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Background Diabetes is an independent risk factor for atrial fibrillation (AF), which is associated with increases in mortality and morbidity, as well as a diminished quality of life. Renal involvement in diabetes is common, and since chronic kidney disease (CKD) shares several of the same putative mechanisms as AF, it may contribute to its increased risk in individuals with diabetes. The objective of this study is to identify the relationship between CKD and the rates of newly-diagnosed AF in individuals with diabetes taking part in a screening program using a self-applied wearable electrocardiogram (ECG) patch. Materials and methods The study included 608 individuals with a diagnosis of diabetes among 1738 total actively monitored participants in the prospective mHealth Screening to Prevent Strokes (mSToPS) trial. Participants, without a prior diagnosis of AF, wore an ECG patch for 2 weeks, twice, over a 4-months period and followed clinically through claims data for 1 year. Definitions of CKD included ICD-9 or ICD-10 chronic renal failure diagnostic codes, and the Health Profile Database algorithm. Individuals requiring dialysis were excluded from trial enrollment. Results Ninety-six (15.8%) of study participants with diabetes also had a diagnosis of CKD. Over 12 months of follow-up, 19 new cases of AF were detected among the 608 participants. AF was newly diagnosed in 7.3% of participants with CKD and 2.3% in those without (P Conclusion Among individuals with diabetes, CKD significantly increases the risk of incident AF. Identification of AF prior to clinical symptoms through active ECG screening could help to improve the clinical outcomes in individuals with CKD and diabetes.

Background Atrial fibrillation (AF) is common, often without symptoms, and is an independent risk factor for mortality, stroke and heart failure. It is unknown if screening asymptomatic individuals for AF can improve clinical outcomes. Methods mSToPS was a pragmatic, direct-to-participant trial that randomized individuals from a single US-wide health plan to either immediate or delayed screening using a continuous-recording ECG patch to be worn for two weeks and 2 occasions, ~3 months apart, to potentially detect undiagnosed AF. The 3-year outcomes component of the trial was designed to compare clinical outcomes in the combined cohort of 1718 individuals who underwent monitoring and 3371 matched observational controls. The prespecified primary outcome was the time to first event of the combined endpoint of death, stroke, systemic embolism, or myocardial infarction among individuals with a new AF diagnosis, which was hypothesized to be the same in the two cohorts but was not realized. Results Over the 3 years following the initiation of screening (mean follow-up 29 months), AF was newly diagnosed in 11.4% (n = 196) of screened participants versus 7.7% (n = 261) of observational controls (p Conclusions At 3 years, screening for AF was associated with a lower rate of clinical events and improved outcomes relative to a matched cohort, although the influence of earlier diagnosis of AF via screening on this finding is unclear. These observational data, including the high event rate surrounding a new clinical diagnosis of AF, support the need for randomized trials to determine whether screening for AF will yield a meaningful protection from strokes and other clinical events. Trail registration The mHealth Screening To Prevent Strokes (mSToPS) Trial is registered on ClinicalTrials.gov with the identifier NCT02506244.

Patients with ulcerative colitis (UC) are at an increased risk of Clostridium difficile infection (CDI) compared with the general population. Recent data suggest that obesity also increases the risk of CDI. To examine whether obesity influences the risk of CDI among patients with UC. We conducted a retrospective cross-sectional study of UC patients seen in gastroenterology clinic between January 1, 2014, and December 31, 2015. Records were reviewed for patients with the diagnosis of UC prior to 2014, and the first diagnosis of CDI between January 1, 2014, and December 31, 2015. Using body mass index (BMI), patients were classified into underweight (BMI

We investigated associations between changes in depression and body composition over a 12-month weight loss trial. Of the 298 adults (BMI > 27 m/kg2), 219 with complete depression and body composition data were included. A 10-item Center for Epidemiologic Studies Depression Scale measured depression; dual-energy x-ray absorptiometry measured body composition. Multinomial logistic regression predicted reliable changes in depression by BMI, body fat (BF) and visceral adiposity (VAT). Multiplicative interaction terms tested modification by sex and ethnicity. Participants with increases in body composition were less likely to experience improvements in depression (BMI: RRR = 0.79 (0.68 – 0.91), p < 0.01; BF: RRR = 0.97 (0.94 – 0.99), p = 0.01; VAT: RRR = 0.99 (0.98 – 1.00), p = 0.02), but not worsening of depression (BMI: RRR= 1.29 (0.96 – 1.73), p = 0.10; BF: RRR = 1.04 (0.99 – 1.09), p = 0.15; VAT: RRR = 1.01 (1.00 – 1.03), p = 0.18). Sex and ethnicity interaction terms were not significant. However, the relationship was only significant among females, among non-Latinos for BMI and BF, and among Latinos for VAT. Our study supports the association between depression and obesity and highlights the need for longitudinal studies investigating VAT and depression in diverse ethnic groups.

OBJECTIVES Few data exist regarding the use of ultrasound (US) to risk stratify ward admissions. Therefore, we evaluated associations between a cardiopulmonary limited ultrasound examination (CLUE) on admission and subsequent hospital outcomes. METHODS Over a 22-month period in a 300-bed hospital, CLUE data reviewed from a series of nonelective ward admissions were correlated with the composite outcome of a hospital stay of longer than 2 days, disposition to hospice, or death. The CLUE included 5 quick-look signs of left ventricular dysfunction, left atrial enlargement, lung B-lines, pleural effusions, and inferior vena cava plethora and had been performed as warranted by 1 of 31 US-trained admitting residents and then repeated by a cardiologist as the reference standard. The admitting condition, medical history, results of routine admission testing, and CLUE were assessed for an association with the outcome in univariate and multivariable models. RESULTS Of 547 patients, the mean age ± SD was 62.9 ± 15.5 years; 59% were male; and the mean stay was 5.6 ± 8.1 days, with 355 (65%) lasting longer than 2 days and 21 (4%) having hospice disposition or death. An abnormal CLUE exam was found in 368 (67%) of patients, was related to the outcome (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.23-2.68; P = .001) when obtained by a resident or cardiologist, and was included in a best-fit multivariable model with renal failure (OR, 2.44; 95% CI, 1.44-4.14; P

Few data exist on the potential utility of a cardiac point-of-care ultrasound (POCUS) examination in the outpatient setting to assist diagnosis of significant cardiac disease. Using a retrospective sequential cohort design, we sought to derive and then validate a POCUS examination for cardiac application and model its potential use for prognostication and cost-effective echo referral.For POCUS examination derivation, we reviewed 233 consecutive outpatient echo studies for 4 specific POCUS "signs" contained therein representing left ventricular systolic dysfunction, left atrial enlargement, inferior vena cava plethora, and lung apical B-lines. The corresponding formal echo reports were then queried for any significant abnormality. The optimal POCUS examination for identifying an abnormal echo was determined. We then reviewed 244 consecutive outpatient echo studies from another institution for associations between the optimal POCUS examination, clinical variables, and referral source with major adverse cardiac events and all-cause mortality in univariate and multivariate models. Assuming a referral model where the absence of POCUS signs or variables would negate initial echo referral, theoretical cost savings were expressed as a percentage in reduction of echo studies.In the derivation cohort, the combination of two signs, denoting left atrial enlargement and inferior vena cava plethora resulted in the highest accuracy of 72% [95% CI: 65%, 78%] in detecting an abnormal echocardiogram. In the validation cohort, mortality at 5.5 years was 14.6% overall, 23% in patients with the left atrial enlargement sign (OR 3.5 [1.6, 7.6]), 25% with inferior vena cava plethora sign (OR 2.2 [0.8, 6.0]), and 8.0% (OR 0.3 [0.2, 0.7]) in those lacking both signs. After adjusting for age, both diabetes (OR 4.8 [2.0, 11.6]), and the left atrial enlargement sign (OR 2.4 [1.1, 5.4]) remained independently associated with mortality (p0.05). In the referral model, patients younger than 65 years of age without diabetes and without the left atrial enlargement sign would not have received echo referral, resulting in a 33% reduction in total echo cost and would have constituted a low-risk group with a 1.2% 5.5-year mortality.A quick-look sign for left atrial enlargement is associated with 5-year mortality and could function as an easily obtained outpatient POCUS examination to help in identifying patients in need of echo referral.

Objectives: This study coupled 2 strategies - trait extremes and genome-wide pooling - to discover a novel blood pressure (BP) locus that encodes a previously uncharacterized thiamine transporter. Background: Hypertension is a heritable trait that remains the most potent and widespread cardiovascular risk factor, although details of its genetic determination are poorly understood. Methods: Representative genomic deoxyribonucleic acid (DNA) pools were created from male and female subjects in the highest- and lowest-fifth percentiles of BP in a primary care population of >50,000 patients. The peak associated single-nucleotide polymorphisms were typed in individual DNA samples, as well as in twins/siblings phenotyped for cardiovascular and autonomic traits. Biochemical properties of the associated transporter were evaluated in cellular assays. Results: After chip hybridization and calculation of relative allele scores, the peak associations were typed in individual samples, revealing an association between hypertension, systolic BP, and diastolic BP and the previously uncharacterized solute carrier SLC35F3. The BP genetic association at SLC35F3 was validated by meta-analysis in an independent sample from the original source population, as well as the International Consortium for Blood Pressure Genome-Wide Association Studies (across North America and western Europe). Sequence homology to a putative yeast thiamine (vitamin B1) transporter prompted us to express human SLC35F3 in Escherichia coli, which catalyzed [3H]-thiamine uptake. SLC35F3 risk-allele homozygotes (T/T) displayed decreased erythrocyte thiamine content on microbiological assay. In twin pairs, the SLC35F3 risk allele predicted heritable cardiovascular traits previously associated with thiamine deficiency, including elevated cardiac stroke volume with decreased vascular resistance, and elevated pressor responses to environmental (cold) stress. Allelic expression imbalance confirmed that cis variation at the human SLC35F3 locus influenced expression of that gene, and the allelic expression imbalance peak coincided with the hypertension peak. Conclusions: Novel strategies were coupled to position a new hypertension-susceptibility locus, uncovering a previously unsuspected thiamine transporter whose genetic variants predicted several disturbances in cardiac and autonomic function. The results have implications for the pathogenesis and treatment of systemic hypertension. © 2014 by the American College of Cardiology Foundation.

This study sought to determine the possibility of interactions between coronary artery calcium (CAC) volume or CAC density with each other, and with age, sex, ethnicity, the new atherosclerotic cardiovascular disease (ASCVD) risk score, diabetes status, and renal function by estimated glomerular filtration rate, and, using differing CAC scores, to determine the improvement over the ASCVD risk score in risk prediction and reclassification.In MESA (Multi-Ethnic Study of Atherosclerosis), CAC volume was positively and CAC density inversely associated with cardiovascular disease (CVD) events.A total of 3,398 MESA participants free of clinical CVD but with prevalent CAC at baseline were followed for incident CVD events.During a median 11.0 years of follow-up, there were 390 CVD events, 264 of which were coronary heart disease (CHD). With each SD increase of ln CAC volume (1.62), risk of CHD increased 73% (p 0.001) and risk of CVD increased 61% (p 0.001). Conversely, each SD increase of CAC density (0.69) was associated with 28% lower risk of CHD (p 0.001) and 25% lower risk of CVD (p 0.001). CAC density was inversely associated with risk at all levels of CAC volume (i.e., no interaction was present). In multivariable Cox models, significant interactions were present for CAC volume with age and ASCVD risk score for both CHD and CVD, and CAC density with ASCVD risk score for CVD. Hazard ratios were generally stronger in the lower risk groups. Receiver-operating characteristic area under the curve and Net Reclassification Index analyses showed better prediction by CAC volume than by Agatston, and the addition of CAC density to CAC volume further significantly improved prediction.The inverse association between CAC density and incident CHD and CVD events is robust across strata of other CVD risk factors. Added to the ASCVD risk score, CAC volume and density provided the strongest prediction for CHD and CVD events, and the highest correct reclassification.

A wide range of personal wireless health-related sensor devices are being developed with hope of improving health management. Factors related to effective user engagement, however, are not well-known. We sought to identify factors associated with consistent long-term use of the Scanadu Scout multi-parameter vital sign monitor among individuals who invested in the device through a crowd-funding campaign. Email invitations to join the study were sent to 4525 crowd-funding participants from the US. Those completing a baseline survey were sent a device with follow-up surveys at 3, 12, and 18 months. Of 3872 participants receiving a device, 3473 used it during Week 1, decreasing to 1633 (47 percent) in Week 2. Median time from first use of the device to last use was 17 weeks (IQR: 5-51 weeks) and median uses per week was 1.0 (IQR: 0.6-2.0). Consistent long-term use (defined as remaining in the study at least 26 weeks with at least 3 recordings per week during at least 80% of weeks) was associated with older age, not having children in the household, and frequent use of other medical devices. In the subset of participants answering the 12-month survey (n = 1222), consistent long-term users were more likely to consider the device easy to use and to share results with a healthcare provider. Thirty percent of this subset overall reported improved diet or exercise habits and 25 percent considered medication changes in response to device results. The study shows that even among investors in a device, frequency of device usage fell off rapidly. Understanding how to improve the value of information from personal health-related sensors will be critical to their successful implementation in care.

Hypertension (HTN) is a major risk factor for intracranial hemorrhage. We, therefore, investigated the prevalence, treatment, and control of HTN in adult patients with hemophilia (PWH). PWH≥18 years (n=458) from 3 geographically different cohorts in the United States were evaluated retrospectively for HTN and risk factors. Results were compared with the nationally representative sample provided by the contemporary National Health and Nutrition Examination Survey (NHANES). PWH had a significantly higher prevalence of HTN compared with NHANES. Overall, the prevalence of HTN was 49.1% in PWH compared with 31.7% in NHANES. At ages 18 to 44, 45 to 64, 65 to 74, and ≥75 years, the prevalence of HTN for PWH was 31.8%, 72.6%, 89.7%, and 100.0% compared with 12.5%, 41.2%, 64.1%, and 71.7% in NHANES, respectively. Of treated hypertensive PWH, only 27.1% were controlled, compared with 47.7% in NHANES (all P

Background Aspirin desensitization is an effective treatment option for aspirin-exacerbated respiratory disease. Aspirin desensitization protocol modifications have improved the safety and efficiency of this procedure, yet some providers remain reluctant to perform it. Objective The primary objective of this study was to evaluate the safety and outcomes of outpatient aspirin desensitization procedures. A secondary objective was to assess clinical characteristics that might predict reaction severity during aspirin desensitization. Methods Two hundred seventy-five patients underwent aspirin desensitization at Scripps Clinic between January 2009 and August 2015. Baseline patient characteristics and reaction results were analyzed in the 167 patients who reacted during desensitization. Results All of the 167 reactors, including 23 who were classified as severe reactors, were successfully desensitized in the outpatient setting. The average desensitization duration among reactors was 1.67 days, and the average duration for gastrointestinal reactors was 2.29 days. The mean baseline Sino-Nasal Outcome Test score was higher in severe reactors compared with nonsevere reactors ( P = .05). Overall, patients receiving omalizumab had a similar reaction profile to those not receiving omalizumab. Conclusions Most patients undergoing aspirin desensitization will have symptoms. It remains difficult to predict the severity of these symptoms. However, desensitization can be done safely and efficiently in an appropriately equipped outpatient setting. This treatment option should be made available to all patients with aspirin-exacerbated respiratory disease. The Sino-Nasal Outcome Test score might be able to predict more severe reactions and merits further study. Eight of the 9 patients receiving omalizumab reacted during desensitization, suggesting that it does not block reactions during aspirin desensitization.

The long-term stability of cryopreserved peripheral blood progenitor cells is an important issue for patients experiencing disease relapse. However, there is no consensus on how to evaluate the long-term effects of cryopreservation. We describe the effect of cryopreservation on viability and progenitor colony activity from 87 individual samples processed at the Scripps Green Hospital Stem Cell Processing Center (La Jolla, CA, USA).We randomly selected 87 peripheral blood hematopoietic stem cell (PBHSC) samples from 60 patients and evaluated the effect of cryopreservation on sample viability and red and white cell colony activity after 24 h and 7, 10 and 15 years of cryopreservation. Viability was assayed via trypan blue dye exclusion and activity was measured following 14 days of culture.An age at collection older than 50 years may result in suboptimal activity and viability following long-term cryopreservation, while gender and disease status had no effect. Cryopreservation did not significantly affect white or red cell activity following 10 years of cryopreservation. However, for samples stored longer than 10 years, viability and activity significantly decreased. We noted a positive association between higher pre-cryopreservation %CD34 count and colony activity.Cryopreservation of peripheral blood progenitor cells for up to 10 years results in no loss of clonogenic capacity, as determined by culture activity, although longer durations of storage may affect activity. Until validated methods are developed, cryopreserved grafts should be evaluated based on pre-freeze CD34(+) cell counts as assayed by flow cytometry, and post-thaw sample evaluation should be reserved for patients identified as poor mobilizers.

In animal studies, caloric restriction resulting in increased longevity is associated with a reduction in body temperature, which is strain specific and likely under genetic control. Small studies in humans have suggested that temperatures may be lower among elderly populations, usually attributed to loss of thermoregulation. We analyzed cross-sectional data from 18,630 white adults aged 20–98 years (mean 58.3 years) who underwent oral temperature measurement as part of a standardized health appraisal at a large U.S. health maintenance organization. Overall, women had higher mean temperatures (97.5 ± 1.2°F) than men (97.2 ± 1.1°F; p < .0001). Mean temperature decreased with age, with a difference of 0.3°F between oldest and youngest groups after controlling for sex, body mass index, and white blood cell count. The results are consistent with low body temperature as a biomarker for longevity. Prospective studies are needed to confirm whether this represents a survival advantage associated with lifetime low steady state temperature.

Importance Opportunistic screening for atrial fibrillation (AF) is recommended, and improved methods of early identification could allow for the initiation of appropriate therapies to prevent the adverse health outcomes associated with AF. Objective To determine the effect of a self-applied wearable electrocardiogram (ECG) patch in detecting AF and the clinical consequences associated with such a detection strategy. Design, Setting, and Participants A direct-to-participant randomized clinical trial and prospective matched observational cohort study were conducted among members of a large national health plan. Recruitment began November 17, 2015, and was completed on October 4, 2016, and 1-year claims-based follow-up concluded in January 2018. For the clinical trial, 2659 individuals were randomized to active home-based monitoring to start immediately or delayed by 4 months. For the observational study, 2 deidentified age-, sex- and CHA 2 DS 2 -VASc–matched controls were selected for each actively monitored individual. Interventions The actively monitored cohort wore a self-applied continuous ECG monitoring patch at home during routine activities for up to 4 weeks, initiated either immediately after enrolling (n = 1364) or delayed for 4 months after enrollment (n = 1291). Main Outcomes and Measures The primary end point was the incidence of a new diagnosis of AF at 4 months among those randomized to immediate monitoring vs delayed monitoring. A secondary end point was new AF diagnosis at 1 year in the combined actively monitored groups vs matched observational controls. Other outcomes included new prescriptions for anticoagulants and health care utilization (outpatient cardiology visits, primary care visits, or AF-related emergency department visits and hospitalizations) at 1 year. Results The randomized groups included 2659 participants (mean [SD] age, 72.4 [7.3] years; 38.6% women), of whom 1738 (65.4%) completed active monitoring. The observational study comprised 5214 (mean [SD] age, 73.7 [7.0] years; 40.5% women; median CHA 2 DS 2 -VASc score, 3.0), including 1738 actively monitored individuals from the randomized trial and 3476 matched controls. In the randomized study, new AF was identified by 4 months in 3.9% (53/1366) of the immediate group vs 0.9% (12/1293) in the delayed group (absolute difference, 3.0% [95% CI, 1.8%-4.1%]). At 1 year, AF was newly diagnosed in 109 monitored (6.7 per 100 person-years) and 81 unmonitored (2.6 per 100 person-years; difference, 4.1 [95% CI, 3.9-4.2]) individuals. Active monitoring was associated with increased initiation of anticoagulants (5.7 vs 3.7 per 100 person-years; difference, 2.0 [95% CI, 1.9-2.2]), outpatient cardiology visits (33.5 vs 26.0 per 100 person-years; difference, 7.5 [95% CI, 7.2-7.9), and primary care visits (83.5 vs 82.6 per 100 person-years; difference, 0.9 [95% CI, 0.4-1.5]). There was no difference in AF-related emergency department visits and hospitalizations (1.3 vs 1.4 per 100 person-years; difference, 0.1 [95% CI, −0.1 to 0]). Conclusions and Relevance Among individuals at high risk for AF, immediate monitoring with a home-based wearable ECG sensor patch, compared with delayed monitoring, resulted in a higher rate of AF diagnosis after 4 months. Monitored individuals, compared with nonmonitored controls, had higher rates of AF diagnosis, greater initiation of anticoagulants, but also increased health care resource utilization at 1 year. Trial Registration ClinicalTrials.gov Identifier:NCT02506244

ObjectivesThe purpose of this study is to understand whether naturally occurring genetic variation in the promoter of chromogranin B (CHGB), a major constituent of catecholamine storage vesicles, is functional and confers risk for cardiovascular disease.BackgroundCHGB plays a necessary (catalytic) role in catecholamine storage vesicle biogenesis. Previously, we found that genetic variation at CHGB influenced autonomic function, with association maximal toward the 5′ region.MethodsHere we explored transcriptional mechanisms of such effects, characterizing 2 common variants in the proximal promoter, A-296C and A-261T, using transfection/cotransfection, electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP). We then tested the effects of promoter variation on cardiovascular traits.ResultsThe A-296C disrupted a c-FOS motif, exhibiting differential mobility shifting to chromaffin cell nuclear proteins during EMSA, binding of endogenous c-FOS on ChIP, and differential response to exogenous c-FOS. The A-261T disrupted motifs for SRY and YY1, with similar consequences for EMSA, endogenous factor binding, and responses to exogenous factors. The 2-SNP CHGB promoter haplotypes had a profound (p = 3.16E-20) effect on blood pressure (BP) in the European ancestry population, with a rank order of CT

Because dopamine D(1) receptors (DRD1) influence renal sodium transport and vascular hemodynamics, we examined whether genetic polymorphisms play a role in renal function. We conducted polymorphism discovery across the DRD1 open reading frame and its 5'-UTR and then performed association studies with estimated glomerular filtration rate (eGFR), plasma creatinine (pCr), and fractional excretion of uric acid (FeUA). We used a twin/family group of 428 subjects from 195 families and a replication cohort of 677 patients from the Kaiser health-care organization sampled from the lower percentiles of diastolic blood pressures. Although the coding region lacked common non-synonymous variants, we identified two polymorphisms in the DRD1 5'-UTR (G-94A, A-48G) that occurred with frequencies of 15 and 30%, respectively. In the twin/family study, renal traits were highly heritable, such that DRD1 G-94A significantly associated with eGFR, pCr, and FeUA. Homozygotes for the G-94A minor allele (A/A) exhibited lower eGFR, higher pCr, and lower FeUA. No effects were noted for DRD1 A-48G. Patients in the Kaiser group had similar effects of G-94A on eGFR and pCr. Kidney cells transfected with the -94A variant but not the wild type vectors had increased receptor density. Because the -94A allele is common and may reduce glomerular capillary hydrostatic pressure, G-94A profiling may aid in predicting survival of renal function in patients with progressive renal disease.

Efficient methods for screening populations for undiagnosed atrial fibrillation (AF) are needed to reduce its associated mortality, morbidity, and costs. The use of digital technologies, including wearable sensors and large health record data sets allowing for targeted outreach toward individuals at increased risk for AF, might allow for unprecedented opportunities for effective, economical screening. The trial's primary objective is to determine, in a real-world setting, whether using wearable sensors in a risk-targeted screening population can diagnose asymptomatic AF more effectively than routine care. Additional key objectives include (1) exploring 2 rhythm-monitoring strategies-electrocardiogram-based and exploratory pulse wave-based-for detection of new AF, and (2) comparing long-term clinical and resource outcomes among groups. In all, 2,100 Aetna members will be randomized 1:1 to either immediate or delayed monitoring, in which a wearable patch will capture a single-lead electrocardiogram during the first and last 2 weeks of a 4-month period beginning immediately or 4 months after enrollment, respectively. An observational, risk factor-matched control group (n = 4,000) will be developed from members who did not receive an invitation to participate. The primary end point is the incidence of new AF in the immediate- vs delayed-monitoring arms at the end of the 4-month monitoring period. Additional efficacy and safety end points will be captured at 1 and 3 years. The results of this digital medicine trial might benefit a substantial proportion of the population by helping identify and refine screening methods for undiagnosed AF.

Background: As a result of the digital revolution coming to medicine, a number of new tools are becoming available and are starting to be introduced in clinical practice. Objective: We aim to assess health care professional and consumer attitudes toward new medical technology including smartphones, genetic testing, privacy, and patient-accessible electronic health records. Methods: We performed a survey with 1406 health care providers and 1102 consumer responders. Results: Consumers who completed the survey were more likely to prefer new technologies for a medical diagnosis (437/1102, 39.66%) compared with providers (194/1406, 13.80%; P

BACKGROUND AND OBJECTIVES:The Military Health System provides universal coverage of all recommended childhood vaccinations. Few studies have examined the effect that being insured by the Military Health System has on childhood vaccination coverage. The purpose of this study was to compare the coverage of the universally recommended vaccines among military dependents versus other insured and uninsured children using a nationwide sample of children.METHODS:The National Immunization Survey is a multistage, random-digit dialing survey designed to measure vaccination coverage estimates of US children aged 19 to 35 months old. Data from 2007 through 2012 were combined to permit comparison of vaccination coverage among military dependent and all other children.RESULTS:Among military dependents, 28.0% of children aged 19 to 35 months were not up to date on the 4:3:1:3:3:1 vaccination series excluding Haemophilus influenzae type b vaccine compared with 21.1% of all other children (odds ratio: 1.4; 95% confidence interval: 1.2–1.6). After controlling for sociodemographic characteristics, compared with all other US children, military dependent children were more likely to be incompletely vaccinated (odds ratio: 1.3; 95% confidence interval: 1.1–1.5).CONCLUSIONS:Lower vaccination coverage rates among US military dependent children might be due to this population being highly mobile. However, the lack of a military-wide childhood immunization registry and incomplete documentation of vaccinations could contribute to the lower vaccination coverage rates seen in this study. These results suggest the need for further investigation to evaluate vaccination coverage of children with complete ascertainment of vaccination history, and if lower immunization rates are verified, assessment of reasons for lower vaccination coverage rates among military dependent children.

The diagnosis of anemia is an important aspect of the practice of hematology. The first step is to decide whether the patient is, in fact, anemic. Unless earlier blood counts are available, and they often are not, the physician must make his or her decision on the basis of the population distribution of hemoglobin values. How likely is it that the patient's hemoglobin value lies below the normal distribution; that is, “the lower limit”?

Studies involving a large number of comparisons have a high likelihood of finding statistically significant associations by chance alone (Type 1 error). Genetic association studies are particularly prone to this pitfall. We tested the effect of multiple comparisons in a study of symptoms among subjects genotyped for mutations of the HFE hemochromatosis gene.Two randomly selected groups were created from a dataset of 30,917 white adult subjects genotyped for the C282Y and H63D mutations of the HFE gene. Frequency of symptoms among subjects with different HFE genotypes was compared to sex-matched wild type controls in Random Group 1 (hypothesis generation). Statistically significant associations (p0.05 by chi2) were then tested in Random Group 2 (hypothesis testing).A total of 101/1765 associations in men and 116/2015 associations in women were statistically significant in Random Group 1. Of these, 12 associations in men and 13 associations in women were also statistically significant in Random Group 2, 11 of which were specific to hemochromatosis. None of the remaining 14 associations (6 in men and 8 in women) involved symptoms with a biologically plausible relationship to hemochromatosis or iron overload.Genetic association studies should be scrutinized for the possibility of Type 1 error.

We undertook a three-year screening program for mutations of the HFE gene among 41,000 subjects attending the Kaiser Permanente Health Appraisal Center in San Diego, California. Our results show that the C282Y and H63D mutations of the HFE gene associated with hemochromatosis have measurable and consistent effects on iron indicators and are associated with liver disorders, but have no measurable effect on other iron overload-related symptoms and life-expectancy. The very low clinical penetrance of the HFE mutations must be taken into account in calculating cost/benefit and risk/benefit ratios in screening for hemochromatosis.

Purpose Mutations of the HFE gene that cause hereditary hemochromatosis may be associated with an increased risk of cardiovascular disease. We examined the relation between two HFE mutations (C282Y and H63D), indicators of iron homeostasis, and the prevalence of coronary heart disease in a large population of white adults. Subjects and methods We conducted a cross-sectional study of 30,916 white adults aged 25 to 98 years who attended a health appraisal center and underwent screening for HFE mutations. Coronary heart disease and cardiovascular risk factors were ascertained by questionnaire and medical records. Results Overall, 12% (1798/15,362) of men and 7% (1074/15,554) of women had a history of coronary heart disease. Of 10 HFE genotypes tested (five genotypes by sex), only men with the C282Y/H63D genotype (compound heterozygotes) had a significantly higher prevalence of coronary heart disease compared with men with no HFE mutations (odds ratio=1.6; 95% confidence interval: 1.1 to 2.4; P = 0.01) after adjusting for cardiovascular risk factors. Elevated serum ferritin levels (>250 ng/mL) were associated with a lower prevalence of coronary heart disease in men (10% [255/2209] vs. 12% [1515/12,461] in controls, P = 0.008), which was not significant after adjusting for use of aspirin and anticoagulants. There were no significant associations between elevated transferrin saturation in either men or women, or between elevated serum ferritin levels or HFE mutations in women, and the prevalence of coronary heart disease. Conclusion The results do not support a consistent association between HFE mutations or serum iron indicators and the prevalence of coronary heart disease.

Objective To determine the prevalence of hemochromatosis-related symptoms in homozygotes for the HFE mutation C282Y compared with controls without HFE mutations identified through a large screening program of subjects attending a health appraisal center. Subjects and Methods Presence of symptoms commonly associated with clinical hemochromatosis was ascertained by self-report on a written questionnaire among C282Y homozygotes and HFE wild-type subjects of white or Hispanic ethnicity identified from screening 41,599 adult subjects between March 1999 and August 2001. A subset of C282Y homozygotes and wild-type subjects identified from 12,756 subjects attending the center in the final year of the study completed a standardized double-blind interview with a physician regarding the presence, duration, and severity of a larger set of symptoms. Prevalence of symptoms among C282Y homozygotes and wild-type controls ascertained by written questionnaire and interview were compared by χ 2 analysis or Fisher exact test. Symptoms among subjects with other combinations of the C282Y and H63D HFE mutations were also assessed by questionnaire. Results The 124 C282Y homozygotes who filled out the written questionnaire and the 17 C282Y homozygotes who completed the physician double-blind interview reported no significantly higher rates of arthritis or joint pain, abdominal pain, arrhythmias, darkening of skin, or other symptoms traditionally associated with hemochromatosis compared with the 22,429 wild-type controls who filled out the written questionnaire and 29 wild-type controls who completed the double-blind interview. The only symptom reported more frequently by C282Y homozygotes was loss of body hair, reported by 5 C282Y/C282Y female subjects compared with 1 wild-type male subject ( P =.02) in the physician interview. Symptoms among subjects with other HFE genotypes were similar to symptoms of wild-type subjects. Conclusions Results of this study indicate that many of the symptoms associated with hemochromatosis are common among HFE wild types and that clinical penetrance of the C282Y/C282Y genotype in regard to these symptoms is low.

Objectives. We determined the prevalence and treatment rates of latent tuberculosis infection (LTBI) in newly arrived refugees in San Diego County, California, and assessed demographic and clinical characteristics associated with these outcomes. Methods. We analyzed data from LTBI screening results of 4280 refugees resettled in San Diego County between January 2010 and October 2012. Using multivariate logistic regression, we calculated the associations between demographic and clinical risk factors and the outcomes of LTBI diagnosis and LTBI treatment initiation. Results. The prevalence of LTBI was highest among refugees from sub-Saharan Africa (43%) and was associated with current smoking and having a clinical comorbidity that increases the risk for active tuberculosis. Although refugees from sub-Saharan Africa had the highest prevalence of infection, they were significantly less likely to initiate treatment than refugees from the Middle East. Refugees with postsecondary education were significantly more likely to initiate LTBI treatment. Conclusions. Public health strategies are needed to increase treatment rates among high-risk refugees with LTBI. Particular attention is required among refugees from sub-Saharan Africa and those with less education.

Hairy cell leukemia (HCL) is a rare, indolent B-cell disorder in which single courses of cladribine induce high rates of complete responses. We report on 88 young HCL patients (≤40 years of age at diagnosis) treated with cladribine from the Scripps Clinic HCL Database, of whom 83 were evaluable for response. Seventy-three patients (88%) achieved an initial complete response and 10 (12%) a partial response, with a median response duration of 57 months. Forty-eight patients (58%) relapsed, with a median time to first relapse for all responders of 54 months. Eight patients developed 11 second primary malignancies with an excess frequency of 1.60 (95% confidence interval, 0.80-2.89). Thirteen (15%) patients died with a mortality ratio compared with age-matched normals of 1.85 (95% confidence interval, 1.07-3.18). Median overall survival for all patients following the first cladribine course was 231 months, and 251 months from diagnosis. Single courses of cladribine induce high rates of complete and durable responses in the majority of young HCL patients and are therefore recommended for HCL patients regardless of age.

Oral retinoids are among the drugs of choice for pustular and erythrodermic psoriasis. In addition, retinoids are effective in combination with other topical and systemic agents for the treatment of plaque-type psoriasis. Acitretin, the active retinoid metabolite, has replaced etretinate in retinoid therapy of psoriasis because of its more favorable pharmacokinetic profile, including a significantly shorter half-life. Retinoids, including acitretin, are potent teratogens, leading to strict requirements for pregnancy prevention during and after their use. Other retinoid side effects are generally preventable or manageable through proper patient selection, dose adjustments, and routine monitoring. Mucocutaneous side effects such as cheilitis and hair loss are the most common dose-dependent side effects, requiring dose reduction in some patients. Less common effects such as hepatotoxicity, serum lipid alterations, pancreatitis, and possible skeletal effects are also discussed.

It has been proposed that the anemia of ageing may be caused, at least in part, by elevated hepcidin levels, representing a response to increased IL-6 levels. Using a recently developed immunoassay, we have measured the plasma hepcidin levels of eight patients with the anemia of ageing and sex- and age-matched controls, and found that the levels of hepcidin were not increased in patients with the anemia of ageing. In contrast, patients with the anemia of inflammation have higher hepcidin levels than sex- and age-matched controls. In the overall group there was a strong correlation between serum ferritin levels and hepcidin levels, as has been found previously.

The opportunistic bacterial pathogen Pseudomonas aeruginosa causes chronic lung infections in cystic fibrosis (CF) patients. Importantly, virulence factor expression and biofilm formation in P. aeruginosa is coordinated by quorum sensing (QS) and one of the key QS signaling molecules is 3-oxo-C12-HSL. Remarkably, a tetramic acid, (C12-TA), with antibacterial properties is formed spontaneously from 3-oxo-C12-HSL under physiological conditions. Seeking to better understand this relationship, we sought to investigate whether 3-oxo-C12-HSL and C12-TA may be contributing factors to the overall pathogenicity of P. aeruginosa in CF individuals and if their detection and quantitation in sputum samples might be used as an indicator to assess disease states and monitor therapy success in CF patients. To this end, 3-oxo-C12-HSL and C12-TA concentrations were initially analyzed in P. aeruginosa flow cell biofilms using liquid chromatography coupled with mass spectrometry (LC-MS). A liquid chromatography tandem mass spectrometry (LC-MS/MS)-based method was then developed and validated for their detection and quantification in the sputa of CF patients. To the best of our knowledge, this is the first report to show the presence of both the quorum sensing molecule (3-oxo-C12-HSL) and its rearranged product (C12-TA) in human clinical samples such as sputum. A total of 47 sputum samples from 20 CF and 2 non-CF individuals were analyzed. 3-Oxo-C12-HSL was detected and quantified in 45 samples with concentrations ranging from 20 to >1000 nM; C12-TA was found in 14 samples (13-900 nM). On the basis of our findings, quorum sensing autoinducers merit further investigation as biomarkers for infectious disease states.

Background— Essential hypertension, a common complex disease, displays substantial genetic influence. Contemporary methods to dissect the genetic basis of complex diseases such as the genomewide association study are powerful, yet a large gap exists betweens the fraction of population trait variance explained by such associations and total disease heritability. Methods and Results— We developed a novel, integrative method (combining animal models, transcriptomics, bioinformatics, molecular biology, and trait-extreme phenotypes) to identify candidate genes for essential hypertension and the metabolic syndrome. We first undertook transcriptome profiling on adrenal glands from blood pressure extreme mouse strains: the hypertensive BPH (blood pressure high) and hypotensive BPL (blood pressure low). Microarray data clustering revealed a striking pattern of global underexpression of intermediary metabolism transcripts in BPH. The MITRA algorithm identified a conserved motif in the transcriptional regulatory regions of the underexpressed metabolic genes, and we then hypothesized that regulation through this motif contributed to the global underexpression. Luciferase reporter assays demonstrated transcriptional activity of the motif through transcription factors HOXA3, SRY, and YY1. We finally hypothesized that genetic variation at HOXA3 , SRY , and YY1 might predict blood pressure and other metabolic syndrome traits in humans. Tagging variants for each locus were associated with blood pressure in a human population blood pressure extreme sample with the most extensive associations for YY1 tagging single nucleotide polymorphism rs11625658 on systolic blood pressure, diastolic blood pressure, body mass index, and fasting glucose. Meta-analysis extended the YY1 results into 2 additional large population samples with significant effects preserved on diastolic blood pressure, body mass index, and fasting glucose. Conclusions— The results outline an innovative, systematic approach to the genetic pathogenesis of complex cardiovascular disease traits and point to transcription factor YY1 as a potential candidate gene involved in essential hypertension and the cardiometabolic syndrome.

Background The cardiometabolic syndrome comprised of multiple correlated traits, but its origin is incompletely understood. Chromogranin A (CHGA) is required for formation of the catecholamine secretory pathway in sympathochromaffin cells. In twin pair studies, we found that CHGA traits aggregated with body mass index (BMI), as well as its biochemical determinant leptin.MethodsHere we used the twin method to probe the role of heredity in generating such risk traits, and then investigated the role of risk-trait-associated CHGA promoter genetic variation in transfected chromaffin cells. Trait heritability (h 2 ) and shared genetic determination among traits (pleiotropy, genetic covariance, P G ) were estimated by variance components in twin pairs. Results CHGA, BMI, and leptin each displayed substantial h 2 , and the traits also aggregated with several features of the metabolic syndrome (e.g., insulin resistance, blood pressure (BP), hypertension, catecholamines, and C-reactive protein (CRP)). Twin studies demonstrated genetic covariance (pleiotropy, P G ) for CHGA, BMI, and leptin with other metabolic traits (insulin resistance, BP, and CRP). We therefore investigated the CHGA locus for mechanisms of codetermination with such metabolic traits. A common functional variant in the human CHGA promoter (G-462A, rs9658634, minor allele frequency ∼21%) was associated with leptin and CRP secretion, as well as BMI, especially in women; marker-on-trait effects on BMI were replicated across twin populations on two continents. In CHGA promoter/luciferase reporter plasmids transfected into chromaffin cells, G-462A alleles differed markedly in reporter expression. The G-462A variant disrupted predicted transcriptional control by a PPARγ/RXRα motif and costimulation by PPARγ/RXRα and their cognate ligands, differentially activated the two alleles. During chromatin immunoprecipitation, endogenous PPARγ bound the motif. Conclusion sMultiple features of the metabolic syndrome are thus under joint (pleiotropic) genetic determination, with CHGA as one such contributory locus a common polymorphism in the promoter (G-462A) of CHGA predicts such heritable metabolic traits as BMI and leptin. CHGA promoter variant G-462A was not only associated with such metabolic traits but also disrupted a PPARγ/RXRα motif and responded differentially to characteristic trans-activators of that motif. The Results suggest novel links between the catecholaminergic system and risk for the metabolic syndrome as well as systemic hypertension. Refereed/Peer-reviewed

Epidemiologic studies have documented an increasing frequency of anaemia in individuals 65 yrs and older. Elderly individuals with anaemia have been categorised into the following: those with chronic disease, those with iron, B12 or folate deficiency and those with anaemia of unknown aetiology (AUE). There is considerable interest and debate as to whether AUE has an inflammatory component, is caused by cytokine dysregulation affecting production or response to erythropoietin (EPO) or iron availability or represents a novel pathologic process. Here, we compare a large cohort of AUE cases with a matched, non-anaemic control group and with individuals who have anaemia of defined cause. IL-6, hepcidin, GDF15, EPO and testosterone levels were compared. IL6 and hepcidin levels did not differ significantly between AUE and control groups, indicating that inflammation or iron restriction is not central feature of anaemia in this group. GDF15 levels were significantly elevated when comparing AUE with controls and were markedly elevated in patients with renal disease. Testosterone levels were lower in men from the AUE group compared with non-anaemic controls. EPO levels in the AUE group were increased relative to controls but were inappropriately low for the degree of anaemia. Our data indicate that an impaired EPO response, in the absence of evidence for iron restriction or inflammation, is characteristic of AUE.

BACKGROUND Dopamine β-hydroxylase (DBH) plays an indispensable role in catecholamine synthesis by converting dopamine into norepinephrine. Here, we characterized a DBH promoter polymorphism (C-2073T; rs1989787; minor allele frequency ~16%) that influences not only gene transcription but also enzyme secretion and blood pressure (BP) in vivo. METHODS Plasma DBH activity was measured spectrophotometrically. DBH genetic effects on BP were tested in subjects with the most extreme BP values in a large primary care population. Functional effects of promoter variants were studied by site-directed mutagenesis in DBH promoter haplotype/luciferase reporter plasmids transfected into chromaffin cells. Sequence motifs were predicted from position weight matrices, and endogenous transcription factor binding was probed by Chromatin ImmunoPrecipitation (ChIP). RESULTS The T-allele of common promoter variant C-2073T was contained in a promoter haplotype that associated with plasma DBH activity, a trait also predicted by that variant itself. Promoter haplotypes including C-2073T predicted BP in the population, and the effect was also referable to C-2073T itself. Computationally, C-2073 disrupted a predicted match for transcription factor c-FOS. Site-directed mutagenesis at C-2073T altered not only basal promoter activity, but also transactivation by c-FOS, as well as the chromaffin cell secretory stimuli nicotine or pituitary adenylate cyclase-activating polypeptide (PACAP). Endogenous c-FOS bound to the motif in chromatin. CONCLUSIONS These results suggest that DBH promoter variant C-2073T is functional in vivo: this promoter variant seems to initiate a cascade of transcriptional and biochemical changes including augmented DBH secretion, eventuating in elevation of basal BP, and hence cardiovascular risk. The observations suggest new strategies for probing the pathophysiology, risk, and treatment of hypertension.

Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca(2+) influx, which is controlled by the regulatory β₁-subunit (KCNMB1) of large-conductance heteromeric K+ ('BK') channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline.We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance).The 65Lys variant was relatively common, occurring on ∼5-10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019).Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease.

Background— Whether mutations in the hemochromatosis (HFE) gene increase cardiovascular disease risk is still undetermined. The main reason is the low frequency of the mutations, in particular of the compound C282Y/H63D genotype. We combined the data of 11 observational studies for an individual patient data meta-analysis. Methods and Results— Individual patient data were obtained from published as well as unpublished studies that had information available on the C282Y mutation as well as the H63D mutation in relation to coronary heart disease risk. Individual records were provided on each of the 53 880 participants in 11 studies. In total, 10 541 patients with coronary events were documented, of whom 5724 had an acute myocardial infarction. The crude and adjusted association between HFE genotypes and coronary events was examined by logistic regression analysis. We explored potential effect modification of the association between traditional cardiovascular risk factors and coronary events by HFE genotypes. After full adjustment, the odds ratio for coronary heart disease was 1.12 (95% CI, 0.92 to 1.37) for subjects with the compound heterozygous (C282Y/H63D) genotype relative to those with the wild-type/wild-type genotype. The odds ratios for C282Y/C282Y, C282Y/wild-type, H63D/H63D, and H63D/wild-type were 0.78 (95% CI, 0.49 to 1.26), 0.98 (95% CI, 0.90 to 1.07), 1.16 (95% CI, 0.97 to 1.38), and 1.07 (95% CI, 1.00 to 1.14), respectively. There was no evidence for effect modification. Conclusions— The results of this large individual patient data meta-analysis do not support the view that HFE gene mutations are associated with an increased risk of coronary heart disease or acute myocardial infarction.

BackgroundObesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS) signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs), combined with genotyping for mutations in fatty acid amide hydrolase (FAAH) would identify circulating biomarkers of ECS activation in severe obesity.Methodology/principal findingsPlasma samples were obtained from 96 severely obese subjects with body mass index (BMI) of > or = 40 kg/m(2), and 48 normal weight subjects with BMI of < or = 26 kg/m(2). Triple-quadrupole mass spectroscopy methods were used to measure plasma ECS analogs. Subjects were genotyped for human FAAH gene mutations. The principal analysis focused on the FAAH 385 C-->A (P129T) mutation by comparing plasma ECS metabolite levels in the FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. The main finding was significantly elevated mean plasma levels of anandamide (15.1+/-1.4 pmol/ml) and related NAEs in study subjects that carried the FAAH 385 A mutant alleles versus normal subjects (13.3+/-1.0 pmol/ml) with wild-type FAAH genotype (p = 0.04), and significance was maintained after controlling for BMI.Conclusions/significanceSignificantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.

Because the penetrance of HFE hemochromatosis is low, traditional population screening measuring the transferrin saturation is unlikely to be cost-effective because the majority of subjects detected neither have clinical disease nor are likely to develop it. Three independent studies show that only patients with serum ferritin concentrations more than 1000 μg/L are at risk for cirrhosis, one of the main morbidities of hemochromatosis. Among 29 699 white subjects participating in the Scripps/Kaiser hemochromatosis study, only 59 had serum ferritin levels more than 1000 μg/L; 24 had homozygous mutant or compound heterozygous mutant HFE genotypes. In all but 5 of the other subjects, the causes of elevated ferritin were excessive alcohol intake, cancer, or liver disease. Screening for hemochromatosis with serum ferritin levels will detect the majority of patients who will be clinically affected and may detect other clinically significant disease in patients who do not have hemochromatosis genotypes. Because the ferritin level of the majority of adult homozygotes for HFE mutations does not rise over long periods of time, excluding subjects with serum ferritin levels less than or equal to 1000 μg/L should not result in missed opportunities for early treatment of patients who could benefit.

Obese individuals display circulating proinflammatory cytokine elevations similar to those in patients with rheumatoid arthritis (RA). We wished to determine if extremely obese individuals were overrepresented among a group of patients with RA.We performed both multi- and univariate analyses of data from a large, community-based population attending the "wellness" clinic of a large health maintenance organization in Southern California. We also examined the data from 5 other studies that examined the relationship between various environmental factors and the incidence and prevalence of RA.We found no relationship between the prevalence of RA and body mass index (BMI) in our own data or in the preponderance of previously published studies examining the same question.Although both RA and obesity have been reported to be characterized by high serum levels of inflammatory cytokines, the frequency of one disorder was not increased in the other. We propose that the lack of association in prevalence between the 2 inflammatory states, rather than reflecting a post-hoc effect of the disease on BMI, is a function of the relative amounts of pro- and antiinflammatory mediators produced in adipose tissue, which under many circumstances leads to an overall systemic antiinflammatory tone.

The brain endogenous cannabinoid system modulates reward and craving pathways and consequently may affect body weight. A naturally occurring missense polymorphism in the gene encoding fatty acid amide hydrolase (FAAH), the primary enzyme for inactivation of endocannabinoids, is associated with problem drug use. To investigate the relationship between the FAAH cDNA 385 A/A (P129T) polymorphism and overweight disorders in subjects of multiple ethnic backgrounds attending a medical screening clinic. A total of 2667 subjects of white, black and Asian ancestry were genotyped and stratified by a standardized clinic-based assessment of body mass index (BMI, weight in kilograms/(height in meters)2 or kg/m2). Subjects were genotyped for the FAAH cDNA 385 C → A polymorphism using allele-specific oligonucleotide hybridization methods by investigators blinded to all clinical information. BMI was calculated based on exact clinical measurements and World Health Organization ranges were used to stratify subjects. Statistical methods included the Fisher exact test, Mann–Whitney U-test and multivariable logistic regression analysis. The homozygous FAAH 385 A/A genotype was significantly associated with overweight and obesity in white subjects (P=0.005) and in black subjects (P=0.05) but not in a small group of Asians. The median BMI for all subjects was significantly greater in the FAAH 385 A/A genotype group compared to heterozygote and wild-type groups (P=0.0001). In white subjects, there was an increasing frequency of the FAAH 385 A/A genotype with increasing BMI categories of overweight (P=0.02) and obese (P=0.006) with the same trend in black subjects. These results suggest a role for the FAAH 385 A/A missense polymorphism as an endocannabinoid risk factor in overweight/obesity and may provide indirect evidence to support cannabinoid antagonist treatment strategies in overweight disorders.

We find that in the Black American population average ferritin levels are higher than those in Whites, both among men and women. African-Americans have an increased prevalence of iron storage disease characterized by prominent iron deposition in macrophages of the liver and other organs. The iron distribution in patients with mutations of the ferroportin gene is similar. A c.744 G→T (Gln 248 His) mutation was detected among African-Americans at polymorphic frequencies. This variant is associated with increased ferritin levels in African-Americans and may play a role in their propensity to develop iron overload.

High frequencies of the C282Y and H63D mutations of the HFE gene occur in European populations, even though homozygous and compound heterozygous states are associated with hereditary haemochromatosis, which is a disease that decreases fitness. This suggests that heterozygotes may possess a selective advantage. HFE mutations increase iron absorption in patients with haemochromatosis, and the mean transferrin saturations and ferritin levels are mildly increased in heterozygotes, suggesting that HFE mutations may protect against iron depletion and iron deficiency anaemia. In this study of 23,681 Caucasian adults, mean transferrin saturation, serum ferritin and haemoglobin levels were significantly higher in subjects carrying HFE mutations compared with wild types. Analysed by ethnicity, mean haemoglobin and mean erythrocyte volume (MCV) were significantly lower in those with a southern versus northern European ancestry. C282Y mutation carriers had an increased mean haemoglobin level in both ethnic groups. Prevalence of non-anaemic iron deficiency was significantly lower among female carriers of the C282Y mutation compared with HFE wild types. However, prevalence of frank iron deficiency anaemia did not differ significantly among genotypes. Quantile:quantile plots showed a small but significant upward shift in the mid-range of the haemoglobin distribution among C282Y mutation carriers that was consistent with an increased mean haemoglobin level without significant changes in the anaemic range.

Routine screening for intimate partner violence (IPV) is endorsed by numerous health professional organizations. Screening rates in health care settings, however, remain low. In this article, we present a review of studies focusing on provider-specific barriers to screening for IPV and interventions designed to increase IPV screening in clinical settings.A review of published studies containing original research with a primary focus on screening for IPV by health professionals was completed.Twelve studies identifying barriers to IPV screening as perceived by health care providers yielded similar lists; top provider-related barriers included lack of provider education regarding IPV, lack of time, and lack of effective interventions. Patient-related factors (e.g., patient nondisclosure, fear of offending the patient) were also frequently mentioned. Twelve additional studies evaluating interventions designed to increase IPV screening by providers revealed that interventions limited to education of providers had no significant effect on screening or identification rates. However, most interventions that incorporated strategies in addition to education (e.g., providing specific screening questions) were associated with significant increases in identification rates.Barriers to screening for IPV are documented to be similar among health care providers across diverse specialties and settings. Interventions designed to overcome these barriers and increase IPV-screening rates in health care settings are likely to be more effective if they include strategies in addition to provider education.

The mechanism of excessive iron storage in patients with hereditary hemochromatosis caused by mutations of the HFE gene seems to be a failure to up-regulate hepcidin in the face of increased body iron. Since the cytokines IL-1 and IL-6 stimulate hepcidin transcription in the absence of HFE, chronic inflammatory states might counteract the effect of HFE mutations. We measured the pre-phlebotomy plasma levels of C reactive protein (CRP) and of interleukin 6 (IL-6) in homozygotes for the C282Y mutation of HFE. There was no difference in these levels in subjects with high iron stores than in those with low iron stores, suggesting that the phenotypic differences between such homozygotes is not appreciably affected by ongoing chronic inflammation.

Background Rapid influenza diagnosis is important for early identification of outbreaks, effective management of high-risk contacts, appropriate antiviral use, decreased inappropriate antibiotic use and avoidance of unnecessary laboratory testing. Given the inconsistent performance of many rapid influenza tests, clinical diagnosis remains integral for optimizing influenza management. However, reliable clinical diagnostic methods are not well-established. This study assesses predictors of influenza, and its various subtypes, in a broad population at the point of care, across age groups, then evaluates the performance of clinical case definitions composed of identified predictors. Methods Respiratory specimens and demographic and clinical data were obtained from 3- to 80-year-old US military family members presenting for care with influenza-like illness (ILI) from November 2007 to April 2008. Molecular and virus isolation techniques were used to detect and subtype influenza viruses. Associations between influenza diagnosis and demographic/clinical parameters were assessed by logistic regression, including influenza type and subtype analyses. The predictive values of multiple combinations of identified clinical predictors (case definitions), and the Centers for Disease Control and Prevention (CDC) ILI case definition, were estimated. Results Of 789 subjects, 220 (28%) had laboratory-confirmed influenza (51 A(H1), 46 A(H3), 19 A(unsubtypeable), 67 B, 1 AB coinfection), with the proportion of influenza A to B cases highest among 6- to 17-year-olds (p = 0.019). Independent predictors of influenza included fever, cough, acute onset, body aches, and vaccination status among 6- to 49-year-olds, only vaccination among 3- to 5-year-olds, and only fever among 50- to 80-year-olds. Among 6- to 49-year-olds, some clinical case definitions were highly sensitive (100.0%) or specific (98.6%), but none had both parameters over 60%, though many performed better than the CDC ILI case definition (sensitivity 37.7%, 95% confidence interval 33.6–41.9% in total study population). Conclusions Patterns of influenza predictors differed across age groups, with most predictors identified among 6- to 49-year-olds. No combination of clinical and demographic predictors served as a reliable diagnostic case definition in the population and influenza season studied. A standardized clinical case definition combined with a point-of-care laboratory test may be the optimal rapid diagnostic strategy available.