified: serum α-carotene, ß-carotene, serum ß-cryptoxanthin, serum vitamin C, serum vitamin D, vigorous physical activity and aspartame intake. In contrast to the other factors which showed inverse associations with abdominal obesity, aspartame intake displayed a positive relationship with this outcome (OR: 1.18, 95% CI: 1.10-1.26 for each log increase in aspartame intake in women). Principal component analysis suggested three principal components underlying such associations, each comprising: (1) serum antioxidants; (2) serum vitamin D and vigorous physical activity; and (3) aspartame intake. All three principal components also displayed significant associations with abdominal obesity. CONCLUSION: Our observational investigation that systematically investigates multiple modifiable factors simultaneously has enabled the creation of data-driven hypotheses regarding the possible role of determinants of abdominal obesity and has identified potential avenues for mechanistic investigations to clarify suitable targets of intervention.

How do changes in body mass index in infancy and childhood associate with cardiometabolic profile in adulthood? Findings from the Northern Finland Birth Cohort 1966 Study.

BACKGROUND/OBJECTIVE: Postnatal growth patterns leading to obesity may have adverse influences on future cardiometabolic health. This study evaluated age and body mass index (BMI) at infant BMI peak (BMIP) and childhood BMI rebound (BMIR) in relation to adult cardiometabolic outcomes in the Northern Finland Birth Cohort 1966. METHODS: BMI at various ages was calculated from frequent height and weight measurements obtained from child health and welfare clinical records. Age and BMI at BMIP and BMIR were derived from random effect models fitted at >0-1.5 years (N=3 265) and >1.5-13 years (N=4 121). Cardiometabolic outcomes were obtained from a clinical examination at age 31 years. Multiple regression models were used to analyse associations between the derived growth parameters and cardiometabolic outcomes. RESULTS: Age and BMI at BMIP were positively associated with adult BMI and waist circumference (WC), independently of birth weight and infant height growth (P<0.05). Later BMIR was associated with a better cardiometabolic profile: adult BMI and insulin were 14% lower, WC and triglycerides were 10% lower and the odds of metabolic syndrome (MetS) were 74% lower per 2 s.d. (1.86 years) higher age at BMIR (P<0.0001). BMI at rebound had generally weaker associations with cardiometabolic outcomes, which attenuated after adjustment for age at BMIR. CONCLUSIONS: Age and BMI at infant BMIP were associated with adult adiposity but not with other cardiometabolic outcomes. Earlier timing of BMIR was a risk factor of an adverse cardiometabolic profile, independently of early growth or BMI at rebound. Identifying growth patterns harmful to cardiovascular health will give opportunities for early interventions.

Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables.

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.

Review and meta-analysis of epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease risks, and their possible mechanisms.

Although the link between high doses of ionizing radiation and damage to the heart and coronary arteries has been well established for some time, the association between lower-dose exposures and late occurring cardiovascular disease has only recently begun to emerge, and is still controversial. In this paper, we extend an earlier systematic review by Little et al. on the epidemiological evidence for associations between low and moderate doses of ionizing radiation exposure and late occurring blood circulatory system disease. Excess relative risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well-known (but unobserved) risk factors, and there is statistically significant (p < 0.00001) heterogeneity between the risks. This heterogeneity is reduced, but remains significant, if adjustments are made for the effects of fractionated delivery or if there is stratification by endpoint (cardiovascular disease vs. stroke, morbidity vs. mortality). One possible biological mechanism is damage to endothelial cells and subsequent induction of an inflammatory response, although it seems unlikely that this would extend to low-dose and low-dose-rate exposure. A recent paper of Little et al. proposed an arguably more plausible mechanism for fractionated low-dose effects, based on monocyte cell killing in the intima. Although the predictions of the model are consistent with the epidemiological data, the experimental predictions made have yet to be tested. Further epidemiological and biological evidence will allow a firmer conclusion to be drawn.

A systematic review of epidemiological associations between low and moderate doses of ionizing radiation and late cardiovascular effects, and their possible mechanisms.

Little, M. P., Tawn, E. J., Tzoulaki, I., Wakeford, R., Hildebrandt, G., Paris, F., Tapio, S. and Elliott, P. A Systematic Review of Epidemiological Associations Between Low and Moderate Doses of Ionizing Radiation and Late Cardiovascular Effects, and Their Possible Mechanisms. Radiat. Res. 169, 99-109 (2008). The link between high doses of ionizing radiation and damage to the heart and coronary arteries is established. In this paper, we systematically review the epidemiological evidence for associations between low and moderate doses (<5 Gy) of ionizing radiation and late-occurring cardiovascular disease. Risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding factors. An examination of possible biological mechanisms indicates that the most likely causative effect of radiation exposure is damage to endothelial cells and subsequent induction of an inflammatory response, although it seems unlikely that this would extend to low-dose and low-dose-rate exposure. However, a role for somatic mutation has been proposed that would indicate a stochastic effect. In the absence of a convincing mechanistic explanation of epidemiological evidence that is less than persuasive at present, a cause-and-effect interpretation of the reported statistical associations cannot be reliably inferred, although neither can it be reliably excluded. Further epidemiological and biological evidence will allow a firmer conclusion to be drawn.