At-risk Subjects Research Articles

Interactive effect of obesity and metabolic profile on renal risk in hypertensive patients

Obesity and metabolic disorders are known risk factors for impaired renal function. The objective of this study is to determine the nature of the interactive effect between obesity and metabolic profile on the increase in urinary albumin excretion and the decrease in estimated glomerular filtration rate (eGFR) in hypertensive patients. This is a prospective cross-sectional study, which involved a population of 499 hypertensive subjects. Based on BMI values and metabolic profile, subjects were classified into four metabolic phenotype groups: group I: metabolically healthy non-obese (MHNO), group II: metabolically healthy but obese (MHO), Group III: metabolically unhealthy non-obese (MUHNO) and group IV: metabolically unhealthy obese (MUHO). The effect of the biological interaction between obesity and metabolic profile on impaired renal function was tested on both scales: multiplicative and additive. A significant difference in renal function was noted between the four groups. After adjustment for confounding factors, patients who are both obese and at metabolic risk (MUHO) have the highest risk of microalbuminuria and decreased eGFR (OR = 6; 95 CI%[2.7–13], OR = 5.4; 95 CI%[1.1–26] respectively). Analysis of the additive biological interaction shows that 51% and 53% of the risk of elevated ACR and high ACR-low DFGe association respectively is explained by the obesity-metabolic disorder association. The interaction mechanism is synergistic (SI = 2.6; 95 CI%[1.2–5.3]). The decline in renal function in hypertensive subjects is significantly associated with the interaction of obesity and metabolic disorders. The management of these at-risk subjects must include, in addition to the therapeutic regimen, a dietary and physical program to preserve glomerular function.

Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells.

Dysfunction of FOXP3-positive regulatory Tcells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D-associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non-HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody-positive at-risk subjects, and 215 islet autoantibody-negative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 × 10-6 ) and naïve (p = 4 × 10-5 ) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody-negative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for naïve Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood.

A clinical staging approach to improving diagnostics in anxiety disorders: Is it the way to go?

Clinical staging is a paradigm in which stages of disease progression are identified; these, in turn, have prognostic value. A staging model that enables the prediction of long-term course in anxiety disorders is currently unavailable but much needed as course trajectories are highly heterogenic. This study therefore tailored a heuristic staging model to anxiety disorders and assessed its validity. A clinical staging model was tailored to anxiety disorders, distinguishing nine stages of disease progression varying from subclinical stages (0, 1A, 1B) to clinical stages (2A-4B). At-risk subjects and subjects with anxiety disorders (n = 2352) from the longitudinal Netherlands Study of Depression and Anxiety were assigned to these nine stages. The model's validity was assessed by comparing baseline (construct validity) and 2-year, 4-year and 6-year follow-up (predictive validity) differences in anxiety severity measures across stages. Differences in depression severity and disability were assessed as secondary outcome measures. Results showed that the anxiety disorder staging model has construct and predictive validity. At baseline, differences in anxiety severity, social avoidance behaviors, agoraphobic avoidance behaviors, worrying, depressive symptoms and levels of disability existed across all stages (all p-values < 0.001). Over time, these differences between stages remained present until the 6-year follow-up. Differences across stages followed a linear trend in all analyses: higher stages were characterized by the worst outcomes. Regarding the stages, subjects with psychiatric comorbidity (stages 2B, 3B, 4B) showed a deteriorated course compared with those without comorbidity (stages 2A, 3A, 4A). A clinical staging tool would be useful in clinical practice to predict disease course in anxiety disorders.

Therapeutic potential of quercetin on human breast cancer in different dimensions.

There has been an extensive range of incidence and mortality of breast cancer (BC), and the comprehensively available treatments for BC have not been completely successful in achieving satisfactory outcomes up to date. Recently, we are watching intense attention paid to the utilization of natural compounds as a novel therapeutic strategy for cancer treatment. Quercetin, a dietary flavonol in a large group of commonly consumed foods, is widely illustrated to apply inhibitory effects on cancer progression through several mechanisms including apoptosis enhancement, cell cycle arrest, metastasis and angiogenesis inhibition, antioxidant replication and estrogen receptor modulation. We reviewed the most relevant papers published from 2009 to 2018 (except 15 articles), using "pub med" and "web of science" and the search terms "Quercetin"; "Breast cancer"; "Flavonoid"; "Apoptosis"; "Cell cycle"; "chemotherapy"; "Drug resistance"; "Metastasis; "Oxidative stress", "Breast cancer receptors" and "Quercetin derivatives". We selected studies on the association of quercetin with breast cancer in different dimensions. Despite the remarkable number of studies on quercetin's efficacy, multiple aspects of this herbal compound have not been clarified well and this review provides a summarized update of the recent evidence on biologically available efficacies of quercetin which would establish a further biological basis for the potential therapeutic acquisition of quercetin as an anticancer drug. Basic, epidemiological and genetic studies point to the potential role of quercetin in the treatment of breast cancer, but randomized and controlled trials are of great importance to establish the clinical efficacy of quercetin in ill or at-risk subjects.

2885. A Host Transcriptional Signature for Accurate Diagnosis of Candidemia in the Hospital Setting

BackgroundCandidemia is one of the most common nosocomial bloodstream infections in the United States and causes significant morbidity and mortality in hospitalized patients. Improved rapid diagnostics capable of differentiating candidemia from other causes of febrile illness in the hospitalized patient are of paramount importance. Pathogen class-specific biomarker-based diagnostics such as those focusing on host gene expression patterns in circulating leukocytes may offer a promising alternative.MethodsRNA sequencing was performed on peripheral blood samples from 27 hospitalized patients with blood culture positive invasive candidiasis. Samples from healthy controls as well as at-risk subjects with acute febrile illness and similar clinical backgrounds but other infectious or noninfectious etiologies were used as comparator phenotypes (35 subjects with culture-proven bacterial infection, 49 with confirmed viral infection, and 17 with acute noninfectious illness). Bayesian techniques were utilized to develop infection-specific classifiers and leave one out cross-validation was used to estimate the predictive probability of each pathogen class.ResultsCandidemia triggers a unique, robust and conserved transcriptomic response in human hosts with 1,170 genes differentially upregulated compared with healthy controls. Based on this strength of signal, we developed a transcriptomic classifier that was capable of identifying candidemia, viral, or bacterial infection with a high degree of accuracy (auROC for Candida 0.93, Bacterial 0.98, Viral 0.99). The Candida component of this classifier (29-genes) was able to diagnose candidemia with a sensitivity of 88% and specificity of 100%.ConclusionThe host transcriptomic response during candidemia in hospitalized adults is highly conserved and unique from the genomic responses to acute viral and bacterial infection. This approach shows promise for the development of host response-based classifiers capable of differentiating multiple types of clinical illnesses at once in at-risk febrile patients.DisclosuresEphraim L. Tsalik, MD MHS PhD, Immunexpress: Consultant; Predigen, Inc.: Officer or Board Member, Research Grant.

Subjective Cognitive Decline and Biomarkers of Preclinical Alzheimer’s Disease

Here, we have provided an overview of previous biomarker studies to support the importance of subjective cognitive decline (SCD) in early identification of at-risk subjects and differentiation between normal and pathological aging, including Alzheimer’s disease (AD). We have identified several major areas that would require future research to address current gaps in knowledge and increase the value of SCD in preclinical AD. SCD in clinically normal individuals has received increasing attention by clinicians and AD researchers. SCD is etiologically heterogeneous. Biomarker studies have and will continue to increase our knowledge of the biological factors contributing to the manifestation and progression of SCD in AD. Future research with current and new generations of biomarkers is needed to disentangle the biological basis of SCD, improve the utility of SCD for early AD diagnosis, and understand factors that influence SCD characteristics, including sex differences and cognitive reserve.

Education modulates brain maintenance in presymptomatic frontotemporal dementia

ObjectiveCognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie,...

Multi-omics signature of brain amyloid deposition in asymptomatic individuals at-risk for Alzheimer's disease: The INSIGHT-preAD study.

BackgroundOne of the biggest challenge in Alzheimer's disease (AD) is to identify pathways and markers of disease prediction easily accessible, for prevention and treatment. Here we analysed blood samples from the INveStIGation of AlzHeimer's predicTors (INSIGHT-preAD) cohort of elderly asymptomatic individuals with and without brain amyloid load.MethodsWe performed blood RNAseq, and plasma metabolomics and lipidomics using liquid chromatography-mass spectrometry on 48 individuals amyloid positive and 48 amyloid negative (SUVr cut-off of 0·7918). The three data sets were analysed separately using differential gene expression based on negative binomial distribution, non-parametric (Wilcoxon) and parametric (correlation-adjusted Student't) tests. Data integration was conducted using sparse partial least squares-discriminant and principal component analyses. Bootstrap-selected top-ten features from the three data sets were tested for their discriminant power using Receiver Operating Characteristic curve. Longitudinal metabolomic analysis was carried out on a subset of 22 subjects.FindingsUnivariate analyses identified three medium chain fatty acids, 4-nitrophenol and a set of 64 transcripts enriched for inflammation and fatty acid metabolism differentially quantified in amyloid positive and negative subjects. Importantly, the amounts of the three medium chain fatty acids were correlated over time in a subset of 22 subjects (p < 0·05). Multi-omics integrative analyses showed that metabolites efficiently discriminated between subjects according to their amyloid status while lipids did not and transcripts showed trends. Finally, the ten top metabolites and transcripts represented the most discriminant omics features with 99·4% chance prediction for amyloid positivity.InterpretationThis study suggests a potential blood omics signature for prediction of amyloid positivity in asymptomatic at-risk subjects, allowing for a less invasive, more accessible, and less expensive risk assessment of AD as compared to PET studies or lumbar puncture.FundInstitut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epiniere (IHU-A-ICM), French Ministry of Research, Fondation Alzheimer, Pfizer, and Avid.

Serum miR-204 is an early biomarker of type 1 diabetes-associated pancreatic beta-cell loss

Pancreatic beta-cell death is a major factor in the pathogenesis of type 1 diabetes (T1D), but straightforward methods to measure beta-cell loss in humans are lacking, underlining the need for novel biomarkers. Using studies in INS-1 cells, human islets, diabetic mice, and serum samples of subjects with T1D at different stages, we have identified serum miR-204 as an early biomarker of T1D-associated beta-cell loss in humans. MiR-204 is a highly enriched microRNA in human beta-cells, and we found that it is released from dying beta-cells and detectable in human serum. We further discovered that serum miR-204 was elevated in children and adults with T1D and in autoantibody-positive at-risk subjects but not in type 2 diabetes or other autoimmune diseases and was inversely correlated with remaining beta-cell function in recent-onset T1D. Thus, serum miR-204 may provide a much needed novel approach to assess early T1D-associated human beta-cell loss even before onset of overt disease.

Polysaccharide A-Dependent Opposing Effects of Mucosal and Systemic Exposures to Human Gut Commensal Bacteroides fragilis in Type 1 Diabetes.

Bacteroides fragilis (BF) is an integral component of the human colonic commensal microbiota. BF is also the most commonly isolated organism from clinical cases of intra-abdominal abscesses, suggesting its potential to induce proinflammatory responses upon accessing the systemic compartment. Hence, we examined the impact of mucosal and systemic exposures to BF on type 1 diabetes (T1D) incidence in NOD mice. The impact of intestinal exposure to BF under a chemically induced enhanced gut permeability condition, which permits microbial translocation, in T1D was also examined. While oral administration of heat-killed (HK) BF to prediabetic mice caused enhanced immune regulation and suppression of autoimmunity, resulting in delayed hyperglycemia, mice that received HK BF by intravenous injection showed rapid disease progression. Importantly, polysaccharide A-deficient BF failed to produce these opposing effects upon oral and systemic deliveries. Furthermore, BF-induced modulation of disease progression was observed in wild-type, but not TLR2-deficient, NOD mice. Interestingly, oral administration of BF under enhanced gut permeability conditions resulted in accelerated disease progression and rapid onset of hyperglycemia in NOD mice. Overall, these observations suggest that BF-like gut commensals can cause proinflammatory responses upon gaining access to the systemic compartment and contribute to T1D in at-risk subjects.

Mucosa-Environment Interactions in the Pathogenesis of Rheumatoid Arthritis.

Mucosal surfaces play a central role in the pathogenesis of rheumatoid arthritis (RA). Several risk factors, such as cigarette smoking, environmental pollution, and periodontitis interact with the host at the mucosal level, triggering immune system activation. Moreover, the alteration of microbiota homeostasis is gaining increased attention for its involvement in the disease pathogenesis, modulating the immune cell response at a local and subsequently at a systemic level. Currently, the onset of the clinical manifest arthritis is thought to be the last step of a series of pathogenic events lasting years. The positivity for anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), in absence of symptoms, characterizes a preclinical phase of RA—namely systemic autoimmune phase- which is at high risk for disease progression. Several immune abnormalities, such as local ACPA production, increased T cell polarization towards a pro-inflammatory phenotype, and innate immune cell activation can be documented in at-risk subjects. Many of these abnormalities are direct consequences of the interaction between the environment and the host, which takes place at the mucosal level. The purpose of this review is to describe the humoral and cellular immune abnormalities detected in subjects at risk of RA, highlighting their origin from the mucosa–environment interaction.

Cortisol response to stress as a predictor for suicidal ideation in youth

To examine the association between cortisol response to stress and suicidal ideation (SI) cross-sectionally and longitudinally in our sample of bereaved and non-bereaved youth. The sample included 114 youth bereaved by sudden parental death and 109 non-bereaved controls, mean age of 12.3 (SD=3.6), evaluated at four time-points over an average follow-up period of 7 years. The Trier Social Stress Test (TSST) was conducted on average 6 years after bereavement. We used latent class analyses to examine the trajectories of SI over follow-up and up to the time of the TSST and compare them on cortisol measures. We examined whether cortisol measures predicted future SI at 18.5 months on average after the TSST. Bereavement was associated with higher cortisol reactivity after controlling for covariates [β=0.96, 95% CI (0.28, 1.65), p<0.01, d = 0.41]. Cortisol reactivity to stress was higher in those belonging to the high SI trajectory [β = 1.23, 95% CI (0.41, 2.06), p = 0.004, d = 0.23] compared to the low SI trajectory. Higher baseline cortisol showed small to medium effect size in predicting future SI [β = 2.34, 95% CI (0.17, 4.51), p = 0.03, d = 0.38]. The persistence of SI is associated with higher cortisol reactivity to stress, and higher baseline cortisol may predict future SI. These results emphasize the importance of HPA-axis activity in youth exposed to major stressors, and those with SI. More research is needed to further clarify biological mechanisms linking SI and behavior, bereavement, and HPA axis response to stress, to better identify at-risk subjects for targeted prevention and intervention efforts.

Abnormal Amyloid Load in Mild Cognitive Impairment: The Effect of Reducing the PiB-PET Threshold.

In vivo detection of β-amyloid (Aβ) plaques in Alzheimer's disease (AD) is now possible with 11 C-PiB positron emission tomography (PET). Conventionally, a cortical:cerebellar PiB uptake ratio threshold of 1.4-1.5 has been used to categorize at-risk subjects as "amyloid-positive" and "amyloid-negative." It has been suggested that this threshold is too conservative and may miss early amyloid pathology. We investigated the relationship between conventional and lower baseline 11 C-PiB PET thresholds for raised amyloid load and the subsequent clinical and radiological progression of mild cognitive impairment (MCI) cases longitudinally. We serially determined the cortical amyloid load with 11 C-PiB PET of 44 MCI subjects over 2 years and compared findings with those for 12 healthy controls (HC) and 5 AD cases. Twenty-four subjects were classified as normal at baseline with mean cortical PiB standard uptake value ratios (SUVR) between 1.2 and 1.5. Their cognitive status remained stable over time. Three of these cases increased their amyloid load above a threshold of 1.5 over 2 years. Twenty-seven "raised amyloid" MCI cases with baseline cortical SUVRs above 1.5, showed deteriorating cognition. Note that 50% of these cases converted clinically to AD during the follow-up period. Use of a PiB SUVR threshold of >1.5 for raised amyloid missed 14.3% of MCI cases who likely had Thal stage 1 or 2 pathology and showed a progressive amyloid increase over 2 years. Lowering the threshold for abnormality to 1.3 abolished all false negatives but resulted in 75% of HCs being falsely diagnosed as raised amyloid subjects.

MF59-adjuvanted seasonal trivalent inactivated influenza vaccine: Safety and immunogenicity in young children at risk of influenza complications

ObjectiveTo assess the safety and immunogenicity of the MF59-adjuvanted seasonal trivalent inactivated influenza vaccine (aIIV3; Fluad) in children aged 6 months through 5 years who are at risk of influenza complications. MethodsA retrospective analysis was performed to examine unsolicited adverse events (AEs) in an integrated dataset from six randomized clinical studies that compared aIIV3 with non-adjuvanted inactivated influenza vaccines (IIV3). The integrated safety set comprised 10 784 children, of whom 373 (3%) were at risk of influenza complications. ResultsThe at-risk safety population comprised 373 children aged 6 months through 5 years: 179 received aIIV3 and 194 received non-adjuvanted IIV3 (128 subjects received a licensed IIV3). The most important risk factors were respiratory system illnesses (62–70%) and infectious and parasitic diseases (33–39%). During the treatment period, unsolicited AEs occurred in 54% of at-risk children and 55% of healthy children who received aIIV3; of those receiving licensed IIV3, 59% of at-risk and 62% of healthy subjects reported an unsolicited AE. The most common AEs were infections, including upper respiratory tract infection. Serious AEs (SAEs) were reported in <10% of at-risk subjects, and no vaccine-related SAEs were observed. In the immunogenicity subset (involving 103 participants from one study), geometric mean titers (GMTs) were approximately 2- to 3-fold higher with aIIV3 than with IIV3 for all three homologous strains (A/H1N1, A/H3N2, and B). Seroconversion rates were high for both aIIV3 (79–96%) and IIV3 (83–89%). ConclusionsIn young children at risk of influenza complications, aIIV3 was well-tolerated and had a safety profile that was generally similar to that of non-adjuvanted IIV3. Similar to the not-at-risk population, the immune response in at-risk subjects receiving aIIV3 was increased over those receiving IIV3, suggesting aIIV3 is a valuable option in young children at risk of influenza complications.

Adjuvanted influenza vaccine for the Italian elderly in the 2018/19 season: an updated health technology assessment.

BackgroundThe elderly, defined here as subjects aged ≥ 65 years, are among at-risk subjects for whom annual influenza vaccination is recommended. For the 2018/19 season, three vaccine types are available for the elderly in Italy: trivalent inactivated vaccine (TIV), adjuvanted TIV (aTIV) and quadrivalent inactivated vaccines (QIV). No health technology assessment (HTA) of seasonal influenza vaccination in the elderly has previously been conducted in Italy.MethodsAn HTA was conducted in 2017 to analyze the burden of influenza illness, the characteristics, efficacy, safety and cost-effectiveness of available vaccines and the related organizational and ethical implications. This was then contextualized to the 2018/19 influenza season. Comprehensive literature reviews/analyses were performed and a static mathematical model developed in order to address the above issues.ResultsIn Italy, influenza is usually less common in the elderly than in other age-classes, but the burden of disease is the highest; >10% of infected elderly subjects develop complications, and about 90% of all influenza-related deaths occur in this age-class. All available vaccines are effective, safe and acceptable from an ethical standpoint. However, aTIV has proved more immunogenic and effective in the elderly. Furthermore, from the third payer’s perspective, aTIV is highly cost-effective and cost-saving in comparison with TIV and QIV, respectively. Nevertheless, vaccination coverage needs to be improved.ConclusionsAccording to this HTA, aTIV appeared the vaccine of choice in the elderly. HTA should be reapplied whenever new relevant data become available.

Longitudinal proton spectroscopy study of the prefrontal cortex in youth at risk for bipolar disorder before and after their first mood episode.

To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode. Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n=117) and matched healthy controls (HC group, n=61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr+Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects. There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr+Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P=0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects. We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr+Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation.

Is there a difference in regional read [18F]flutemetamol amyloid patterns between end-of-life subjects and those with amnestic mild cognitive impairment?

PurposeVisual interpretation of PET [18F]flutemetamol images relies on systematic review of five brain regions and is considered positive when an elevated signal is observed in at least one region. Amnestic mild cognitive impairment (aMCI) is an early clinical presentation of Alzheimer’s disease (AD); hence it is of interest to determine if the pattern of visually read regional positivity between end-of-life (EoL) patients with and without dementia and aMCI patients is different.MethodsA total of 180 EoL patients with and without dementia (mean age 81 years, range 59 to 95 years) and 232 aMCI patients (mean age 71 years, range 53 to 91 years) were scanned following intravenous administration of 185–370 MBq [18F]flutemetamol. Images from both studies were read by two groups of five blinded readers who independently classified each of the five regions as either positive or negative. The majority interpretation made by at least three of the five readers was used as the imaging endpoint and compared with a composite standardized uptake value ratio (SUVR) analysis using a predetermined threshold.ResultsAmyloid-positive images from 71 of 106 EoL patients coming to autopsy and from 97 aMCI patients were included. In the images from the EoL patients widespread deposition of amyloid was observed, with 76% of the images positive in all five regions and a further 20% positive in four regions. In the images from the aMCI patients, similar results were observed with 87% of the images positive in five regions and a further 5% positive in four regions. The mean SUVR of these positively read images was 2.24 (range 1.48 to 3.14) and 2.08 (range 1.28 to 3.04) in the autopsy and aMCI groups, respectively. There was 95.3% agreement between the visual reading and SUVR quantitation in the aMCI group and 90.4% agreement in the autopsy group.ConclusionPatients with aMCI showed a similar distribution of amyloid deposition determined by both visual reading and SUVR to that observed in patients with and without dementia coming to autopsy. Most of the aMCI patients, who are already within the AD continuum, had widespread amyloid deposition in terms of amount and topographical progression. Attempts to observe potential initial signs of amyloid deposition should focus on populations earlier in the dementia spectrum such as patients with subjective cognitive decline or even at-risk subjects with earlier stages of disease.

Abstract P048: Early Cardiometabolic Risk: The Prevalence of Compensatory Hyperinsulinemia in U.S. Populations

Introduction: Metabolic syndrome (MetS) and prediabetes (PreD) identify individuals at increased cardiometabolic risk. However, by the time those conditions develop, a significant decline in beta-cell insulin secretion has already occurred. The earliest stage in the pathogenesis of type 2 diabetes includes compensatory hyperinsulinemia, the robust response of intact beta cells to peripheral insulin resistance. This state of early metabolic dysregulation is not detected by conventional glucose and lipid screening. Hypothesis: The U.S. prevalence of compensatory hyperinsulinemia is high. Methods: Population-weighted data from the 2013-2014 cohort of the U.S. National Health and Nutrition Examination Survey (NHANES) were analyzed. The inclusion criteria were ages 12 and up, and the exclusion criteria were type 2 diabetes (fasting glucose ≥ 125 mg/dL, HbA1c ≥ 6.5 or 2-Hr glucose from OGTT ≥ 200 mg/dL), fasting triglycerides ≥ 885 mg/dL (familial hypertriglyceridemia), pregnancy or missing lab values. After population weighting, the 2,128 subjects sampled represented 198,424,653 non-diabetic individuals, approximately 62% of the U.S. population. Results: The subjects were categorized into four groups: NN: no MetS or PreD, no hyperinsulinemia; NY: no MetS or PreD with hyperinsulinemia; YN: MetS and/or PreD, no hyperinsulinemia; and YY: MetS and/or PreD with hyperinsulinemia. Hyperinsulinemia was defined as fasting insulin ≥ 12.2 μIU/ml based on prior calibration against the euglycemic clamp. The NY group represented compensatory hyperinsulinemia (CH). The 2013-2014 prevalence of CH was 11.2% of the non-diabetic U.S. population (95% CI: 11.17, 11.18). This group represented ~20% of the total at-risk subjects, defined as the sum of the NY, YN and YY groups. The prevalence of CH was highest in the youngest age groups and declined with age: 21.1% (21.08, 21.12) for ages 12-19, 13.2% (13.22,13.24) for ages 20-39, 7.7% (7.74, 7.75) for ages 40-59, 6.4% (6.34, 6.36) for ages 60-79, and 2.6% (2.63, 2.66) for ages 80 and up. The CH prevalence was higher in females vs. males: 12.7% (12.72, 12.73) vs. 9.6% (9.60, 9.61). In addition, CH prevalence was highest among Mexican Americans (17.0%; 16.98, 17.01) and other Hispanics (18.2%; 18.22, 18.27), followed by non-Hispanic blacks (12.3%; 12.29, 12.31), Native American/mixed race/other (10.8%; 10.79, 18.84), non-Hispanic whites (9.8%; 9.79, 9.80) and Asians (6.3%; 6.26, 6.29). Conclusion: The prevalence of compensatory hyperinsulinemia is high, especially in adolescents and young adults. These findings highlight a target population for early screening and intervention strategies to improve diabetes prevention outcomes.

A Contagion Model for Within-Family Transmission of Drug Abuse.

The purpose of this study was to determine whether, controlling for genetic effects, drug abuse was transmitted within families as predicted by a contagion model. The authors examined 65,006 parent-offspring, sibling, and cousin pairs ascertained from Swedish population registries in which the primary case subject had a drug abuse registration. The rate of drug abuse registration among at-risk secondary case subjects ages 19-23 was studied. Utilizing matched control pairs, a difference-in-difference approach was used to infer causal effects. In offspring, risk for drug abuse registration in the 3 years after an index registration of a parent residing in the same household, neighborhood, or municipality increased 5.9%, 3.4%, and 1.8%, respectively. For siblings of sibling index case subjects, parallel results were 5.9%, 3.9%, and 1.2%. For cousins of cousin index case subjects, excess risk for those in the same neighborhood or municipality was 2.9% and 0.9%, respectively. In all sets of relatives, drug abuse transmission was strongest in male-male pairs and in pairs closest in age. In sibling pairs, stronger transmission was observed in older to younger siblings compared with younger to older siblings. Transmission was stronger within than across the two drug classes with sufficient data (opiates and cannabis). These results suggest that drug abuse can be transmitted within families by an environmentally mediated temporally defined model of contagion. The most important methodological limitation is that drug abuse registration is an inaccurate measure of the onset of drug abuse. Indeed, as predicted, drug abuse risk increased among potential secondary case subjects in the year before drug abuse registration of the index case subject.

Early Somatosensory Processing Over Time in Individuals at Risk to Develop Psychosis.

Objective: Somatosensory evoked potentials (SEPs) enable the investigation of thalamocortical and early cortical processing. Previous studies reported alterations of SEPs in patients with schizophrenia as well as in individuals in the prodromal stage. Moreover, cannabis use as an environmental risk factor for the development of schizophrenia has been demonstrated to influence SEP parameters in individuals at risk to develop psychosis. The aim of this study was to explore the course of SEP changes and the impact of concomitant cannabis use in individuals at risk to develop psychosis who sought medical help.Methods: Median nerve SEPs including high-frequency oscillations (HFOs) superimposed on the primary cortical response (N20) were investigated using multichannel EEG in individuals (n = 54 at baseline) remaining at risk to develop psychosis at follow-up after 1 year (high-risk: n = 19; ultra-high-risk: n = 27) vs. subjects with conversion to psychosis (n = 8) and a healthy control group (n = 35). Longitudinal and cross-sectional analyses of SEP components as estimated by dipole source analysis were performed.Results: The longitudinal development of the N20 strength depended on cannabis use. In cannabis non-users, a greater decrease of N20 strengths over time was associated with more negative symptoms at baseline. At baseline, converters did not differ from subjects remaining at risk. At follow-up, converters showed increased low- and high-frequency activity than at-risk subjects and did not differ from controls.Conclusion: The results of this study lead to the suggestion that the deficits in early somatosensory processing in individuals at risk to develop psychosis may not represent a marker for a genetic risk for psychosis but rather reflect state-dependent factors such as negative symptoms. On the other hand, the transition to psychosis seems to represent an interstage between reduced sensory registration from the at-risk state and gating deficits in the chronic state.