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Background Screening for asymptomatic, undiagnosed atrial fibrillation (AF) has the potential to allow earlier treatment, possibly resulting in prevention of strokes, but also to increase medical resource utilization. Objective To compare healthcare utilization rates during the year following initiation of screening among participants screened for AF by electrocardiogram (ECG) sensor patch compared with a matched observational control group. Methods A total of 1718 participants recruited from a health care plan based on age and comorbidities who were screened with an ECG patch (actively monitored group) as part of a prospective, pragmatic research trial were matched by age, sex, and CHA2DS2-VASc score with 3371 members from the same health plan (observational control group). Healthcare utilization, including visits, prescriptions, procedures, and diagnoses, during the 1 year following screening was compared between the groups using health plan claims data. Results Overall, the actively monitored group had significantly higher rates of cardiology visits (adjusted incidence rate ratio [aIRR] [95% confidence interval (CI)]: 1.43 [1.27, 1.60]), no difference in primary care provider visits (aIRR [95% CI]: 1.0 [0.95, 1.05]), but lower rates of emergency department (ED) visits and hospitalizations (aIRR [95% CI]: 0.80 [0.69, 0.92]) compared with controls. Among those with newly diagnosed AF, the reduction in ED visits and hospitalizations was even greater (aIRR [95% CI]: 0.27 [0.17, 0.43]). Conclusion AF screening in an asymptomatic, moderate-risk population with an ECG patch was associated with an increase in cardiology outpatient visits but also significantly lower rates of ED visits and hospitalizations over the 1 year following screening.

Background:Pregnant women living in rural locations in the USA have higher rates of maternal and infant mortality compared to their urban counterparts. One factor contributing to this disparity may be lack of representation of rural women in traditional clinical research studies of pregnancy. Barriers to participation often include transportation to research facilities, which are typically located in urban centers, childcare, and inability to participate during nonwork hours.Methods:POWERMOM is a digital research app which allows participants to share both survey and sensor data during their pregnancy. Through non-targeted, national outreach a study population of 3612 participants (591 from rural zip codes and 3021 from urban zip codes) have been enrolled so far in the study, beginning on March 16, 2017, through September 20, 2019.Results:On average rural participants in our study were younger, had higher pre-pregnancy weights, were less racially diverse, and were more likely to plan a home birth compared to the urban participants. Both groups showed similar engagement in terms of week of pregnancy when they joined, percentage of surveys completed, and completion of the outcome survey after they delivered their baby. However, rural participants shared less HealthKit or sensor data compared to urban participants.Discussion:Our study demonstrated the feasibility and effectiveness of enrolling pregnant women living in rural zip codes using a digital research study embedded within a popular pregnancy app. Future efforts to conduct remote digital research studies could help fill representation and knowledge gaps related to pregnant women.

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.

Hairy cell leukemia (HCL) is a rare hematologic disorder characterized by pancytopenia and splenomegaly for which a single course of cladribine is highly effective in inducing complete remissions. However, there is limited real-world data on outcomes and complications among geriatric patients with HCL treated with cladribine. We conducted a retrospective review of all patients 70 years or older within the Scripps Clinic HCL Database at the time of first treatment with cladribine. Of the 45 patients meeting inclusion criteria, 32 (71%) achieved CR and 4 (9%) achieved PR. Of the 9 remaining patients, 7 achieved normalization of peripheral blood counts after a single course of cladribine (complete hematologic response, CHR) and 2 had no response. The median duration of response for all responders was 119 months. Nine (20%) patients relapsed with a median time to first relapse of 28 months. Ten patients subsequently developed 12 primary malignancies with an excess frequency (observed-to-expected ratio) of 0.85 (95% confidence interval, 0.48-1.49). Median overall survival for the entire cohort was 166 months from time of HCL diagnosis and 119 months from time of first cladribine administration. Forty patient deaths were observed; the standardized mortality ratio (observed-to-expected ratio) was 1.42 (95% confidence interval, 1.03-1.96), representing a statistically significant increase in the risk of death (P = .03). This study supports the high rate of complete and durable responses following a single course of cladribine in geriatric patients.

The development and distribution of new vaccines promises an end to the COVID-19 pandemic. With the elderly and front line workers first in line, the vaccination strategy for the general population remains unclear. In this study we identified 690,000 patients infected with COVID-19 with commercial health insurance coverage across the country between April 1, 2020 and September 30, 2020. From prior health care claims, we determined each person’s pre-existing diseases among 26 common chronic diseases. Across age-sex strata we determined the relationships between these conditions and severe COVID-19 infections: ICU admission and extended in-patient stay. We classify disease according to risk, develop multivariable models to predict infection outcomes, and created an online risk assessment tool to estimate risk of ICU admission based on pre-existing health conditions. Our results could be used to help guide risk, vaccination health policy, and personal decision-making as these become available to the general population.

To compare pain after robotic-assisted laparoscopic hysterectomy when giving preoperative oral compared with intravenous acetaminophen.This double-blind randomized trial included women undergoing robotic-assisted laparoscopic hysterectomy for benign indications. Participants received either acetaminophen 1 g orally then normal saline 100 mL intravenously before surgery, or a placebo orally then acetaminophen 1 g intravenously. The primary outcome measured was difference in pain between the groups 2 hours postoperatively. A sample size of 74 participants (37/group) was needed to achieve 80% power to detect noninferiority using a one-sided, two-sample t-test with an alpha of 0.025 and a noninferiority margin of 10 mm.From April 2016 through August 2017, 77 patients were enrolled, with 75 participants included in the final analysis. Characteristics were similar between groups. No difference in average pain score was noted 2 hours after surgery, nor at any of the measured time points. Average scores for the oral and intravenous group, respectively, at 2 hours were 35 and 36 mm (P=.86), at 4 hours 36 and 37 mm (P=.96), and at 24 hours 35 and 36 mm (P=.79). Thirty-eight percent of participants in the oral group and 19% of participants in the intravenous group experienced nausea (P=.12). The oral group used 9.7 morphine equivalents in the recovery room, and the intravenous group used 9.5 morphine equivalents (P=.9). The oral group requested analgesia in 45 minutes on average, and the intravenous group requested analgesia in 43 minutes (P=.79).No difference in pain was observed 2 hours postoperatively when comparing preoperative administration of oral compared with intravenous acetaminophen. Given the ease of administration and lower cost of oral dosing, this study supports the oral route as part of the enhanced recovery after surgery protocol for minimally invasive gynecologic surgery.ClinicalTrials.gov, NCT03391284.

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

Objectives 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. Background In MESA (Multi-Ethnic Study of Atherosclerosis), CAC volume was positively and CAC density inversely associated with cardiovascular disease (CVD) events. Methods A total of 3,398 MESA participants free of clinical CVD but with prevalent CAC at baseline were followed for incident CVD events. Results 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 Conclusions 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.

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

Objectives: The advent of large databases, wearable technology, and novel communications methods has the potential to expand the pool of candidate research participants and offer them the flexibility and convenience of participating in remote research. However, reports of their effectiveness are sparse. We assessed the use of various forms of outreach within a nationwide randomized clinical trial being conducted entirely by remote means. Methods: Candidate participants at possibly higher risk for atrial fibrillation were identified by means of a large insurance claims database and invited to participate in the study by their insurance provider. Enrolled participants were randomly assigned to one of two groups testing a wearable sensor device for detection of the arrhythmia. Results: Over 10 months, the various outreach methods used resulted in enrollment of 2659 participants meeting eligibility criteria. Starting with a baseline enrollment rate of 0.8% in response to an email invitation, the recruitment campaign was iteratively optimized to ultimately include website changes and the use of a five-step outreach process (three short, personalized emails and two direct mailers) that highlighted the appeal of new technology used in the study, resulting in an enrollment rate of 9.4%. Messaging that highlighted access to new technology outperformed both appeals to altruism and appeals that highlighted accessing personal health information. Conclusions: Targeted outreach, enrollment, and management of large remote clinical trials is feasible and can be improved with an iterative approach, although more work is needed to learn how to best recruit and retain potential research participants. Trial registration: Clinicaltrials.gov NCT02506244. Registered 23 July 2015. Keywords: Clinical trials, Clinical research, Digital technology, Remote enrollment, Remote monitoring, Outreach

Background Although the growth of point-of-care ultrasound has resulted in a proliferation of teaching programs, few data exist on the maintenance of proficiency. The aim of this study was to evaluate the retention of cardiac ultrasound skills and training in physicians up to 7 years after a formal focused curriculum in residency. Methods Thirty internal medicine physicians, deemed proficient at graduation and having passed a practical examination that confirms imaging skills and knowledge base when a score of ≥80% correct is attained, were retested. Twenty graduates (the NOPREP group) did not study any relevant material, and 10 graduates (the PREP group) were encouraged to study online videos. Scores were categorized by length of time (1-7 years) from graduates' last performance of ultrasound. Results The mean original test score of the physicians was 90 ± 6%. With retesting NOPREP ( n = 20), seven physicians were within 1 year of their last use, and five (71%) repassed the examination, scoring 80 ± 15%. Among the remaining 13 NOPREP physicians who had >1 year of nonuse, none repassed, scoring 58 ± 17%. In retesting PREP ( n = 10), one physician was within 1 year of last use and repassed, scoring 95%. Among the remaining nine PREP physicians with >1 year since last use, three (33%) repassed ( P = .05), scoring 72 ± 21%. Diagnostic knowledge was significantly higher when good-quality images were obtained. Conclusions Learned skills in cardiac ultrasound diminish notably within 2 years of nonuse.

Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation.

Objective To examine the influence of smoking on the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI). Background Certain studies suggest smokers may have enhanced clopidogrel-induced platelet inhibition compared to non-smokers after PCI. Whether this is affected by clopidogrel dose is unknown. Methods In this study, we conducted an analysis of 5,429 patients in the Gauging Responsiveness With A VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Platelet reactivity was assessed 12–24 hr after PCI (baseline). Patients with high on-treatment platelet reactivity (OTR) (P2Y12 reaction units [PRU] ≥ 230) were randomized to clopidogrel 75 mg or 150 mg daily. Reactivity was subsequently assessed at 30-days, and 6-months. Patients were stratified by smoking status. Results Smoking was independently associated with lower PRU (P = 0.001), and smokers were less likely to have high OTR (odds ratio 0.80, 95% confidence interval 0.68–0.94; P = 0.006) at baseline. Among patients assigned to clopidogrel 75 mg, smokers had lower PRU and were less likely to still have high OTR at 30-days (P

Physicians are increasingly approached by individuals seeking integrative approaches to health care and well-being. Many integrative modalities include a physical activity component. Patients seek guidance from primary and specialty care providers on the safe and effective incorporation of these modalities into their lifestyle. Physicians and other health professionals receive very limited training in the clinical applications of exercise science. This paper reports on a curriculum designed to teach health professionals key exercise constructs for application to clinical practice for prevention and management of lifestyle-related disease, and incorporating the curriculum into a preventive medicine residency training program. The course was developed in 2012-2013, data collected in 2013-2015, and analysis was done in 2015. Six modules were developed as part of a 24-hour course. Each module included didactic, laboratory, and case examples. The modules included energetics, exercise and cardiorespiratory health, bone health, obesity and sarcopenia, balance and fall prevention, and behavior change and the use of technologies. The delivery was found feasible for all three components, delivered in 2-4-hour segments. The incorporation into the residency curriculum was feasible, efficacious, well received, and easily incorporated into the existing curriculum. This comprehensive curriculum has the potential to close the gap in medical school, residency, graduate, nursing, and integrative curricula on this important topic. Current practitioners would benefit in primary care and geriatric settings. This curriculum would also be useful for cross-disciplinary researchers, including public health, health behaviors, and integrative medicine practitioners.

BACKGROUND Colorectal cancer (CRC) is the second leading cancer-related cause of death in the United States. However, survivorship has been increasing. Both cancer survivors and underserved populations experience unique health-related challenges and disparities that may exist among long-term CRC survivors as it relates to routine preventive care, specifically pneumococcal (PNM) vaccination. OBJECTIVE The aim of this study was to explore the relationship between long-term CRC survival and the receipt of PNM vaccine among Hispanic Medicare recipients compared with non-Hispanic populations. METHODS This study is a cross-sectional analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare claims data examining ethnic differences in the receipt of PNM vaccination among long-term CRC survivors. Multivariable logistic regression models considered Hispanic ethnicity while controlling for sociodemographic characteristics, comorbidity score, age, tumor stage, and SEER registry. RESULTS Our sample revealed 32,501 long-term CRC survivors, and 1509 identified as Hispanic (4.64%) based on an established SEER algorithm. In total, 16,252 CRC survivors, or 50.00% of our sample, received a PNM vaccination. We found that Hispanic CRC survivors had 10% decreased odds of having received a PNM vaccine compared with non-Hispanic survivors (P=.03). CONCLUSIONS Disparities likely exist in the utilization of PNM vaccination among long-term CRC survivors. Among Medicare beneficiaries, the use of claims data regarding PNM vaccination highlights the relatively poor utilization of guideline-directed preventive care.

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.

Sustained virologic response (SVR) after direct-acting antiviral (DAA) therapy for chronic hepatitis C results in significant decreases in liver stiffness measured by transient elastography (TE). The aim of this study was to clarify if TE can guide post-SVR management in patients with advanced fibrosis or cirrhosis prior to treatment as current guidelines are unclear on the role of TE after SVR. In total, 84 patients with hepatitis C virus and advanced fibrosis or cirrhosis and from a single center underwent DAA treatment and achieved SVR. Overall, 62% had improved liver stiffness that was consistent with regression of at least one stage of fibrosis. In the cirrhosis group, 48% showed fibrosis regression by at least two stages by TE (

Objective: Several studies have found that protein concentrations of inflammatory cytokines are significantly increased in tissue and serum from patients with chronic venous insufficiency (CVI) relative to that of healthy controls. We sought to determine whether inflammatory protein concentrations differ between patients with moderate clinical disease, classified as clinical, etiology, anatomy, pathophysiology (CEAP) Classes 2 and 3, and more severe clinical disease, classified as CEAP Class 4. Methods: Twenty patients with abnormal venous function were included in the study. Blood from a competent leg vein and from an incompetent superficial vein was collected in addition to incompetent vein tissue extracted through a phlebectomy procedure. Cytokine levels of venous tissue lysate and serum samples were determined using a multiplex assay. Results: Thirteen patients (65%) were classified as clinical CEAP Class 2 or 3, with seven patients (35%) falling into the more severe Class 4 category. Twenty-seven cytokines were measured. Serum isolated from normal veins had significantly higher levels of IFN-gamma in patients with Classes 2 and 3 than Class 4 disease (95.17 pg/mL vs. 71.97 pg/mL; p=0.036). In serum from incompetent veins, IFN-gamma concentrations averaged 95.47 pg/mL in Class 2 and 3 patients and 76.97 pg/mL in Class 4 patients (p=0.048). Eotaxin levels from diseased vein tissue averaged 3.37 pg/mL in Classes 2 and 3 patients, and 1.57 pg/mL in Class 4 patients (p=0.037). IP-10 levels in diseased vein tissue was also significantly less in Class 4 patients at 74.20 pg/mL in Class 2 and 3 patients versus 31.06 pg/mL in Class 4 patients (p=0.004). Conclusion: Despite several studies documenting increased inflammatory cytokines in patients with CVI, our study shows that those patients with more severe disease have significantly lower levels of several inflammatory cytokines. Thus, particular inflammatory cytokines may function in a reparative capacity following tissue injury or as a control mechanism to inhibit further tissue destruction.

The heritability of obesity has long been appreciated and the genetics of obesity has been the focus of intensive study for decades. Early studies elucidating genetic factors involved in rare monogenic and syndromic forms of extreme obesity focused attention on dysfunction of hypothalamic leptin-related pathways in the control of food intake as a major contributor. Subsequent genome-wide association studies of common genetic variants identified novel loci that are involved in more common forms of obesity across populations of diverse ethnicities and ages. The subsequent search for factors contributing to the heritability of obesity not explained by these 2 approaches ("missing heritability") has revealed additional rare variants, copy number variants, and epigenetic changes that contribute. Although clinical applications of these findings have been limited to date, the increasing understanding of the interplay of these genetic factors with environmental conditions, such as the increased availability of high calorie foods and decreased energy expenditure of sedentary lifestyles, promises to accelerate the translation of genetic findings into more successful preventive and therapeutic interventions.

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.

Objectives The goal of this study was to understand the role of genetic variation in the catecholamine biosynthetic pathway for control of human heart rate (HR). Background Human HR is an integrated cardiovascular trait predictive of morbidity and survival. Because the autonomic pathway exerts rapid control over the heart, we probed the role of heredity in the control of HR, focusing on a component of the autonomic sympathetic pathway already predictive of outflow responses: cytochrome b561 (CYB561), the electron shuttle in catecholamine vesicle membranes for transmitter biosynthesis. Methods We studied hereditary control of HR with the twin pair design, at rest and during environmental (cold) stress. Single nucleotide polymorphism disruption of a microribonucleic acid (microRNA) recognition motif in the human CYB561 3′-UTR was identified computationally, and its differential effect on gene expression was demonstrated in a transfected luciferase reporter/3′-UTR variant. We exposed stem cell–derived human embryoid bodies to the microRNA mimic or antagomir oligonucleotides, and we observed the effects on contraction rate in proto-hearts. Results Substantial heritability (h2) was demonstrated by using twin pair variance components for both basal/resting HR (h2 50.9 ± 6.4% of trait variation, p = 2.47 × 10−10) and stress-augmented HR (h2 55.1 ± 5.9%, p = 8.79 × 10−13), and the 2 HR traits shared genetic determination (genetic covariance ρG 0.747 ± 0.058, p = 2.85 × 10−9). CYB561 displayed 1 common genetic variant in the transcript region: A+1485G (rs3087776), in the 3′-UTR, 1485 bp downstream of the termination codon, in a conserved region, with the A-allele ancestral in primates. In a twin/sibling sample (n = 576), A+1485G influenced HR, both at rest (p = 0.010) and after environmental stress (p = 0.002), with the minor (A) allele displaying a recessive effect with lower HR. The effect of A+1485G on HR was extended by meta-analysis into 2 additional population samples (total n = 2,579), and the influence remained directionally consistent and significant (p = 0.007). A+1485G disrupted a microRNA (human microribonucleic acid-1294 [hsa-miR-1294]) recognition motif in the 3′-UTR, as demonstrated by a transfected luciferase reporter/human 3′-UTR variant system in 2 different neuronal/neuroendocrine cell types. The microRNA effect was further documented by cotransfection of an hsa-miR-1294 mimic, yielding an exaggerated decline in expression of the A-allele (better match) reporter (p = 4.3 × 10−5). Similar findings of differential 3′-UTR allelic susceptibility to hsa-miR-1294 were noted during expression of the full-length human CYB561 messenger ribonucleic acid with its cognate 3′-UTR. Finally, exposure of stem cell–derived human embryoid bodies to hsa-miR-1294 mimic or antagomir oligonucleotides yielded directionally opposite effects on contraction rate in proto-hearts. Conclusions HR is a substantially heritable trait, with genetic influence by variation in the adrenergic pathway, here shown for messenger ribonucleic acid translational control at the CYB561 step of transmitter formation. The results have implications for potentially modifiable autonomic pathways that influence this risk trait in the population.

Background : In actual clinical practice as opposed to published studies, the application of bedside ultrasound requires a perception of need, confidence in one’s skills, and convenience. Objective : As the frequency of ultrasound usage is evidence to its perceived value in patient care, we observed the pattern of autonomous use of a pocket-sized device (PSD) by ultrasound-trained residents during a night hospitalist rotation. Methods : Consecutive internal medicine residents ( n= 24), trained in a cardiac limited ultrasound examination (CLUE) as a mandatory part of their curriculum, were sampled on their PSD use after their admitting nights, regarding perceived necessity, deterring factors, detected abnormalities, and imaging difficulties. A detailed analysis was performed with one resident who used a PSD on every admission to compare the proportion of abnormal CLUEs and utility in patients with and without a perceived need. Results : Residents admitted 542 patients (mean age: 55±17 years, range: 17–95 years) during 101 shifts and performed CLUE on 230 patients (42%, range: 17–85%). Residents elected not to scan 312 (58%) patients due to 1) lack of perceived necessity (231, 74%), 2) time constraints (44, 14%), and 3) patient barriers (37, 12%). In the detailed analysis ( n= 71), the resident felt CLUE was necessary in 32 (45%) patients versus unnecessary in 39 (55%) patients, with abnormality rates of 50% versus 20.5% ( p= 0.01) and utility rates of 28.1% versus 15.4% ( p= 0.25), respectively. Conclusion : When unbiased residents acting as hospitalists are provided with a PSD to augment initial cardiac examination, usage is frequent and suggests clinical value in hospital medicine. Keywords: echocardiography; point-of-care ultrasound; hand-carried ultrasound; pocket-sized; hospitalist; hospital medicine (Published: 15 December 2016) Citation: Journal of Community Hospital Internal Medicine Perspectives 2016, 6 : 33358 - http://dx.doi.org/10.3402/jchimp.v6.3335

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.

Background Colorectal cancer (CRC) is the second leading cancer-related cause of death in the United States. However, survivorship has been increasing. Both cancer survivors and underserved populations experience unique health-related challenges and disparities that may exist among long-term CRC survivors as it relates to routine preventive care, specifically pneumococcal (PNM) vaccination. Objective The aim of this study was to explore the relationship between long-term CRC survival and the receipt of PNM vaccine among Hispanic Medicare recipients compared with non-Hispanic populations. Methods This study is a cross-sectional analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare claims data examining ethnic differences in the receipt of PNM vaccination among long-term CRC survivors. Multivariable logistic regression models considered Hispanic ethnicity while controlling for sociodemographic characteristics, comorbidity score, age, tumor stage, and SEER registry. Results Our sample revealed 32,501 long-term CRC survivors, and 1509 identified as Hispanic (4.64%) based on an established SEER algorithm. In total, 16,252 CRC survivors, or 50.00% of our sample, received a PNM vaccination. We found that Hispanic CRC survivors had 10% decreased odds of having received a PNM vaccine compared with non-Hispanic survivors (P=.03). Conclusions Disparities likely exist in the utilization of PNM vaccination among long-term CRC survivors. Among Medicare beneficiaries, the use of claims data regarding PNM vaccination highlights the relatively poor utilization of guideline-directed preventive care.

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.

Routine ECG screening for AF is not recommended due in part to a lack of healthcare utilization data. In the mSToPS trial asymptomatic individuals underwent screening with an ECG sensor patch. Healthcare utilization was evaluated following monitoring & compared to matched controls. 1738 Aetna

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.

Objectives This study sought to understand whether genetic variation at the Neuropeptide Y ( NPY ) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells. Background The NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15. Methods Our approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population. Results Systematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ∇−880Δ (2-bp TG/—, Ins/Del, rs3037354) minor/Δ allele was associated with several heritable (h 2 ) stress traits: higher NPY secretion (h 2 = 73 ± 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ∇−880Δ and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele −880Δ to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter −880Δ interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same −880Δ allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes. Conclusions We conclude that common genetic variation at the NPY locus, especially in proximal promoter ∇−880Δ, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states.

Cathepsin L (CTSL1) catalyzes the formation of peptides that influence blood pressure (BP). Naturally occurring genetic variation or targeted ablation of the Ctsl1 locus in mice yield cardiovascular pathology. Here, we searched for genetic variation across the human CTSL1 locus and probed its functional effects, especially in the proximal promoter.Systematic polymorphism discovery by re-sequencing across CTSL1 in 81 patients uncovered 38 genetic variants, five of which were relatively common (MAF5%), creating a single linkage disequilibrium block in multiple biogeographic ancestries. One of these five common variants lay in a functional domain of the gene: promoter C-171A (rs3118869), which disrupts a predicted xenobiotic response element (XRE; match CA). In transfected CTSL1 promoter/luciferase reporter plasmids, C-171A allele influenced transcription (CA, P = 3.36E-6), and transcription was also augmented by co-exposure to the aryl hydrocarbon receptor (AHR) complex (AHR:ARNT) in the presence of their ligand dioxin (P = 6.81E-8); allele (C vs. A) and AHR:ARNT/dioxin stimulus interacted to control gene expression (interaction P = 0.033). Endogenous Ctsl1, Ahr, and Arnt transcripts were present in chromaffin cells. Promoter functional C-171A genotype also predicted hypertension (P = 1.0E-3), SBP (P = 4.0E-4), and DBP (P = 3.0E-3), in an additive pattern for diploid genotypes (A/AC/AC/C) in 868 patients, and the results were extended by validation analysis into an independent population sample of 986 patients.We conclude that common genetic variation in the proximal CTSL1 promoter, especially at position C-171A, is functional in cells, and alters transcription so as to explain the association of CTSL1 with BP in vivo. At the XRE, endogenous genetic variation plus exogenous aryl hydrocarbon stimulation interact to control CTSL1 gene expression. These results unveil a novel control point whereby heredity and environment can intersect to control a complex trait, and point to new transcriptional strategies for intervention into transmitter biosynthesis and its cardiovascular consequences.

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.

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.

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.