The aim of this work was to evaluate whether the association of prediabetes with dementia is explained by the intervening onset of diabetes. Among participants of the Atherosclerosis Risk in Communities (ARIC) study we defined baseline prediabetes as HbA1c 39–46 mmol/mol (5.7–6.4%) and subsequent incident diabetes as a self-reported physician diagnosis or use of diabetes medication. Incident dementia was ascertained via active surveillance and adjudicated. We quantified the association of prediabetes with dementia risk before and after accounting for the subsequent development of diabetes among ARIC participants without diabetes at baseline (1990–1992; participants aged 46–70 years). We also evaluated whether age at diabetes diagnosis modified the risk of dementia. Among 11,656 participants without diabetes at baseline, 2330 (20.0%) had prediabetes. Before accounting for incident diabetes, prediabetes was significantly associated with the risk of dementia (HR 1.12 [95% CI 1.01, 1.24]). After accounting for incident diabetes, the association was attenuated and non-significant (HR 1.05 [95% CI 0.94, 1.16]). Earlier age of onset of diabetes had the strongest association with dementia: HR 2.92 (95% CI 2.06, 4.14) for onset before 60 years; HR 1.73 (95% CI 1.47, 2.04) for onset at 60–69 years; and HR 1.23 (95% CI 1.08, 1.40) for onset at 70–79 years. Prediabetes is associated with dementia risk but this risk is explained by the subsequent development of diabetes. Earlier age of onset of diabetes substantially increases dementia risk. Preventing or delaying progression of prediabetes to diabetes will reduce dementia burden.

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<p>Objective: Fibroblast growth factor 23 (FGF23) concentration increases in response to declining kidney function to preserve normal phosphate concentrations. However, the etiological association of change in FGF23 concentration with mortality has not been examined in the general population.</p>

Sickle cell trait (SCT), the carrier status of the sickle cell gene, has a prevalence of 7%-9% among Black Americans, 1 and is associated with haemoglobin S (HbS) polymerisation and red blood cell (RBC) sickling under conditions of hy-poxia, hypertonicity or extreme exertion. 2 Sickle nephropa-thy, thought to be caused by HbS polymerisation in the low oxygen, hypertonic environment of the renal medulla, is observed both with heterozygous and homozygous inheritance of the HbS gene. 3 SCT has also been prospectively associated with albuminuria, chronic kidney disease (CKD), and end-stage renal disease. 4,5 However, less focus has been directed at hyposthenuria, or the inability to concentrate urine. While hyposthenuria is a known complication of SCT, 6 its functional consequences such as chronic dehydration have not been described in the adult SCT general population. Because hyposthenuria induces polydipsia, it remains uncertain whether SCT is associated with chronic dehydration or related adverse events in the Black general population. To date, most evaluations have been limited to case reports of exercise-induced dehydration in military personnel or athletes with SCT. 2 The Atherosclerosis Risk in Communities (ARIC) study recruited a population-based sample (N = 4266) of Black adults with informed consent, who were aged 45-64 years in 1987-1989. Research activities were approved by Institutional Review Boards. Study participant retention has been excellent across 30 years of follow-up, with 80% of survivors participating in the annual survey in 2019. Black study participants were genotyped for HbS (rs334) and haemoglobin C (rs33930165) using functionally tested TaqMan® SNP Genotyping Assays (Life Technologies), as previously described. 7,8 Clinical characteristics were ascertained at ARIC visit 1 (1987-1989) by standardised clinical examination. Fasting blood samples were analysed by ARIC central laboratories. Calculated plasma osmolality was derived using the following equation: [(2 × serum sodium) + (blood urea nitrogen/2.8) + (blood glucose/18)]. 9 Plasma osmolality of >295 mOsm/kg was considered evidence of dehydration. 9 Hospitalisations and deaths were captured by the ARIC study through active surveillance. Hospitalisations with International Classification of Diseases (ICD)-9 discharge codes 276.0, 276.50, or ICD-10 codes E86.x or E87.0 (in any position) were considered hos-pitalisations for dehydration. A total of 4110 Black study participants was successfully genotyped for HbS and haemoglobin C. After excluding eight participants with HbSC disease or sickle cell anaemia and 383 who were missing fasting blood glucose, serum cre-atinine, and blood urea nitrogen at ARIC visit 1, a total of 3719 remained (Figure S1). Of these, 228 (6%) were identified with SCT. The baseline characteristics of study participants with and without SCT were largely comparable, with the notable exception of factors related to dehydration (plasma os-molality, blood sodium, estimated glomerular filtration rate, and prevalence of CKD; Table S2). At baseline, mean plasma osmolality was higher for SCT than non-carrier genotype, both overall (295 vs. 294 mOsm/kg, p = 0.003) and when excluding participants with CKD or diabetes mellitus (DM) (294 vs. 293 mOsm/kg, p = 0.02). Classification of baseline dehydration also tended to be higher with SCT, both overall (48% vs. 40%, p = 0.02) and among the subset without CKD or DM (42% vs. 35%, p = 0.08). For both genotypes, dehydration was more often noted in women, and was associated with CKD, DM, and phlebotomy during the colder months of the year (Table 1). SCT remained associated with baseline dehydration after adjustment for demographics, season, prevalent CKD and DM (odds ratio [OR] 1.40, 95% confidence interval [CI] 1.06-1.85). In a sensitivity analysis limited to the subset without CKD or DM, a similar adjusted association was observed (OR 1.38, 95% CI 1.00-1.91). Over a median follow-up of 27 years, 373 study participants were hospitalised with dehydration and 2006 deaths occurred. The overall death rate was somewhat higher for individuals with SCT than non-carriers (57% vs. 54%); however , the cumulative incidence of dehydration hospitalisa-tions was the same (10% for both). Baseline dehydration was associated with higher mortality, both for participants with SCT (62% vs. 53%) and non-carriers (58% vs. 51%; Figures S3 and S4). After adjustments, baseline dehydration was associated with a 43% higher risk of death for participants with SCT (hazard ratio [HR] 1.43, 95% CI 1.01-2.03), compared with a 10% increased risk of death for non-carriers (HR 1.10, 95% CI 1.00-1.21; Figure 1). However, there was no significant association between baseline dehydration and subsequent hospitalisation for dehydration, for either genotype. Hyposthenuria is commonly observed with sickle hae-moglobinopathies, including SCT. In this analysis of ARIC study participants from the general Black adult population,

<h2>ABSTRACT</h2><h3>Background</h3><p>Atrial fibrillation (AF) is widely perceived to originate from the left atrium (LA). It is unclear whether increases in right ventricular (RV) afterload in older adults plays an etiological role in AF genesis independent of LA and left ventricular (LV) remodeling.</p><h3>Research Question</h3><p>Is higher RV afterload associated with greater AF risk independent of LA and LV remodeling?</p><h3>Study Design and Methods</h3><p>In this observational prospective study, we included 2246 community-dwelling older adults (mean age, 75 years) without known cardiovascular disease, with LV ejection fraction >50%, LA volume index <34 ml/m², and E/e' ratio <14 and a measurable functional tricuspid regurgitation jet velocity. From 2D-echocardiograms, we estimated pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR). We ascertained incident AF (through 2018) from hospital discharge codes and death certificates. We estimated hazard ratios (HR) by Cox regression.</p><h3>Results</h3><p>During follow-up (median 6.3 years, interquartile interval 5.5-6.9 years), 215 participants developed AF. AF risk was significantly higher in the third (vs first) tertile of PASP [HR 1.65, 95% confidence interval (CI) 1.08 - 2.54] and PVR [HR 1.38, 95% CI 1.00 - 2.08] independent of LA and LV structure and function, heart rate, body mass index, prevalent sleep apnea, systemic blood pressure, antihypertensive medications, lung, kidney, and thyroid function. These associations persisted after further exclusion of participants with tricuspid regurgitation jet velocity >2.8 m/s and lateral and septal mitral annular velocity above age- and sex-specific reference limits.</p><h3>Interpretation</h3><p>In older adults, higher RV afterload is associated with greater AF risk independent of LA and LV remodeling. Future research should focus on confirming this novel association and elucidate underlying mechanisms.</p>

Elevated levels of testosterone and fibroblast growth factor 23 (FGF-23) are both independently associated with a higher risk of cardiovascular disease (CVD). However, the relationship between sex hormones and FGF-23 is not well established. We explored the association between sex hormones and FGF-23 among middle-aged to older men and women in MESA. We studied 3,052 men and 2,868 postmenopausal women free of CVD at the time of enrollment with baseline serum sex hormones [total testosterone (T), free T, estradiol (E2) and sex hormone binding globulin (SHBG)] and intact FGF-23. In sex-stratified analyses, we examined the cross-sectional associations between log-transformed sex hormones (per 1 SD) and log-transformed FGF-23 using multiple linear regression adjusted for socio-demographics, CVD risk factors, estimated glomerular filtration rate and mineral metabolites (25-hydroxyvitamin D, calcium, phosphorus and parathyroid hormone). The mean (SD) age of study participants was 64 (10) years. The median (IQR) of FGF-23 was similar in women and men [38 (30–46) vs 38 (31–47) pg/mL]. In adjusted analyses, among women, 1 SD increment in free T was associated with 3% higher FGF-23 while SHBG was associated with 2% lower FGF-23. In men, 1 SD increment in E2 was associated with 6% higher FGF-23 whereas total T/E2 ratio was associated with 7% lower FGF-23. In conclusion, this exploratory analysis found that a more androgenic sex hormone profile was directly associated with FGF-23 in women and inversely associated with FGF-23 in men. Longitudinal studies are required to determine whether FGF-23 mediates the relationship between sex hormones and CVD risk.