Treatment Of High-risk Individuals Research Articles

Ancestry-aligned polygenic scores combined with conventional risk factors improve prediction of cardiometabolic outcomes in African populations

BackgroundCardiovascular diseases (CVD) are a major health concern in Africa. Improved identification and treatment of high-risk individuals can reduce adverse health outcomes. Current CVD risk calculators are largely unvalidated in African populations and overlook genetic factors. Polygenic scores (PGS) can enhance risk prediction by measuring genetic susceptibility to CVD, but their effectiveness in genetically diverse populations is limited by a European-ancestry bias. To address this, we developed models integrating genetic data and conventional risk factors to assess the risk of developing cardiometabolic outcomes in African populations.MethodsWe used summary statistics from a genome-wide association meta-analysis (n = 14,126) in African populations to derive novel genome-wide PGS for 14 cardiometabolic traits in an independent African target sample (Africa Wits-INDEPTH Partnership for Genomic Research (AWI-Gen), n = 10,603). Regression analyses assessed relationships between each PGS and corresponding cardiometabolic trait, and seven CVD outcomes (CVD, heart attack, stroke, diabetes mellitus, dyslipidaemia, hypertension, and obesity). The predictive utility of the genetic data was evaluated using elastic net models containing multiple PGS (MultiPGS) and reference-projected principal components of ancestry (PPCs). An integrated risk prediction model incorporating genetic and conventional risk factors was developed. Nested cross-validation was used when deriving elastic net models to enhance generalisability.ResultsOur African-specific PGS displayed significant but variable within- and cross- trait prediction (max.R2 = 6.8%, p = 1.86 × 10−173). Significantly associated PGS with dyslipidaemia included the PGS for total cholesterol (logOR = 0.210, SE = 0.022, p = 2.18 × 10−21) and low-density lipoprotein (logOR = − 0.141, SE = 0.022, p = 1.30 × 10−20); with hypertension, the systolic blood pressure PGS (logOR = 0.150, SE = 0.045, p = 8.34 × 10−4); and multiple PGS associated with obesity: body mass index (max. logOR = 0.131, SE = 0.031, p = 2.22 × 10−5), hip circumference (logOR = 0.122, SE = 0.029, p = 2.28 × 10−5), waist circumference (logOR = 0.013, SE = 0.098, p = 8.13 × 10−4) and weight (logOR = 0.103, SE = 0.029, p = 4.89 × 10−5). Elastic net models incorporating MultiPGS and PPCs significantly improved prediction over MultiPGS alone. Models including genetic data and conventional risk factors were more predictive than conventional risk models alone (dyslipidaemia: R2 increase = 2.6%, p = 4.45 × 10−12; hypertension: R2 increase = 2.6%, p = 2.37 × 10−13; obesity: R2 increase = 5.5%, 1.33 × 10−34).ConclusionsIn African populations, CVD and associated cardiometabolic trait prediction models can be improved by incorporating ancestry-aligned PGS and accounting for ancestry. Combining PGS with conventional risk factors further enhances prediction over traditional models based on conventional factors. Incorporating data from target populations can improve the generalisability of international predictive models for CVD and associated traits in African populations.

Diabetes mellitus in stroke unit: prevalence and outcomes-the Verona acute coronary syndrome and stroke in diabetes outcome (VASD-OUTCOME) study.

Cerebrovascular accidents (CVA) represent a major complication in diabetes (DM). Real-life evidence as to whether modern management of CVA and DM have softened this relationship is limited. Therefore, we estimated prevalence and impact of DM on in-hospital survival and complications in a contemporary cohort of subjects with CVA. We retrospectively evaluated the records of 937 patients admitted for CVA at the Stroke Unit of Verona University Hospital during a 3-year period. Pre-existing or de novo DM was ascertained by prior diagnosis, glucose-lowering therapy at admission/discharge or admittance plasma glucose ≥ 200mg/dL. Multiple regressions were applied to test DM as predictor of in-hospital mortality, complications (composite of infections, cardio- and cerebrovascular complications, major bleeding and pulmonary complications), duration and costs of hospitalization. Diabetes prevalence was 21%, of which 22% de novo diagnoses. Compared to non-DM, diabetic individuals were older and carried an increased burden of cardiovascular risk factors. Compared to known DM, de novo DM individuals were younger, had higher admittance plasma glucose and poorer cardiovascular comorbidities. Overall, DM versus non-DM individuals did not show significantly increased risk of death (14.0 vs. 9.3%; crude-OR 1.59 95% CI 0.99-2.56). Controlling for confounders did not improve significance. DM resulted independent predictor for in-hospital complications (36.2% vs. 26.9%; adj-OR 1.49, 1.04-2.13), but not for duration and costs of hospitalization. DM frequently occurs in patients admitted for stroke and carries an excess burden of adverse in-hospital complications, urgently calling for strategies to anticipate DM diagnosis and tailored treatment in high-risk individuals.

Time-varying exposure to anti-osteoporosis drugs and risk of first-time hip fracture: a population wide study within the Norwegian Epidemiologic Osteoporosis Studies (NOREPOS)

SummaryWe investigated the association between bisphosphonate and denosumab use and risk of hip fracture in Norway. These drugs protect against fractures in clinical trials, but their population-level effect is unknown. Our results showed lowered risk of hip fracture for treated women. Treatment of high-risk individuals could prevent future hip fractures.PurposeTo investigate whether bisphosphonates and denosumab reduced the risk of first-time hip fracture in Norwegian women when adjusting for a medication-based comorbidity index.MethodsNorwegian women aged 50–89 in 2005–2016 were included. The Norwegian prescription database (NorPD) supplied data on exposures to bisphosphonates, denosumab, and other drugs for the calculation of the Rx-Risk Comorbidity Index. Information on all hip fractures treated in hospitals in Norway was available. Flexible parametric survival analysis was used with age as time scale and with time-varying exposure to bisphosphonates and denosumab. Individuals were followed until hip fracture or censoring (death, emigration, age 90 years), or 31 December 2016, whichever occurred first. Rx-Risk score was included as a time-varying covariate. Other covariates were marital status, education, and time-varying use of bisphosphonates or denosumab with other indications than osteoporosis.ResultsOf 1,044,661 women 77,755 (7.2%) were ever-exposed to bisphosphonate and 4483 (0.4%) to denosumab. The fully adjusted hazard ratios (HR) were 0.95 (95% confidence interval (CI): 0.91–0.99) for bisphosphonate use and 0.60 (95% CI: 0.47–0.76) for denosumab use. Bisphosphonate treatment gave a significantly reduced risk of hip fracture compared with the population after 3 years and denosumab after 6 months. Fracture risk was lowest in denosumab users who had previously used bisphosphonate: HR 0.42 (95% CI: 0.29–0.61) compared with the unexposed population.ConclusionsIn population-wide real-world data, women exposed to bisphosphonates and denosumab had a lower hip fracture risk than the unexposed population after adjusting for comorbidity. Treatment duration and treatment history impacted fracture risk.

Bispecific antibodies and its applications: a novel approach for targeting SARS-Cov-2.

The COVID-19 pandemic remains a severe global threat, with the world engulfed in the struggle against the disease's second or third waves, which are approaching frightening proportions in terms of cases and mortality in many nations. Despite the critical need for effective therapy, there is still uncertainty about the optimal practices for treating COVID-19 with various pharmaceutical approaches. This being third year, global immunity and eradication of SARS-CoV-2 is currently seems to be out of reach. Efforts to produce safe and effective vaccinations have shown promise, and progress is being made. Additional therapeutic modalities, as well as vaccine testing in children, are required for prophylaxis and treatment of high-risk individuals. As a result, neutralising antibodies and other comparable therapeutic options offer a lot of promise as immediate and direct antiviral medications. Bispecific antibodies offer a lot of potential in COVID-19 treatment because of their qualities including stability, small size and ease of manufacture. These can be used to control the virus's infection of the lungs because they are available in an inhalational form. To combat the COVID-19 pandemic, innovative approaches with effective nanobodies, high-expression yield and acceptable costs may be required.

A CHANGE OF HEART: A CASE OF CARDIAC AMYLOIDOSIS

A CHANGE OF HEART: A CASE OF CARDIAC AMYLOIDOSIS

WITHDRAWN: Mental health intervention for subthreshold depression in childhood experiences

Promotion, preventive and early development interventions may have the greatest effect on children's health and wellbeing. Early mental health intervention strategies can enable better health pathways, take steps well before health conditions worsen, or deter them from occurring. Subthreshold depression applies to clinically significant signs that may not fulfill major depression disorders (MDD) requirements. Depression is more probable than an assortment of individual groups to be explained as a spectrum. Minor and sub-threshold depression is normal, and diagnosis levels are significantly impaired in patients and negatively affect their living standards. Present diagnostics programs continue to re-examine and differentiate thresholds from normal feelings of truth for depressive disorders. Therefore, a Psychological Behavior Analysis Model (PBSM) has been proposed to identify children's mental health problems. The proposed PBSM model shows a fair success in forecasting potential MDD diagnosis in the extrapolation test system for children outside the model spectrum. These conclusions indicate that the identification and treatment of high-risk individuals may be detected in children with subthreshold that have significant clinical effects. The simulation analysis PBSM identifies the children mental health problem high student high- mental health score of 92.5%, low depression level of 21.8%, somatic symptoms score of 23.5%, improved social dysfunction rate of 93.7%, high probability ratio of 96.3% and better psychological behavior rate of 90.1% when compared to other methods.

CAR-NK Cells Effectively Target SARS-CoV-2-Spike-Expressing Cell Lines In Vitro.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious and presents a significant public health issue. Current therapies used to treat coronavirus disease 2019 (COVID-19) include monoclonal antibody cocktail, convalescent plasma, antivirals, immunomodulators, and anticoagulants. The vaccines from Pfizer and Moderna have recently been authorized for emergency use, which are invaluable for the prevention of SARS-CoV-2 infection. However, their long-term side effects are not yet documented, and populations with immunocompromised conditions (e.g., organ-transplantation and immunodeficient patients) may not be able to mount an effective immune response. In addition, there are concerns that wide-scale immunity to SARS-CoV-2 may introduce immune pressure that could select for escape mutants to the existing vaccines and monoclonal antibody therapies. Emerging evidence has shown that chimeric antigen receptor (CAR)- natural killer (NK) immunotherapy has potent antitumor response in hematologic cancers with minimal adverse effects in recent studies, however, the potentials of CAR-NK cells in treating COVID-19 has not yet been fully exploited. Here, we improve upon a novel approach for the generation of CAR-NK cells for targeting SARS-CoV-2 and its various mutants. CAR-NK cells were generated using the scFv domain of S309 (henceforward, S309-CAR-NK), a SARS-CoV and SARS-CoV-2 neutralizing antibody (NAbs) that targets the highly conserved region of SARS-CoV-2 spike (S) glycoprotein and is therefore more likely to recognize different variants of SARS-CoV-2 isolates. S309-CAR-NK cells can specifically bind to pseudotyped SARS-CoV-2 virus and its D614G, N501Y, and E484K mutants. Furthermore, S309-CAR-NK cells can specifically kill target cells expressing SARS-CoV-2 S protein in vitro and show superior killing activity and cytokine production, compared to that of the recently reported CR3022-CAR-NK cells. Thus, these results pave the way for generating ‘off-the-shelf’ S309-CAR-NK cells for treatment in high-risk individuals as well as provide an alternative strategy for patients unresponsive to current vaccines.

Integrating proteomic, sociodemographic and clinical data to predict future depression diagnosis in subthreshold symptomatic individuals

Individuals with subthreshold depression have an increased risk of developing major depressive disorder (MDD). The aim of this study was to develop a prediction model to predict the probability of MDD onset in subthreshold individuals, based on their proteomic, sociodemographic and clinical data. To this end, we analysed 198 features (146 peptides representing 77 serum proteins (measured using MRM-MS), 22 sociodemographic factors and 30 clinical features) in 86 first-episode MDD patients (training set patient group), 37 subthreshold individuals who developed MDD within two or four years (extrapolation test set patient group), and 86 subthreshold individuals who did not develop MDD within four years (shared reference group). To ensure the development of a robust and reproducible model, we applied feature extraction and model averaging across a set of 100 models obtained from repeated application of group LASSO regression with ten-fold cross-validation on the training set. This resulted in a 12-feature prediction model consisting of six serum proteins (AACT, APOE, APOH, FETUA, HBA and PHLD), three sociodemographic factors (body mass index, childhood trauma and education level) and three depressive symptoms (sadness, fatigue and leaden paralysis). Importantly, the model demonstrated a fair performance in predicting future MDD diagnosis of subthreshold individuals in the extrapolation test set (AUC = 0.75), which involved going beyond the scope of the model. These findings suggest that it may be possible to detect disease indications in subthreshold individuals up to four years prior to diagnosis, which has important clinical implications regarding the identification and treatment of high-risk individuals.

Risk prediction in chronic kidney disease

Accurate risk stratification in patients with chronic kidney disease (CKD) is highly desirable to help guide earlier, targeted treatment in high-risk individuals. In this review, we report recent developments in our understanding of risk factors and risk prediction in patients with CKD. A large meta-analysis has shown that conventional cardiovascular risk factors continue to play an important role in disease progression and adverse outcomes in patients with advanced CKD where the estimated glomerular filtration rate (eGFR) is < 30 ml/min/1.73 m). Several studies have shed light on novel biomarkers in CKD, including peptides (LG1 M), genes (MUC1) and metabolic factors (urinary oxalate excretion). Cortical oxygenation measured by BOLD-MRI also provides a novel radiological measure predictive of future eGFR decline. A new risk prediction score for patients with CKD G4-5 has been developed, offering an aid to decision-making in these patients. Ongoing work across various disciplines continues to unravel the determinants of CKD progression. A few notable risk prediction tools in CKD have now surfaced but whether they can be utilised to offer improved care remains a key unanswered question.

A systematic, deep sequencing-based methodology for identification of mixed-genotype hepatitis C virus infections

Hepatitis C virus (HCV) mixed genotype infections can affect treatment outcomes and may have implications for vaccine design and disease progression. Previous studies demonstrate 0–39% of high-risk, HCV-infected individuals harbor mixed genotypes however standardized, sensitive methods of detection are lacking. This study compared PCR amplicon, random primer (RP), and probe enrichment (PE)-based deep sequencing methods coupled with a custom sequence analysis pipeline to detect multiple HCV genotypes. Mixed infection cutoff values, based on HCV read depth and coverage, were identified using receiver operating characteristic curve analysis. The methodology was validated using artificially mixed genotype samples and then applied to two clinical trials of HCV treatment in high-risk individuals (ACTIVATE, 114 samples from 90 individuals; DARE-C II, 26 samples from 18 individuals) and a cohort of HIV/HCV co-infected individuals (Canadian Coinfection Cohort (CCC), 3 samples from 2 individuals with suspected mixed genotype infections). Amplification bias of genotype (G)1b, G2, G3 and G5 was observed in artificially mixed samples using the PCR method while no genotype bias was observed using RP and PE. RP and PE sequencing of 140 ACTIVATE and DARE-C II samples identified the following primary genotypes: 15% (n = 21) G1a, 76% (n = 106) G3, and 9% (n = 13) G2. Sequencing of ACTIVATE and DARE-C II demonstrated, on average, 2% and 1% of HCV reads mapping to a second genotype using RP and PE, respectively, however none passed the mixed infection cutoff criteria and phylogenetics confirmed no mixed infections. From CCC, one mixed infection was confirmed while the other was determined to be a recombinant genotype. This study underlines the risk for false identification of mixed HCV infections and stresses the need for standardized methods to improve prevalence estimates and to understand the impact of mixed infections for management and elimination of HCV.

Endogenous CHRNA7-ligand SLURP1 as a potential tumor suppressor and anti-nicotinic factor in pancreatic cancer.

Smoking is associated with increased risk and poorer prognosis of pancreatic ductal adenocarcinoma (PDAC). Nicotine acts through cholinergic nicotinic receptors, preferentially α7 (CHRNA7) that also binds the endogenous ligand SLURP1 (Secreted Ly-6/uPAR-Related Protein 1). The clinical significance of SLURP1 and its interaction with nicotine in PDAC are unclear. We detected similar levels of SLURP1 in sera from healthy donors and patients with chronic pancreatitis or PDAC; higher preoperative values were associated with significantly better survival in patients with resected tumors. Pancreatic tissue was not a source of circulating SLURP1 but contained diverse CHRNA7-expressing cells, preferentially epithelial and immune, whereas stromal stellate cells and a quarter of the tumor cells lacked CHRNA7. The CHRNA7 mRNA levels were decreased in PDAC, and CHRNA7high-PDAC patients lived longer. In CHRNA7high COLO357 and PANC-1 cultures, opposing activities of SLURP1 (anti-malignant/CHRNA7-dependent) and nicotine (pro-malignant/CHRNA7-infidel) were exerted without reciprocally interfering with receptor binding or downstream signaling. These data suggested that the ligands act independently and abolish each other’s effects through a mechanism resembling functional antagonism. Thus, SLURP1 might represent an inborn anti-PDAC defense being sensitive to and counteracting nicotine. Boosting SLURP1-CHRNA7 interaction might represent a novel strategy for treatment in high-risk individuals, i.e., smokers with pancreatic cancer.

Gene Phenotypes: The Role Can't Be Ignored in Etiology of Dental Caries

Gene Phenotypes: The Role Can't Be Ignored in Etiology of Dental Caries

Wide Variation in Absolute Cardiovascular Risk Assessment in Aboriginal and Torres Strait Islander People with Type 2 Diabetes.

Absolute cardiovascular risk assessment (CVRA) is based on the combined effects of multiple risk factors and can identify asymptomatic individuals at high risk of cardiovascular disease (CVD). Aboriginal and Torres Strait Islander people, the Indigenous people of Australia, are disproportionately affected by CVD and diabetes. Our study aimed to investigate variations in the use of absolute CVRA in patients with diabetes at Indigenous community healthcare centers and to identify patient and health center characteristics that may contribute to this variation. Audits of clinical records of 1,728 patients with a known diagnosis of diabetes across 121 health centers in four Australian States/Territories [Northern Territory (NT), South Australia, Western Australia, and Queensland] over the period 2012-2014 were conducted as part of a large-scale continuous quality improvement program. Multilevel regression modeling was used to quantify variation in recording of CVRA attributable to health center and patient characteristics. The proportion of eligible patients with documented CVRA was 33% (n = 574/1,728). The majority (95%) of assessments were conducted in the NT. Multilevel regression analysis showed health center characteristics accounted for 70% of the variation in assessments in the NT. Government-operated health centers had 18.8 times the odds (95% CI 7.7-46.2) of recording CVRA delivery compared with other health centers. Health centers in the NT delivered the majority of absolute CVRA to Indigenous patients with diabetes in our study. Health systems factors that may have facilitated provision of CVRA in the NT include decision support tools and a reporting process for CVRA delivery. Implementation of similar systems in other jurisdictions may help improve CVRA delivery. Early identification and treatment of high risk individuals through wider use of CVRA may help reduce the burden of CVD in Indigenous Australians with diabetes.

Psychosocial well-being assessment in women with breast cancer.

207 Background: A breast cancer (BC) diagnosis can affect psychosocial wellbeing. The goal of the current study is to identify the severity of and specific risk factors for depression, anxiety, and quality of life impairment in a sample of BC patients. Early identification of at risk individuals can expedite appropriate referrals and interventions. Methods: Data from 53 female BC patients referred to a Behavioral Medicine service at a large academic medical center in 2013-2015 by medical providers who identified distress at routine clinic visits were analyzed. Patients completed the Center for Epidemiology Studies Depression Scale, State Trait Anxiety Inventory, McGill Pain Questionnaire, and the Short Form 12 Quality of Life Inventory as part of their initial assessment following referral. Demographic factors, disease and treatment related factors were analyzed for correlation with psychosocial wellbeing. Results: Mean age was 52. The majority of the population were Caucasian (79%), and 53% were married. All stages of disease were represented. Significant depression, anxiety and psychological quality of life impairment were seen in 53%, 50%, and 39% of patients respectively. There was a trend towards a significant difference in higher anxiety scores in patients who were not on chemotherapy (M=44.2, SD 5.4) compared to those on chemotherapy at the time of assessment (M=38.54, SD 9.3; t (51) = -1.94 p=0.077). A positive correlation was seen between depression and pain scores (r 0.294, p=0.038). Depression and psychological quality of life scores were negatively correlated (r -0.632 p&lt;0.001), as were pain and physical quality of life scores (r -.343, p 0.024). There was no correlation between higher rates of depression or anxiety with type of surgical intervention or stage of disease. Conclusions: Significant depression, anxiety and quality of life impairment were seen in a large percentage of BC patients referred to Behavioral Medicine for perceived distress, regardless of type of surgery and disease stage. Higher rates of anxiety were seen in patients referred while not on chemotherapy compared to patients who were on chemotherapy at the time of referral. Early referral is the key to proper identification and treatment of high risk individuals.

Abstract 17147: No Changes in Average Lipid Profiles in the United States From 2003 to 2012: The National Health and Nutrition Examination Survey 2003-2012

Introduction: Lipid-lowering therapies (LLT) are now regularly used in the management of dyslipidemia, but it is not known how the increased use of LLT has influenced lipid levels of the US population. We determined the average lipid profiles of the US population from 2003-2012 in the National Health and Nutrition Examination Survey (NHANES). Methods: Coronary heart disease risk using NCEP ATP III criteria was assessed in adult participants in 2-yearly NHANES surveys from 2003-2004 to 2011-2012. Fasting serum values were used to determine lipid profiles of men and women in each risk group. The proportion of participants in each risk group receiving LLT was also calculated. Results: Estimates for the US population were based on 11,256 observations in NHANES from 2003-2012. From the 2003-2004 survey to the 2011-2012 survey, a significant increase in the use of LLT was observed in the low- (6% to 11%; p&lt;0.0001) and high-risk (41% to 52%; p=0.008) groups. A possible trend for reduction in median triglyceride (TG) levels was observed in women in the high-risk group only, from 170 mg/dL (2003-2004) to 127 mg/dL (2011-2012). However, sample sizes are small (165-248 participants), and variability is high; therefore, this may impact on the applicability of the TG results. For both men and women and in all risk categories, no obvious trend for change in mean levels of non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), and HDL-C was observed (Figure). Mean HDL-C levels were higher in women than in men in all risk groups, consistently over the time period (Figure). Conclusion: Despite an increase in the use of LLT, we observed no trend for change in lipid profiles in low-, intermediate- or high-risk men and women in the US population. This may be due to the variability in response to LLT, and highlights the need for more aggressive identification and treatment of high-risk individuals, as recommended in the ACC/AHA guideline.

Application of mass spectrometry-based metabolomics in identification of early noninvasive biomarkers of alcohol-induced liver disease using mouse model.

A rapid, non-invasive urine test for early stage alcohol-induced liver disease (ALD) would permit risk stratification and treatment of high-risk individuals before ALD leads to irreversible liver damage and death. Urinary metabolomic studies were carried out to identify ALD-associated metabolic biomarkers using Ppara-null mouse model that is susceptible to ALD development on chronic alcohol consumption. Two successive studies were conducted to evaluate the applicability of mass spectrometry-based metabolomics in identification of ALD-specific signatures and to examine the robustness of these biomarkers against genetic background. Principal components analysis of ultraperformance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-generated urinary metabolic fingerprints showed that alcohol-treated wild-type and Ppara-null mice could be distinguished from control animals. It also showed that a combined endogenous biomarker panel helps to identify subjects with ALD as well as those at risk of developing ALD even without any information on alcohol intake or genetics. Quantitative analysis showed that increased excretion of indole-3-lactic acid and phenyllactic acid was a genetic background-independent signature exclusively associated with ALD pathogenesis in Ppara-null mice that showed liver pathologies similar to those observed in early stages of human ALD. These findings demonstrated that mass spectrometry-based metabolomic analysis could help in the identification of ALD-specific signatures, and that metabolites such as indole-3-lactic acid and phenyllactic acid, may serve as robust noninvasive biomarkers for early stages of ALD.

Uric acid is associated with metabolic syndrome in children and adults in a community: the Bogalusa Heart Study.

BackgroundElevated serum uric acid (UA) is commonly found in subjects with metabolic syndrome (MetS). This study examined the association of UA with levels of individual MetS components and the degree of their clustering patterns in both children and adults.MethodsThe study sample consisted of 2614 children aged 4–18 years and 2447 adults aged 19–54 years. MetS components included body mass index (BMI), mean arterial pressure (MAP), triglycerides to high-density lipoprotein cholesterol ratio (TG/HDLC), and homeostasis model assessment of insulin resistance (HOMA). Observed/expected (O/E) ratio and intra-class correlation coefficient (ICC) were used as a measure of the degree of clustering of categorical and continuous MetS variables, respectively.ResultsUA was positively and significantly associated only with BMI in children but with all four components in adults. The odds ratio for MetS associated with 1 mg/dL increase of UA was 1.74 (p<0.001) in children and 1.92 (p<0.001) in adults. O/E ratios showed a significant, increasing trend with increasing UA quartiles in both children and adults for 3- and 4-variable clusters with p-values for trend <0.001, except for BMI-MAP-TG/HDLC and MAP-TG/HDLC-HOMA clusters in children and MAP-TG/HDLC-HOMA cluster in adults. ICCs of 3 and 4 components increased with increasing UA quartiles in children and adults.ConclusionsThese results indicate that UA may play a role in the development of MetS in both pediatric and adult populations alike, which may aid in the identification and treatment of high risk individuals for MetS and related clinical disorders in early life.

Predicted long-term cardiovascular risk among young adults in the national longitudinal study of adolescent health.

We estimated the distribution of predicted long-term cardiovascular disease (CVD) risk among young adults in the United States. Our data were derived from National Longitudinal Study of Adolescent Health participants (n = 14 333; average age: 28.9 years). We used a Framingham-derived risk prediction function to calculate 30-year risks of "hard" and "general" CVD by gender and race/ethnicity. Average 30-year risks for hard and general CVD were 10.4% (95% confidence interval [CI] = 10.1%, 10.7%) and 17.3% (95% CI = 17.0%, 17.7%) among men and 4.4% (95% CI = 4.3%, 4.6%) and 9.2% (95% CI = 8.9%, 9.5%) among women. Average age-adjusted risks of hard and general CVD were higher among Blacks and American Indians than among Whites and lower among Asian/Pacific Islander women than White women. American Indian men continued to have a higher risk of general CVD after adjustment for socioeconomic status. Four percent of women (95% CI = 3.6%, 5.0%) and 26.2% of men (95% CI = 24.7%, 27.8%) had a 20% or higher risk of general CVD. Racial differences were detected but were not significant after adjustment for socioeconomic status. Average CVD risk among young adults is high. Population-based prevention strategies and improved detection and treatment of high-risk individuals are needed to reduce the future burden of CVD.

Transmission of parental neuroticism to offspring's depression: the mediating role of rumination.

Rumination is a cognitive process that involves repetitively focusing on the causes, situational factors and consequences of one's negative emotion, and it is a potent risk factor for depression. Parental depression and neuroticism may exert an influence on offspring's development of rumination, which may increase offspring's risk for depression. The current study included 375 biological parent-offspring dyads. Parents were assessed for depressive symptoms and neuroticism; adult offspring were assessed for depressive symptoms and rumination. Structural equation modelling was used to examine the effects of parental depressive symptoms and parental neuroticism on adult offspring's depression, and to determine whether offspring's rumination mediated this relationship. Results provided evidence that offspring's rumination fully mediated the relationship between parental neuroticism and offspring's depressive symptoms. Parental depressive symptoms and neuroticism may contribute a genetic predisposition for depressive symptoms in offspring, but it also may promote an environment in which maladaptive cognitive processes, such as rumination, are learned. Given the role that rumination plays in mediating the association between neuroticism and depressive symptoms-targeting rumination in the treatment of high risk individuals would be important in reducing onset of depressive disorders.

Evaluation of oseltamivir prophylaxis regimens for reducing influenza virus infection, transmission and disease severity in a ferret model of household contact.

ObjectivesThe emergence of the pandemic influenza A(H1N1)pdm09 virus in 2009 saw a significant increase in the therapeutic and prophylactic use of neuraminidase inhibitors (NAIs) to mitigate the impact of this highly transmissible virus. Prior to the pandemic, many countries stockpiled NAIs and developed pandemic plans for the use of antiviral drugs, based on either treatment of high-risk individuals and/or prophylaxis of contacts. However, to date there has been a lack of in vivo models to test the efficacy of treatment or prophylaxis with NAIs, for influenza-infected individuals or exposed contacts, in a household setting.MethodsA ferret model of household contact was developed to study the efficacy of different prophylaxis regimens in preventing infection in contact ferrets exposed to influenza A(H1N1)pdm09-infected index ferrets.ResultsAmong the different prophylactic regimens, contact ferrets receiving oseltamivir prophylaxis twice daily showed better outcomes than those receiving oseltamivir once daily. Benefits included a significant delay in the time to secondary infection, lower weight loss and higher activity levels. The treatment of index ferrets at 36 h post-infection did not influence either secondary infection rates or clinical symptoms in exposed contact ferrets. Neither prophylaxis nor treatment prevented infection or reduced the duration of viral shedding, although clinical symptoms did improve in infected animals receiving prophylaxis.ConclusionsDifferent oseltamivir prophylaxis regimens did not prevent infections, but consistently resulted in a reduction in symptoms in infected ferrets. However, oseltamivir prophylaxis failed to reduce viral titres, which warrants further investigation in humans.