Established Risk Factors Research Articles

Machine learning-based biomarker profile derived from 4210 serially measured proteins predicts clinical outcome of patients with heart failure.

Risk assessment tools are needed for timely identification of patients with heart failure (HF) with reduced ejection fraction (HFrEF) who are at high risk of adverse events. In this study, we aim to derive a small set out of 4210 repeatedly measured proteins, which, along with clinical characteristics and established biomarkers, carry optimal prognostic capacity for adverse events, in patients with HFrEF. In 382 patients, we performed repeated blood sampling (median follow-up: 2.1 years) and applied an aptamer-based multiplex proteomic approach. We used machine learning to select the optimal set of predictors for the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization). The association between repeated measures of selected proteins and PEP was investigated by multivariable joint models. Internal validation (cross-validated c-index) and external validation (Henry Ford HF PharmacoGenomic Registry cohort) were performed. Nine proteins were selected in addition to the MAGGIC risk score, N-terminal pro-hormone B-type natriuretic peptide, and troponin T: suppression of tumourigenicity 2, tryptophanyl-tRNA synthetase cytoplasmic, histone H2A Type 3, angiotensinogen, deltex-1, thrombospondin-4, ADAMTS-like protein 2, anthrax toxin receptor 1, and cathepsin D. N-terminal pro-hormone B-type natriuretic peptide and angiotensinogen showed the strongest associations [hazard ratio (95% confidence interval): 1.96 (1.17-3.40) and 0.66 (0.49-0.88), respectively]. The multivariable model yielded a c-index of 0.85 upon internal validation and c-indices up to 0.80 upon external validation. The c-index was higher than that of a model containing established risk factors (P = 0.021). Nine serially measured proteins captured the most essential prognostic information for the occurrence of adverse events in patients with HFrEF, and provided incremental value for HF prognostication beyond established risk factors. These proteins could be used for dynamic, individual risk assessment in a prospective setting. These findings also illustrate the potential value of relatively 'novel' biomarkers for prognostication. https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 24.

Helicobacter pylori infection and rheumatoid arthritis as risk enhancers' factors for atherosclerotic cardiovascular diseases.

In addition to established risk factors for atherosclerotic cardiovascular diseases (aCVDs), infections and autoimmune diseases, such as Helicobacter pylori (H. pylori) and rheumatoid arthritis (RA), have been reported as risk-enhancer factors. In this retrospective single-center, case-control study, the relative weight of RA and H. pylori infection on aCVD was evaluated in a cohort of patients from Northern Sardinia, Italy, where both conditions are frequent. Data were retrieved from records of subjects undergoing upper endoscopy and screened for H. pylori infection by at least four biopsies. The presence of H. pylori and chronic-active gastritis were labeled as a current infection or a long-lasting infection (LLHp) when atrophy and/or metaplasia and/or dysplasia were detected in at least one gastric specimen. Diagnosis of aCVD and RA was made by the cardiologist and the rheumatologist, respectively, according to guidelines. Odd ratios (ORs) for aCVD were evaluated, adjusting for age, sex, excess weight, cigarette smoking, blood hypertension, dyslipidemia, diabetes, H. pylori status, and RA. Among 4821 records (mean age 52.1 ± 16.7 years; 66.0% female), H. pylori infection was detected in 2262 patients, and more specifically, a LLHp infection was present in 1043 (21.6%). Three-hundred-three (6.3%) patients were diagnosed with aCVD, and 208 (4.3%) with RA. In patients with aCVD (cases), the LLHp infection (33.3% vs. 20.8%, p < 0.0001) and RA (12.2% vs. 3.8%, p < 0.0001) were more frequent in cases compared with controls (patients without aCVD). After adjusting for traditional aCVD risk factors, ORs significantly increased for LLHp infection (1.57; 95% CI 1.20-2.06) and RA (2.63; 95% CI 1.72-4.02). Interestingly, the LLHp infection in patients with RA showed an overall addictive effect on the risk for aCVD (7.89; 95% CI 4.29-14.53). According to our findings, patients with RA should benefit from being screened and eventually treated for H. pylori infection.

Correlates of posttraumatic stress in cancer patients and their family caregivers across two years following diagnosis.

To examine risk-factors of cancer-related PTSS in the 2-years post-diagnosis in adult colorectal cancer patients and caregivers. Patients with colorectal cancer and their caregivers (N=130 dyads) self-reported sociodemographic, psychosocial, and medical factors at diagnosis/treatment initiation (T1), at 1- (T2), and 2-year (T3) post-diagnosis. Cancer-related PTSS were assessed, and path analysis examined associations between proposed correlates and PTSS. Among patients, higher neuroticism and greater physical symptom distress were concurrently associated with higher PTSS (Bs≥0.10, ps≤0.02); greater physical symptom distress at T1 and greater social support at T2 were associated with higher PTSS at T3 (Bs≥0.37, ps≤0.04). Among caregivers, female gender, higher neuroticism (Bs≥0.12, ps<0.01), and lower social support (Bs≤-0.24, ps≤0.02) were associated with higher concurrent PTSS; lower patient physical symptom distress and social support at T1 (Bs≤-0.27, ps≤0.03) and longer hours spent caregiving at T2 (B=0.03, p=0.05) were associated with higher PTSS at T3. Findings identify cancer-specific risk factors (physical symptoms, hours caregiving), in addition to established risk factors (female, neuroticism, social support) in non-medical populations. The identified subgroups should receive ongoing screening and psychosocial referral for cancer-related PTSS.

Determinants of the heart rate variability in type 1 diabetes mellitus.

Evaluation of heart rate variability (HRV) detects the early subclinical alterations of the autonomic nervous system. Thus, impaired HRV is the earliest subclinical marker of cardiac autonomic neuropathy (CAN) in type 1 diabetes mellitus (T1DM). We aimed to explore the HRV parameters in asymptomatic T1DM patients and compare them with the results obtained in healthy subjects. Potential associations between HRV parameters and the established risk factors for CAN and cardiovascular diseases were also investigated. Seventy T1DM patients (38 ± 12 years, 46 females) and 30 healthy subjects were enrolled into the study. For HRV analysis, beat-to-beat heart rate was recorded for 30min. The less noisy 5-min segment of the recording was analyzed by Bittium Cardiac Navigator HRV analysis software. Time domain, frequency domain, and nonlinear indices were calculated. Regarding ratio of low to high frequency component (LF/HF), no differences were found between the two populations (p = 0.227). All the further, time domain, frequency domain, and nonlinear HRV indices were significantly lower in T1DM patients (each p < 0.001). In multiple linear models, disease duration remained the only independent predictor of LF/HF ratio (p = 0.019). HbA1c was found to be significant independent predictor of all further time domain (SDNN, p < 0.001; rMSSD, p < 0.001), frequency domain (VLF, p < 0.001; LF, p = 0.002; HF, p = 0.006; Total Power, p = 0.002), and nonlinear indices (SD1, p = 0.006; SD2, p = 0.007), alone, or in combination with other factors, such as age or body mass index. Asymptomatic T1DM patients have significantly reduced overall HRV as compared with healthy subjects, indicating subclinical CAN. Quality of the glycemic control is important determinant of HRV among T1DM patients. This relationship is independent of other risk factors for CAN or cardiovascular diseases.

Prevalence and Risk Factors of Early Initiation of Alcohol Consumption and Smoking in School-Aged Adolescents

Introduction: Despite a constant focus on prevention of health-risk behaviors among adolescents and young people in many countries and regions, teenagers still show interest and engage in smoking and alcohol consumption. Objective: To study the prevalence and risk factors of early initiation of alcohol consumption and smoking in schoolaged children in order to substantiate and develop appropriate preventive measures to be taken in secondary schools of Yekaterinburg. Materials and methods: In 2022, we conducted an anonymous questionnaire-based cross-sectional study of 742 secondary school students in grades 8 to 11 (aged 14–18 years) living in Yekaterinburg. We assessed associations between the use of psychoactive substances, behavioral risk factors, such as daily routine, physical activity, attitude to smoking and alcohol consumption, health literacy, disease prevention habits, and psychosocial factors, and health. The data were analyzed using Pearson’s chi-squared test and the Student’s t-test; odd ratios (OR) were calculated with the 95 % confidence interval. Results: The proportion of cigarette smokers and alcohol consumers among school-aged adolescents amounted to 21.3 % and 43.4 %. Among the risk factors contributing to early initiation of smoking and alcohol consumption, the most significant were bad relationships with adults (parents and teachers), lack of parental support, poor awareness of adverse effects of alcohol consumption and smoking, loyal attitude of parents and schoolchildren to the problem. The use of psychoactive substances correlated statistically with poor well-being of the school-aged youth. Conclusion: We observed lower prevalence rates of smoking and alcohol consumption in the adolescents compared with the 2000s. This problem, however, still requires preventive interventions. The established risk factors should be taken into account when developing school-based prevention programs.

The Role of Pre-bone Marrow Transplantation Pulmonary Function Test in Predicting Post-transplant Noninfectious Pulmonary Complications

Background: Pulmonary function test (PFT) is used as a tool for pre-transplant risk assessment and as a predictor of post-transplant outcomes. As there are currently few studies that discuss the role of PFT in bone marrow transplantation (BMT) patients in Saudi settings, and as the number of transplant patients with benign and malignant conditions continues to increase, this study was conducted with the aim of assessing the local practice. Methods: This retrospective cohort study included all adult patients who underwent BMT at Princess Noorah Oncology Center, King Abdulaziz Medical City, Jeddah, between 2014 and 2020. The association between established patient-related risk factors and the incidence of pulmonary complications among autologous and allogeneic groups was assessed. Results: A total of 186 patients were included (autologous = 143; allogenic = 43), of which 115 (61.8%) were male. At the pre-BMT phase, about 30% of the patients had comorbidities and 51% had received two rounds of salvage chemotherapy, while 16.1% had received radiation therapy. In the autologous group, the only PFT parameter that was a significant predictor of post-BMT pulmonary complications was forced vital capacity &lt;80% (P = 0.012), while in the allogenic group, no parameter was significantly associated with pulmonary complications. The patient-related factors that were associated with respiratory distress in the autologous group were lung involvement (P = 0.03) and pre-transplant radiation (P = 0.044). Conclusion: The findings of this study indicated that forced vital capacity &lt;80% was a significant factor in predicting non-infectious complications in the autologous group. Furthermore, lung involvement and pre-transplant radiation were the patient-related factors associated with pulmonary complications.

Genetics and Ischemic Heart Disease: Should We Opt for Genetic Testing for Primary Prevention?

Cardiovascular diseases (CVD) are a prevalent health concern within the general population of Pakistan, where the average lifespan is notably lower than the global average, with men typically living to 67 years and women to 69 years. According to the 2019 Global Burden of Disease study, Pakistan had an estimated age-standardized incidence rate of CVD at 918.18 per 100,000 (compared to the global rate of 684.33 per 100,000), along with an age-standardized death rate of 357.88 per 100,000 (globally, this rate is 239.85 per 100,000).1 Coronary heart disease (CHD), as revealed by the Framingham Heart Study focusing on individuals aged 40 to 94 without prior heart disease, displayed a lifetime risk of 49% for men and 32% for women when reaching the age of 40.2 There has been a declining trend in death rates in the United States attributed to CVD, CHD, and stroke since 1975. Data from 2000 to 2008 also indicate a decline in CHD mortality.3 Worryingly, the World Health Organization (WHO) reports a concerning rise in CHD-related fatalities in Pakistan. In 2020, 240,720 individuals died due to CHD, accounting for 16.49% of all deaths. This highlights an escalating trend of CHD-related mortality in Pakistan. It's important to note that most individuals presenting with cardiac events have one or more established or borderline risk factors aside from age and gender.4-6 While some essential risk factors are discernible, others may remain elusive. The screening of these risk factors and the evidence for targeted therapeutic interventions are still emerging and require further exploration.7 The starting point for assessing CVD risk factors is variables used to predict major cardiovascular events. These include age, sex, blood pressure, cholesterol levels, diabetes mellitus, and smoking status. Although risk assessment tools like the Pooled Cohort Equation in 2014 and Astro-CHARM have been developed, they have yet to provide satisfactory assessments for potential new CVD risk factors.8 CHD is recognized as a multifactorial disorder resulting from genetic and environmental factors interplay. Environmental risk factors have been identified in approximately 80% of CHD cases.9 Several risk scores, such as the Framingham Risk Score, PROCAM, Reynolds Risk Score, and QRISK 2, have been proposed to guide the use of statins in high-risk groups.10-14 Yet, these risk scores often lack precision and may either overestimate or underestimate future CHD events.15,16 The variation in disease susceptibility among individuals with similar environmental factors and conventional coronary artery disease risk factors (CRFs) may be attributed to genetic variations.17 Genetic analysis can potentially enhance risk discrimination beyond the consideration of CRFs alone. Family history of heart disease, accounting for more than 40% of risk estimation, has long been considered a part of CRFs.18 Candidate gene studies have been conducted to identify common variants in genes associated with disease pathways.19 Single-nucleotide polymorphisms (SNPs) have been employed as markers of genetic diversity. Among these SNPs, those located on the 9p21 locus have shown the strongest association with CHD risk to date.20,21 However, despite the clear link between these variants and incident CHD, 9p21 locus SNPs have not definitively improved the prediction or classification of CHD risk compared to traditional risk factors.22-24 It is important to note that most genetic studies on CHD have predominantly focused on European/Caucasian populations, and their applicability to the South Asian population, including Pakistan, requires further investigation.25,26 In this context, the Pakistani population, much like other Asian countries, is underrepresented in genetic research on CHD. Shahid SU et al. did some work in this respect,27 showing 21 SNPs risk score for genetic risk analysis in the Pakistani population. In conclusion, while different risk assessment tools have been developed for the Pakistani population aged 40 years and above, there is an urgent need to expand cardiac risk evaluation by identifying genetic markers related to CHD, particularly in the younger population. This will be crucial for advancing our understanding of CHD risk factors and developing more effective prevention and intervention strategies.

Robust cross-vendor mammographic texture models using augmentation-based domain adaptation for long-term breast cancer risk.

Risk-stratified breast cancer screening might improve early detection and efficiency without comprising quality. However, modern mammography-based risk models do not ensure adaptation across vendor-domains and rely on cancer precursors, associated with short-term risk, which might limit long-term risk assessment. We report a cross-vendor mammographic texture model for long-term risk. The texture model was robustly trained using two systematically designed case-control datasets. Textural features, indicative of future breast cancer, were learned by excluding samples with diagnosed/potential malignancies from training. An augmentation-based domain adaption technique, based on flavorization of mammographic views, ensured generalization across vendor-domains. The model was validated in 66,607 consecutively screened Danish women with flavorized Siemens views and 25,706 Dutch women with Hologic-processed views. Performances were evaluated for interval cancers (IC) within 2 years from screening and long-term cancers (LTC) from 2 years after screening. The texture model was combined with established risk factors to flag 10% of women with the highest risk. In Danish women, the texture model achieved an area under the receiver operating characteristic curve (AUC) of 0.71 and 0.65 for ICs and LTCs, respectively. In Dutch women with Hologic-processed views, the AUCs were not different from AUCs in Danish women with flavorized views. The AUC for texture combined with established risk factors increased to 0.68 for LTCs. The 10% of women flagged as high-risk accounted for 25.5% of ICs and 24.8% of LTCs. The texture model robustly estimated long-term breast cancer risk while adapting to an unseen processed vendor-domain and identified a clinically relevant high-risk subgroup.

The Ratio of Monocytes to HDL-Cholesterol Is Associated with Cardiovascular Risk and Insulin Resistance in Patients with Rheumatoid Arthritis.

The monocytes to high-density lipoprotein (HDL)-cholesterol ratio (MHR) indicates inflammation based on the anti-inflammatory properties of HDL-cholesterol as well as the pro-inflammatory effect of monocytes. Several studies have investigated MHR in various disorders, specifically in cardiovascular diseases. Consequently, MHR has been significantly associated with cardiovascular and all-cause mortality in the general population, regardless of established risk factors. However, its role in the augmented risk of cardiovascular disease found in rheumatoid arthritis (RA) has not been studied to date. This is a cross-sectional study that encompassed 430 patients with RA and 208 controls matched by sex and age. Complete blood cell count and complete lipid profile were evaluated. Multivariable analysis was made to analyze the relationship between MHR and RA disease and features subclinical carotid atherosclerosis, and traditional CV factors including insulin resistance and beta cell function indices. MHR values did not differ between controls and patients after multivariable adjustment (12 ± 6 vs. 11 ± 6, p = 0.18). No relationship between this ratio and the characteristics of the disease was found excluding ESR, which showed a significant and positive association with MHR after adjustment for covariates. MHR significantly correlated with Systematic Coronary Risk Evaluation-2 (SCORE2) cardiovascular risk algorithm, and insulin resistance and beta cell function parameters after adjustment. In conclusion, MHR does not differ between patients with RA and controls. The relationship of this biomarker with disease-related data is poor. However, MHR is highly and positively related to cardiovascular risk and insulin resistance in RA.

Incidence of Necrotizing Enterocolitis and an Assessment of Related Risk Factors and Outcomes

Necrotizing Enterocolitis (NEC), defined as inflammation of the intestines most commonly due to a bacterial cause, is a relatively rare condition widely encountered in premature infants. Established risk factors for developing NEC include low gestational age, extremely low birth weight, sepsis, and hypotension. However, studies have investigated other causes that may alter the gut microbiome, such as blood transfusions, antibiotic use, and co-morbid conditions. The study design is a retrospective cohort study, and patient data were collected from King Hamad University Hospital (KHUH) after receiving the necessary approvals. Patients included in this study were from 2012 to 2020. The variables assessed included gestational age, birth weight, hemoglobin and hematocrit levels, prenatal and postnatal antibiotic use, blood transfusions, other transfusion products the patients received, and blood culture results. A total of 16 patients were identified as having NEC after thoroughly reviewing their files, and the data were analyzed at the KHUH Research Department. Although a small sample size was involved in this study, antibiotic use was a significant factor in the development of NEC as antibiotics such as ampicillin, gentamicin, and cefotaxime have been shown to alter the gut microbiome, which can predispose a patient to the development of NEC, as was reflected in our study. We also observed a 10.4-time relative risk for developing NEC in patients who had received blood transfusions. The use of antibiotics in patients with NEC has been shown to increase the likelihood of developing the condition, especially with the predominance of Enterobacteriaceae. Although controversial, blood transfusions have also been associated with the development of NEC. Due to the fragile vascular system in patients with NEC, constant phlebotomies and the introduction of packed red blood cells can alter the levels of nitric oxide present, predisposing premature infants to hypoxic conditions and, therefore, the development of NEC.

The spectrum of glomerular and vascular kidney pathology associated with myeloproliferative neoplasms

A high prevalence of chronic kidney disease (CKD) occurs in patients with myeloproliferative neoplasms (MPN). However, MPN-related glomerulopathy (MPN-RG) may not account for the entirety of CKD risk in this population. The systemic vasculopathy encountered in these patients raises the hypothesis that vascular nephrosclerosis may be a common pattern of injury in patients with MPN and with CKD. In an exhaustive, retrospective, multicenter study of MPN kidney biopsies in four different pathology departments, we now describe glomerular and vascular lesions and establish clinicopathologic correlations. Our study encompassed 47 patients with MPN who underwent a kidney biopsy that included 16 patients with chronic myeloid leukemia (CML) and 31 patients with non-CML MPN. Fourteen cases met a proposed definition of MPN-RG based on mesangial sclerosis and hypercellularity, as well as glomerular thrombotic microangiopathy. MPN-RG was significantly associated with both myelofibrosis and poorer kidney survival. Thirty-three patients had moderate-to-severe arteriosclerosis while 39 patients had moderate-to-severe arteriolar hyalinosis. Multivariable models that included 188 adult native kidney biopsies as controls revealed an association between MPN and chronic kidney vascular damage, which was independent of established risk factors such as age, diabetes mellitus and hypertension. Therefore, MPN-RG is associated with myelofibrosis and has a poor kidney prognosis. Thus, our findings suggest that the kidney vasculature is a target during MPN-associated vasculopathy and establish a new link between MPN and CKD. Hence, these results may raise new hypotheses regarding the pathophysiology of vascular nephrosclerosis in the general population.

Prenatal Exposure to Nonpersistent Environmental Chemicals and Postpartum Depression

Postpartum depression (PPD) affects up to 20% of childbearing individuals, and a significant limitation in reducing its morbidity is the difficulty in modifying established risk factors. Exposure to synthetic environmental chemicals found in plastics and personal care products, such as phenols, phthalates, and parabens, are potentially modifiable and plausibly linked to PPD and have yet to be explored. To evaluate associations of prenatal exposure to phenols, phthalates, parabens, and triclocarban with PPD symptoms. This was a prospective cohort study from 5 US sites, conducted from 2006 to 2020, and included pooled data from 5 US birth cohorts from the National Institutes of Health Environmental Influences on Child Health Outcomes (ECHO) consortium. Participants were pregnant individuals with data on urinary chemical concentrations (phenols, phthalate metabolites, parabens, or triclocarban) from at least 1 time point in pregnancy and self-reported postnatal depression screening assessment collected between 2 weeks and 12 months after delivery. Data were analyzed from February to May 2022. Phenols (bisphenols and triclosan), phthalate metabolites, parabens, and triclocarban measured in prenatal urine samples. Depression symptom scores were assessed using the Edinburgh Postnatal Depression Scale (EPDS) or the Center for Epidemiologic Studies Depression Scale (CES-D), harmonized to the Patient-Reported Measurement Information System (PROMIS) Depression scale. Measures of dichotomous PPD were created using both sensitive (EPDS scores ≥10 and CES-D scores ≥16) and specific (EPDS scores ≥13 and CES-D scores ≥20) definitions. Among the 2174 pregnant individuals eligible for analysis, nearly all (>99%) had detectable levels of several phthalate metabolites and parabens. PPD was assessed a mean (SD) of 3 (2.5) months after delivery, with 349 individuals (16.1%) and 170 individuals (7.8%) screening positive for PPD using the sensitive and specific definitions, respectively. Linear regression results of continuous PROMIS depression T scores showed no statistically significant associations with any chemical exposures. Models examining LMW and HMW phthalates and di (2-ethylhexyl) phthalate had estimates in the positive direction whereas all others were negative. A 1-unit increase in log-transformed LMW phthalates was associated with a 0.26-unit increase in the PROMIS depression T score (95% CI, -0.01 to 0.53; P = .06). This corresponded to an odds ratio (OR) of 1.08 (95% CI, 0.98-1.19) when modeling PPD as a dichotomous outcome and using the sensitive PPD definition. HMW phthalates were associated with increased odds of PPD (OR, 1.11; 95% CI, 1.00-1.23 and OR, 1.10; 95% CI, 0.96-1.27) for the sensitive and specific PPD definitions, respectively. Sensitivity analyses produced stronger results. Phthalates, ubiquitous chemicals in the environment, may be associated with PPD and could serve as important modifiable targets for preventive interventions. Future studies are needed to confirm these observations.

A deep learning system for retinal vessel calibre improves cardiovascular risk prediction in Asians with chronic kidney disease.

Cardiovascular disease (CVD) and mortality is elevated in chronic kidney disease (CKD). Retinal vessel calibre in retinal photographs is associated with cardiovascular risk and automated measurements may aid CVD risk prediction. Retrospective cohort study of 860 Chinese, Malay and Indian participants aged 40-80 years with CKD [estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2] who attended the baseline visit (2004-2011) of the Singapore Epidemiology of Eye Diseases Study. Retinal vessel calibre measurements were obtained by a deep learning system (DLS). Incident CVD [non-fatal acute myocardial infarction (MI) and stroke, and death due to MI, stroke and other CVD] in those who were free of CVD at baseline was ascertained until 31 December 2019. Risk factors (established, kidney, and retinal features) were examined using Cox proportional hazards regression models. Model performance was assessed for discrimination, fit, and net reclassification improvement (NRI). Incident CVD occurred in 289 (33.6%) over mean follow-up of 9.3 (4.3)years. After adjusting for established cardiovascular risk factors, eGFR [adjusted HR 0.98 (95% CI: 0.97-0.99)] and retinal arteriolar narrowing [adjusted HR 1.40 (95% CI: 1.17-1.68)], but not venular dilation, were independent predictors for CVD in CKD. The addition of eGFR and retinal features to established cardiovascular risk factors improved model discrimination with significantly better fit and better risk prediction according to the low (<15%), intermediate (15-29.9%), and high (30% or more) risk categories (NRI 5.8%), and with higher risk thresholds (NRI 12.7%). Retinal vessel calibre measurements by DLS were significantly associated with incident CVD independent of established CVD risk factors. Addition of kidney function and retinal vessel calibre parameters may improve CVD risk prediction among Asians with CKD.

Elevated circulating follistatin associates with increased risk of mortality and cardiometabolic disorders

Background and aimsPrevious study showed that elevated circulating hepatokine follistatin (FST) associates with an increased risk of type 2 diabetes by inducing adipose tissue insulin resistance. Here we explore further the relationships between plasma FST levels with mortality and health outcomes. Methods and resultsThe population-based Malmö Diet Cancer cardiovascular cohort (n = 4733, age 45–68 years) was used to study plasma FST in relation to incidence of health outcomes, by linkage with national patient registers. Cox regression analysis was used to assess the associations of plasma FST and outcomes, with adjustments for multiple potential confounding factors. During the mean follow-up time of 22.64 ± 5.84 years in 4,733 individuals, 526 had incident stroke, 432 had ischemic stroke, 530 had incident coronary events (CE), 339 had incident heart failure (HF), 320 had incident chronic kidney disease (CKD) and 1,843 individuals died. Hazard ratio (HR) per standard deviation increase in FST levels adjusted for multiple risk factors was 1.05 (95%CI: 1.00–1.11, p = 0.036) for mortality; 1.10 (95%CI: 1.00–1.20, p = 0.042) for stroke; 1.13 (95%CI: 1.03–1.25, p = 0.014) for ischemic stroke; 1.16 (95%CI: 1.03–1.30, p = 0.015) for HF; and 1.38 (95%CI: 1.12–1.70, p = 0.003) for a diagnosis of CKD. In MDC-CC individuals without prevalent or incident diabetes, the association between FST and stroke, CE and CKD remained significant; but not with mortality or HF. ConclusionsElevated circulating FST associates with an increased risk of mortality and HF, which partly may be mediated by diabetes. FST also associated with stroke, ischemic stroke, CE and CKD, independently of established risk factors including diabetes.

Copeptin, Natriuretic Peptides, and Cardiovascular Outcomes in Patients With CKD: The German Chronic Kidney Disease (GCKD) Study

Copeptin and Midrange pro-atrial natriuretic peptide (MR-pro-ANP) are associated with outcomes independently of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in patients with heart failure (HF). The value of these markers in patients with chronic kidney disease (CKD) has not been studied. Prospective cohort study. A total of 4,417 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60mL/min/1.73m2 or overt proteinuria (urinary albumin-creatinine ratio>300mg/g or equivalent). Copeptin, MR-pro-ANP, and NT-pro-BNP levels were measured in baseline samples. Noncardiovascular death, cardiovascular (CV) death, major adverse CV event (MACE), and hospitalization for HF. HRs for associations of Copeptin, MR-pro-ANP, and NT-pro-BNP with outcomes were estimated using Cox regression analyses adjusted for established risk factors. During a maximum follow-up of 6.5 years, 413 non-CV deaths, 179 CV deaths, 519 MACE, and 388 hospitalizations for HF were observed. In Cox regression analyses adjusted for established risk factors, each one of the 3 markers were associated with all the 4 outcomes, albeit the highest HRs were found for NT-pro-BNP. When models were extended to include all the 3 markers, NT-pro-BNP remained associated with all 4 outcomes. Conversely, from the 2 novel markers, associations remained only for Copeptin with non-CV death (HR, 1.62; 95% CI, 1.04-2.54 for highest vs lowest quintile) and with hospitalizations for HF (HR, 1.73; 95% CI, 1.08-2.75). Single-point measurements of Copeptin, MR-pro-ANP, and NT-pro-BNP. In patients with moderately severe CKD, we confirm NT-pro-BNP to be strongly associated with all outcomes examined. As the main finding, the novel marker Copeptin demonstrated independent associations with non-CV death and hospitalizations for HF, and should therefore be evaluated further for risk assessment in CKD. A blood sample-based biomarker that indicates high cardiovascular risk in a patient with kidney disease would help to guide interventions and has the potential to improve outcomes. In 4,417 patients of the German Chronic Kidney Disease study, we assessed the relationship of Copeptin, pro-atrial natriuretic peptide, and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) with important outcomes over a follow-up period of 6.5 years. NT-pro-BNP was strongly associated with all of the 4 outcomes, including death unrelated to cardiovascular disease, death because of cardiovascular disease, a major cardiovascular event, and hospitalization for heart failure. Copeptin was associated with death unrelated to cardiovascular disease and hospitalization for heart failure. NT-pro-BNP and Copeptin are, therefore, promising candidates for a blood sample-based strategy to identify patients with kidney disease at high cardiovascular risk.

Value Uncertainty

We examine how time-series volatility of book-to-market (UNC) is priced in equity returns and the relative contributions of its book volatility (variations in earnings and book value) and market volatility components (shocks in required return). UNC captures valuation risk, so stocks with high valuation risk earn higher return. An investment strategy long in high-UNC firms and short in low-UNC firms generates 8.5% annual risk-adjusted return. UNC valuation risk premium is driven by outperformance of high-UNC firms facing higher information risk and is not explained by established risk factors and firm characteristics. This paper was accepted by Agostino Capponi, finance. Funding: The authors acknowledge financial support from Spain’s Ministry of Education [Grant EC02011-24928], Generalitat de Catalonia [Grant 2014-SGR-1079], Banc Sabadell, the Bank of Cyprus, and the European Social Fund. M. El Hefnawy acknowledges financial support from the Spanish Ministry of Science and Innovation [Grant PID2021-128994NA-I00]. Supplemental Material: The data files and online appendix are available at https://doi.org/10.1287/mnsc.2023.4888 .

72 Are so-called ‘mechanical’ falls in later life as benign as we think? Data from TILDA

Abstract Background ‘Mechanical’ or simple falls are those due to slips or trips, and in the absence of injury are often considered benign. Older people with ‘mechanical’ falls are often not referred for a comprehensive falls assessment. The aim of this study was to assess if ‘mechanical’ falls were a risk factor for future falls, falls-related injuries/fractures, and fear of falling. Methods Participants ≥65 years (n = 2,820, mean 73 years) from TILDA were included and followed from Waves 1–5 at 2-yearly intervals (8-year follow-up). ‘Mechanical’ falls were falls caused by a simple slip/trip as reported by participants. Incidence of future falls (total falls/unexplained/injurious) and fracture (hip/wrist/vertebral/other) was by self-report at each Wave. Logistic Regression models reporting odds ratios (OR) assessed the association between explained falls and future further falls/fracture and fear of falling, adjusted for relevant covariates. Results Over 15% (441/2,820) of participants reported ‘mechanical falls’ within the last year at Wave 1, and there was a high prevalence of established falls risk factors, e.g. polypharmacy (32%), heart disease (24%), among this cohort. ‘Mechanical’ falls were associated with a significantly increased likelihood of future injurious falls (OR 1.50 (1.21–1.870; p &amp;lt; 0.001)), unexplained falls (OR 1.27 (1.00–1.62); p 0.050), and fracture (OR 1.37 (1.06–1.76); p 0.015), in fully adjusted models. Reporting ≥2 ‘mechanical’ falls was independently associated with development of fear of falling (OR 1.96 (1.27–3.03); p = 0.002) and was more strongly associated with all future fall types than reporting a single ‘mechanical’ fall. Conclusion Older people with recent simple falls are significantly more likely to present with falls causing injury, unexplained falls, and fracture during follow-up. If simple falls are recurrent, they also have a higher likelihood of developing fear of falling. Comprehensive falls assessment, addressing established risk factors, should therefore be considered for older people with ‘mechanical’ falls, particularly if recurrent.

Study protocol: Identification and validation of integrative biomarkers of physical activity level and health in children and adolescents (INTEGRActiv).

Physical activity (PA) provides health benefits across the lifespan and improves many established cardiovascular risk factors that have a significant impact on overall mortality. However, discrepancies between self-reported and device-based measures of PA make it difficult to obtain consistent results regarding PA and its health effects. Moreover, PA may produce different health effects depending on the type, intensity, duration, and frequency of activities and individual factors such as age, sex, body weight, early life conditions/exposures, etc. Appropriate biomarkers relating the degree of PA level with its effects on health, especially in children and adolescents, are required and missing. The main objective of the INTEGRActiv study is to identify novel useful integrative biomarkers of PA and its effects on the body health in children and adolescents, who represent an important target population to address personalized interventions to improve future metabolic health. The study is structured in two phases. First, biomarkers of PA and health will be identified at baseline in a core cohort of 180 volunteers, distributed into two age groups: prepubertal (n = 90), and postpubertal adolescents (n = 90). Each group will include three subgroups (n = 30) with subjects of normal weight, overweight, and obesity, respectively. Identification of new biomarkers will be achieved by combining physical measures (PA and cardiorespiratory and muscular fitness, anthropometry) and molecular measures (cardiovascular risk factors, endocrine markers, cytokines and circulating miRNA in plasma, gene expression profile in blood cells, and metabolomics profiling in plasma). In the second phase, an educational intervention and its follow-up will be carried out in a subgroup of these subjects (60 volunteers), as a first validation step of the identified biomarkers. The INTEGRActiv study is expected to provide the definition of PA and health-related biomarkers (PA-health biomarkers) in childhood and adolescence. It will allow us to relate biomarkers to factors such as age, sex, body weight, sleep behavior, dietary factors, and pubertal status and to identify how these factors quantitatively affect the biomarkers' responses. Taken together, the INTEGRActiv study approach is expected to help monitor the efficacy of interventions aimed to improve the quality of life of children/adolescents through physical activity. ClinicalTrials.gov, Identifier NCT05907785.

Associations between social isolation and diet quality among US adults with disability participating in the National Health and Nutrition Examination Survey, 2013–2018

Social isolation and disability are established risk factors for poor nutrition. We aimed to assess whether social isolation is associated with diet quality specifically among adults with disabilities.This cross-sectional analysis used data from the National Health and Nutrition Examination Survey, 2013–2018. Adults with a disability, who were not pregnant, breastfeeding, or missing dietary intake data were included (n = 5,167). Disability was defined as a physical functioning limitation based on difficulty with any activities of daily living, instrumental activities of daily living, lower extremity mobility activities, or general physical activities. The Healthy Eating Index (HEI)-2015 measured diet quality; higher scores correspond to higher diet quality. We computed a social isolation index by summing single status, living alone, and two social engagement difficulty measures (one point for each component met; maximum 4 points). Multivariable linear regression, controlling for demographic and health covariates, estimated differences in HEI scores for dietary intake data, by social isolation score.Over half of HEI scores were < 51, corresponding to “poor” diet quality. Higher social isolation score was associated with lower vegetable and seafood/plant proteins intake. Single status and one of two social engagement measures were associated with lower scores on certain adequacy components. Differences were modest. There was little evidence of effect modification by age or gender.Adults with disabilities are not meeting national dietary standards; improving diet quality is a priority. Whether social isolation is associated with specific dietary components in this population requires further investigation. Further research is also needed among younger adults.

Redefining Comorbid Insomnia and Sleep Apnea: The Association of Sleep Breathing Impairment and Insomnia with Incident Diabetes.

Rationale: Obstructive sleep apnea (OSA) is a prevalent sleep disorder that is frequently comorbid with insomnia and often accompanied by metabolic diseases such as type 2 diabetes. Although the apnea-hypopnea index (AHI) is currently the diagnostic criterion for gauging the severity of OSA, the AHI has not consistently predicted incident diabetes. Objectives: To test whether a combined insomnia-OSA (COMISA) phenotype based on comorbid insomnia and sleep breathing impairment index (COMISA-SBII) predicts incident diabetes and to compare the association with an AHI definition of COMISA (COMISA-AHI) in the MrOS (Osteoporotic Fractures in Men) study. Methods: The study samples came from participants in the MrOS sleep study without diabetes at their baseline examination. The SBII was derived as the product of the duration of each respiratory event (apnea and hypopnea) and the accompanying desaturation area from baseline unattended polysomnography. A subgroup of individuals classified as having comorbid insomnia (difficulties falling asleep, waking up in the middle of the night and/or early morning awakenings >15 times per month, and daytime impairments) and sleep breathing impairment (greater than 50th percentile of SBII) were identified at baseline. The primary outcome was incident diabetes during the follow-up visits. Cox proportional models were built to assess the adjusted hazard ratios of COMISA-AHI and COMISA-SBII. Prediction model performances of incident diabetes were compared across different models. Results: A total of 2,365 men (mean age, 76 yr) without diabetes at baseline were included. During a median follow-up of 10.0 years, diabetes developed in 181. After adjusting for demographic characteristics, comorbidities, and behavioral risk factors, participants with COMISA-SBII had a higher risk of incident diabetes (hazard ratio, 1.82; 95% confidence interval, 1.15-2.89) than those without sleep disorders (those with an SBII ⩽13.17 and no insomnia). The result remained significant in the risk competing model. Compared with COMISA-AHI, the addition of COMISA-SBII to a crude model with established risk factors significantly improved the predictive value of incident diabetes. Conclusions: COMISA-SBII, but not COMISA-AHI, predicted incident diabetes after accounting for multiple covariates in a cohort of older men. A comorbid insomnia phenotype based on SBII plus insomnia symptoms may be an important clinical subtype.