Outpatient Complex Case Management: Health System-Tailored Risk Stratification Taxonomy to Identify High-Cost, High-Need Patients.

BACKGROUND: U.S. health systems, incentivized by financial penalties, are designing programs such as case management to reduce service utilization among high-cost, high-need populations. The major challenge is identifying patients for whom targeted programs are most effective for achieving desired outcomes. OBJECTIVE: To evaluate a health system's outpatient complex case management (OPCM) for Medicare beneficiaries for patients overall and for high-risk patients using system-tailored taxonomy, and examine whether OPCM lowers service utilization and healthcare costs. DESIGN: Retrospective case-control study using Medicare data collected between 2012 and 2016 for Ochsner Health System. PARTICIPANTS: Super-utilizers defined as Medicare patients with at least two hospital/ED encounters within 180 days of the index date including the index event. INTERVENTION: Outpatient complex case management. MAIN MEASURES: Propensity score-adjusted multivariable logistic regression analysis was conducted for primary outcomes (90-day hospital readmission; 90-day ED re-visit). A difference-in-difference analysis was conducted to examine changes in per membership per month (PMPM) costs based on OPCM exposure. KEY RESULTS: Among 18,882 patients, 1197 (6.3%) were identified as "high-risk" and 470 (2.5%) were OPCM participants with median enrollment of 49 days. High-risk OPCM cases compared to high-risk controls had lower odds of 90-day hospital readmissions (0.81 [0.40-1.61], non-significant) and lower odds of 90-day ED re-visits (0.50 [0.32-0.79]). Non-high-risk OPCM cases compared to non-high-risk controls had lower odds of 90-day hospital readmissions (0.20 [0.11-0.36]) and 90-day ED re-visits (0.66 [0.47-0.94]). Among OPCM cases, high-risk patients compared to non-high-risk patients had greater odds of 90-day hospital readmissions (4.44 [1.87-10.54]); however, there was no difference in 90-day ED re-visits (0.99 [0.58-1.68]). Overall, OPCM cases had lower total cost of care compared to controls (PMPM mean [SD]: - $1037.71 [188.18]). CONCLUSIONS: Use of risk stratification taxonomy for super-utilizers can identify patients most likely to benefit from case management. Future studies must further examine which OPCM components drive improvements in select outcome for specific populations.

Considerations to increase rates of breast cancer screening across populations.

OBJECTIVES: COVID-19 has caused considerable drops in utilization of breast cancer screening services during the pandemic, especially among certain racial and ethnic groups. Members of the Community Oncology Alliance (COA)-including the COA president, South Carolina oncologist Kashyap Patel, MD-have reported increases in patients, particularly those of color, presenting with stage III and IV cancer at diagnosis. According to data released by the Biden administration, more than 9.5 million recommended cancer screenings had been missed in the United States as a result of the COVID-19 pandemic, as of February 2022. President Joe Biden and First Lady Jill Biden, EdD, aim to address this in the 2022 revitalized Cancer Moonshot Initiative. The findings made by COA as well as by Avalere also suggest that the pandemic has exacerbated existing health care disparities. METHODS: Using a multipayer database, we analyzed breast cancer screening rates for 2 periods-March 1 to September 30, 2019, and March 1 to September 30, 2020-among Medicare fee-for-service (FFS), managed Medicaid, and commercial insurance beneficiaries to understand the potential impact of the COVID-19 pandemic on adherence to the US Preventive Services Task Force breast cancer screening recommendations, which are currently undergoing review. Screening rates were evaluated across 5 racial/ethnic groups and by payer type. RESULTS: Mean monthly mammogram screening rates among eligible White Medicare FFS beneficiaries dropped to 0.6% in April 2020, but these screening rates recovered to 6.5% by June 2020. Screening rates for eligible Black Medicare FFS beneficiaries recovered on a pace slightly slower than that of White beneficiaries, but more rapidly than that of other groups. By comparison, American Indian/Alaska Native beneficiaries had a mean monthly screening rate of 0.5% in April 2020, which recovered to 3.1% in June 2020; these were below 2019 screening rates of 4.2% for April and 3.9% for June. Differences in screening rates by payer type were also observed. Patients with commercial insurance had higher screening rates compared with those covered by Medicare FFS and managed Medicaid. CONCLUSIONS: Our principal finding shows that mean breast cancer screening rates decreased in April 2020 across all payers, but recovery to prepandemic screening levels has occurred more slowly among certain racial and ethnic minority groups. Differences in recovery rates by payer type highlight a strong relationship between income level and screening utilization.

Impact of COVID-19 on Cancer Care: How the Pandemic Is Delaying Cancer Diagnosis and Treatment for American Seniors.

PURPOSE: While the immediate care and access disruptions associated with the COVID-19 pandemic have received growing attention in certain areas, the full range of gaps in cancer screenings and treatment is not yet well understood or well documented throughout the country comprehensively. METHODS: This study used a large medical claims clearinghouse database representing 5%-7% of the Medicare fee-for-service population to characterize changes in the utilization of cancer care services and gain insight into the impact of COVID-19 on the US cancer population, including identification of new patients, gaps in access to care, and disruption of treatment journeys. RESULTS: In March-July 2020, in comparison with the baseline period of March-July 2019, there is a substantial decrease in cancer screenings, visits, therapy, and surgeries, with variation by cancer type and site of service. At the peak of the pandemic in April, screenings for breast, colon, prostate, and lung cancers were lower by 85%, 75%, 74%, and 56%, respectively. Significant utilization reductions were observed in April for hospital outpatient evaluation and management (E&M) visits (-74%), new patient E&M visits (-70%), and established patient E&M visits (-60%). A decrease in billing frequency was observed for the top physician-administered oncology products, dropping in both April (-26%) and July (-31%). Mastectomies were reduced consistently in April through July, with colectomies similarly reduced in April and May and prostatectomies dipping in April and July. CONCLUSION: The current impact of the COVID-19 pandemic on cancer care in the United States has resulted in decreases and delays in identifying new cancers and delivery of treatment. These problems, if unmitigated, will increase cancer morbidity and mortality for years to come.

A major haplotype block at the rho-associated kinase 2 locus is associated with a lower risk of hypertension in a recessive manner: the HYPGENE study.

The goals of our study were to evaluate the haplotype pattern at the Rho-associated kinase 2 (ROCK2) locus and prospectively test the association between the ROCK2 haplotype-tagging single-nucleotide polymorphisms (tagSNPs) with hypertension for verified incident hypertensive patients (n=607) and healthy, normotensive controls (n=586) in a HYPGENE study. Rho-associated kinases (ROCKs) play a central role in signaling pathways that are involved in vascular smooth muscle contraction and endothelial nitric oxide availability. Using a set of stringent criteria (minor allele frequency>or=0.05, pairwise r2>or=0.95), we identified 18 tagSNPs from the 109 SNPs available in the HapMap Caucasian data set. TagSNPs were genotyped using the Illumina BeadStation platform. The 18 tagSNPs consisted of two linkage disequilibrium (LD) blocks. A haplotype defined by four SNPs (rs965665, rs10178332, rs6755196, rs10929732) in LD block 2 was recessively associated with a lower risk of hypertension (p=0.003). Homozygotes for the minor alleles had an 85% lower risk of hypertension than carriers of the common allele. The associations were independent of baseline age, cardiorespiratory fitness, body mass index, sex, and follow-up time. The LD block 2 spans about 137 kb of genomic DNA at the 5'-end of the ROCK2 locus and covers exons encoding the kinase domain of the protein. Our data strongly suggest that a major haplotype block at the ROCK2 locus is recessively associated with a lower risk of hypertension. Identification of functional mutation(s) could thus help in the development of ROCK2-specific treatments.

Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or -4 receptors.

Loss of brain melanocortin receptors (Mc3rKO and Mc4rKO) causes increased adiposity and exacerbates diet-induced obesity (DIO). Little is known about how Mc3r or Mc4r genotype, diet, and obesity affect insulin sensitivity. Insulin resistance, assessed by insulin and glucose tolerance tests, Ser(307) phosphorylation of insulin receptor substrate 1, and activation of protein kinase B, was examined in control and DIO wild-type (WT), Mc3rKO and Mc4rKO C57BL/6J mice. Mc4rKO mice were hyperphagic and had increased metabolic efficiency (weight gain per kilojoule consumed) relative to WT; both parameters increased further on high-fat diet. Obesity of Mc3rKO was more dependent on fat intake, involving increased metabolic efficiency. Fat mass of DIO Mc3rKO and Mc4rKO was similar, although Mc4rKO gained weight more rapidly. Mc4rKO develop hepatic insulin resistance and severe hepatic steatosis with obesity, independent of diet. DIO caused further deterioration of insulin action in Mc4rKO of either sex and, in male Mc3rKO, compared with controls, associated with increased fasting insulin, severe glucose intolerance, and reduced insulin signaling in muscle and adipose tissue. DIO female Mc3rKO exhibited very modest perturbations in glucose metabolism and insulin sensitivity. Consistent with previous data suggesting impaired fat oxidation, both Mc3rKO and Mc4rKO had reduced muscle oxidative metabolism, a risk factor for weight gain and insulin resistance. Energy expenditure was, however, increased in Mc4rKO compared with Mc3rKO and controls, perhaps due to hyperphagia and metabolic costs associated with rapid growth. In summary, DIO affects insulin sensitivity more severely in Mc4rKO compared with Mc3rKO, perhaps due to a more positive energy balance.

Large-scale association study identifies ICAM gene region as breast and prostate cancer susceptibility locus.

We conducted a large-scale association study to identify genes that influence nonfamilial breast cancer risk using a collection of German cases and matched controls and >25,000 single nucleotide polymorphisms located within 16,000 genes. One of the candidate loci identified was located on chromosome 19p13.2 [odds ratio (OR) = 1.5, P = 0.001]. The effect was substantially stronger in the subset of cases with reported family history of breast cancer (OR = 3.4, P = 0.001). The finding was subsequently replicated in two independent collections (combined OR = 1.4, P < 0.001) and was also associated with predisposition to prostate cancer in an independent sample set of prostate cancer cases and matched controls (OR = 1.4, P = 0.002). High-density single nucleotide polymorphism mapping showed that the extent of association spans 20 kb and includes the intercellular adhesion molecule genes ICAM1, ICAM4, and ICAM5. Although genetic variants in ICAM5 showed the strongest association with disease status, ICAM1 is expressed at highest levels in normal and tumor breast tissue. A variant in ICAM5 was also associated with disease progression and prognosis. Because ICAMs are suitable targets for antibodies and small molecules, these findings may not only provide diagnostic and prognostic markers but also new therapeutic opportunities in breast and prostate cancer.

Improved clinical outcomes associated with vitamin D supplementation during adjuvant chemotherapy in patients with HER2+ nonmetastatic breast cancer.

BACKGROUND: Vitamin D (VD) supplementation has pleiotropic effects that extend beyond their impact on bone health, including the disruption of downstream VD receptor signaling and human epidermal growth factor receptor 2 (HER2) signaling through the ErbB2/AKT/ERK pathway. In the present study, we examined our institutional experience with patients having nonmetastatic HER2-positive (HER(+)) breast cancer and hypothesized that those patients who received VD supplementation during neoadjuvant chemotherapy would have improved long-term outcomes. PATIENTS AND METHODS: We performed a retrospective review of all patients (n = 308) given trastuzumab-based chemotherapy between 2006 and 2012 at the University of Miami/Sylvester Comprehensive Cancer Center (UM/SCCC). We identified 2 groups of patients for comparison-those who received VD supplementation during neoadjuvant chemotherapy (n = 134) and those who did not (n = 112). Univariate and multivariate Cox proportional hazard regression models were fitted to overall survival (OS) and disease-free survival (DFS). RESULTS: More than half of the patients received VD during neoadjuvant chemotherapy (54.5%), with 60% receiving a dose < 10,000 units/wk and 33.3% having a VD deficiency at the start of therapy. In our final multivariate model, VD use was associated with improved DFS (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.15-0.88; P = .026], whereas larger tumor size was associated with worse DFS (HR, 3.52; 95% CI, 1.06-11.66; P = .04). There were no differences in OS based on any of the categories, including VD use, tumor size, number of metastatic lymph nodes, age at diagnosis, or lymphovascular invasion (LVI). CONCLUSION: VD supplementation in patients with nonmetastatic HER2(+) breast cancer is associated with improved DFS.

Defining the survival benchmark for breast cancer patients with systemic relapse.

BACKGROUND: Our original paper, published in 1992, reported a median overall survival after first relapse in breast cancer of 26 months. The current retrospective review concentrates more specifically on patients with first systemic relapse, recognizing that subsets of patients with local recurrence are potentially curable. METHODS: Records of 5,168 patients from a largely breast-cancer-specific oncology practice were reviewed to identify breast cancer patients with their first relapse between 1996 and 2006 after primary treatment. There were 189 patients diagnosed with metastatic disease within 2 months of being seen by our therapeutic team and 101 patients diagnosed with metastatic disease greater than 2 months. The patients were divided in order to account for lead-time bias than could potentially confound the analysis of the latter 101 patients. RESULTS: Median survival for our primary study population of 189 patients was 33 months. As expected, the median survival from first systemic relapse (MSFSR) for the 101 patients excluded because of the potential for lead-time bias was better at 46 months. Factors influencing prognosis included estrogen receptor (ER) status, disease-free interval (DFI), and dominant site of metastasis. Compared with our original series, even with elimination of local-regional recurrences in our present series, the median survival from first relapse has improved by 7 months over the past two decades. CONCLUSION: The new benchmark for MSFSR approaches 3 years.

An Internet-based Controlled Trial Aimed to Improve Osteoporosis Prevention among Chronic Glucocorticoid Users.

OBJECTIVE: To address the low prevention and treatment rates for those at risk of glucocorticoid-induced osteoporosis (GIOP), we evaluated the influence of a direct-to-patient, Internet-based educational video intervention using "storytelling" on rates of antiosteoporosis medication use among chronic glucocorticoid users who were members of an online pharmacy refill service. METHODS: We identified members who refilled ≥ 5 mg/day of prednisone (or equivalent) for 90 contiguous days and had no GIOP therapy for ≥ 12 months. Using patient stories, we developed an online video addressing risk factors and treatment options, and delivered it to members refilling a glucocorticoid prescription. The intervention consisted of two 45-day "Video ON" periods, during which the video automatically appeared at the time of refill, and two 45-day "Video OFF" periods, during which there was no video. Members could also "self-initiate" watching the video by going to the video link. We used an interrupted time series design to evaluate the effectiveness of this intervention on GIOP prescription therapies over 6 months. RESULTS: Among 3017 members (64.8%) exposed to the intervention, 59% had measurable video viewing time, of which 3% "self-initiated" the video. The GIOP prescription rate in the "Video ON" group was 2.9% versus 2.7% for the "Video OFF" group. There was a nonsignificant trend toward greater GIOP prescription in members who self-initiated the video versus automated viewing (5.7% vs 2.9%, p = 0.1). CONCLUSION: Among adults at high risk of GIOP, prescription rates were not significantly affected by an online educational video presented at the time of glucocorticoid refill. ClinicalTrials.gov Identifier: NCT01378689.

Establishing mathematical laws of genomic variation.

As the biological arm of the Rasch community, genomic measurement is concerned with asserting and testing hypotheses regarding the quantitative status of genomic variables, including alleles, genotypes, gene expression levels, and phenotypes, as well as DNA, RNA, and protein sequence information. The defining goal of this scientific paradigm, in contrast to the sample-dependent model-fitting and deterministic hypothesis testing of classical statistical genetics, is the identification, validation, and maintenance of a common unit of genomic measurement that maintains its magnitude and meaning, within an allowable range of error, regardless of the laboratory technology used to generate outcomes or the particular group of individuals or organisms under investigation. Such an invariant metric, the basis of a standard genometric scale and associated system of genomic metrology, can be identified, validated, and maintained through 1) routine implementation of the Rasch family of measurement models to construct sample- and scale-free measures from different types of genomic data and 2) cross-calibration of genomic measurement instruments between and among researchers, laboratories, universities, corporations, and databases. This manuscript provides an introductory overview of the guiding principles of fundamental measurement theory and the work of Rasch, connects these concepts to well-known tenets of population genetics, and highlights the potential benefits, both theoretical and applied, associated with achieving objectivity in genomic measurement.

Calibrating the genome.

PURPOSE: This project demonstrates how to calibrate different samples and scales of genomic information to a common scale of genomic measurement. MATERIALS AND METHODS: 1,113 persons were genotyped at the 13 Combined DNA Index System (CODIS) short tandem repeat (STR) marker loci used by the Federal Bureau of Investigation (FBI) for human identity testing. A measurement model of form ln[(P(nik))/(1-P(nik))] = B(n)-D(i)-L(k) is used to construct person measures and locus calibrations from information contained in the CODIS database. Winsteps (Wright and Linacre, 2003) is employed to maximize initial estimates and to investigate the necessity and sufficiency of different rating classification schema. RESULTS: Model fit is satisfactory in all analyses. Study outcomes are found in Tables 1-6. CONCLUSIONS: Additive, divisible, and interchangeable measures and calibrations can be created from raw genomic information that transcend sample- and scale-dependencies associated with racial and ethnic descent, chromosomal location, and locus-specific allele expansion structures.

Improved long-term survival with contralateral prophylactic mastectomy among young women.

BACKGROUND: Despite mixed survival data, the utilization of contralateral prophylactic mastectomy (CPM) for the prevention of a contralateral breast cancer (CBC) has increased significantly over the last 15 years, especially among women less than 40. We set out to look at our own experience with CPM, focusing on outcomes in women less than 40, the sub-population with the highest cumulative lifetime risk of developing CBC. With an extended follow-up, we hoped to demonstrate differences in the long-term disease free survival (DFS) and overall survival (OS) among groups who underwent the procedure (CPM) versus those that did not (NCPM). MATERIALS AND METHODS: We performed a retrospective review of all breast cancer patients less than age 40 diagnosed at Mount Sinai Medical Center between January 1, 1980 and December 31, 2010 (n=481). Among these patients, 42 were identified as having undergone CPM, while 195 were confirmed as being CPM-free during the observation period. A univariate and multivariate analyses were performed. RESULTS: The CPM group had a significantly higher percentage of patients who were diagnosed between 2000 and 2010 (95.2% vs 40%, p=0.0001). The CPM group had significantly smaller tumors (0-2cm.: 41.7% vs 24.8%, p=0.04). Among the entire group of patients, the overall five- and 10-year DFS were 81.3% and 73.3%, respectively. CPM was significantly associated [HR 2.35 (1.02, 5.41); p=0.046] with 10-year OS, although a similar effect was not observed for five-year OS. CONCLUSIONS: We found that CPM has increased dramatically over the last 15 years, especially among white women with locally advanced disease. In patients less than 40, who are thought to be at greatest cumulative risk of secondary breast cancer, CPM provided an OS advantage, regardless of genetics, tumor or patient characteristics, and which was only seen after 10 years of follow-up.

Novel Testing Enhances Irritable Bowel Syndrome Medical Management: The IMMINENT Study.

PRIMARY STUDY OBJECTIVE: To evaluate the economic utility of a fecal biomarker panel structured to suggest alternative, treatable diagnoses in patients with symptoms of irritable bowel syndrome (IBS) by quantifying, comparing, and contrasting health service costs between tested and non-tested patients. STUDY DESIGN: Retrospective, matched cohort study comparing direct medical costs for IBS patients undergoing fecal biomarker testing with those of matched control subjects. METHODS: We examined de-identified medical and pharmacy claims of a large American pharmacy benefit manager to identify plan members who underwent panel testing, were eligible for covered benefits for at least 180 days prior to the test date, and had data available for 30, 90, and 365 days after that date. We used propensity score matching to develop population-based control cohorts for each tested cohort, comprised of records with IBS-related diagnoses but for which panel testing was not performed. Primary outcome measures were diagnostic and medical services costs as determined from claims data. RESULTS: Two hundred nine records from tested subjects met inclusion criteria. The only significant baseline differences between groups were laboratory costs, which were significantly higher in each tested cohort. At each follow-up time point, total medical and gastrointestinal procedural costs were significantly higher in non-tested cohorts. Within tested cohorts, costs declined significantly from baseline, while costs rose significantly in non-tested control cohorts; these differences were also significant between groups at each time point. CONCLUSIONS: Structured fecal biomarker panel testing was associated with significantly lower medical and gastrointestinal procedural costs in this study of patients with IBS symptoms.

Association between energy intake and viewing television, distractibility, and memory for advertisements.

BACKGROUND: The effect of television viewing (TVV) with and without advertisements (ads) on energy intake is unclear. OBJECTIVE: The objectives were to test 1) the effect of TVV, with and without ads, on energy intake compared with a control and reading condition and 2) the association of distractibility and memory for ads with energy intake and body weight. DESIGN: Forty-eight (26 female) adults (age: 19-54 y) with a body mass index (in kg/m(2)) of 20-35 completed this laboratory-based study. All participants completed 4 buffet-style meals in random order in the following conditions: 1) control, 2) while reading, 3) while watching TV with food and nonfood ads (TV-ads), and 4) while watching TV with no ads (TV-no ads). Energy intake was quantified by weighing foods. Distractibility and memory for ads in the TV-ads condition were quantified with a norm-referenced test and recognition task, respectively. RESULTS: Repeated-measures analysis of variance indicated that energy and macronutrient intake did not differ significantly among the 4 conditions (P > 0.65). Controlling for sex, memory for ads was associated with body weight (r = 0.36, P < 0.05) and energy intake but only when viewing TV (r = 0.39, P < 0.05 during the TV-no ads condition, and r = 0.29, P = 0.06 during the TV-ads condition). Controlling for sex, distractibility was associated with body weight (r = 0.36, P < 0.05) but not energy intake. Distractibility, however, accounted for 13% of the variance in men's energy intake (P = 0.11). CONCLUSIONS: TVV did not affect energy intake, but individual characteristics (memory for ads) were associated with body weight and energy intake in certain conditions. These characteristics should be considered in food intake and intervention studies.

Metabolically favorable remodeling of human adipose tissue by human adenovirus type 36.

OBJECTIVE: Experimental infection of rats with human adenovirus type 36 (Ad-36) promotes adipogenesis and improves insulin sensitivity in a manner reminiscent of the pharmacologic effect of thiozolinediones. To exploit the potential of the viral proteins as a therapeutic target for treating insulin resistance, this study investigated the ability of Ad-36 to induce metabolically favorable changes in human adipose tissue. RESEARCH DESIGN AND METHODS: We determined whether Ad-36 increases glucose uptake in human adipose tissue explants. Cell-signaling pathways targeted by Ad-36 to increase glucose uptake were determined in the explants and human adipose-derived stem cells. Ad-2, a nonadipogenic human adenovirus, was used as a negative control. As a proof of concept, nondiabetic and diabetic subjects were screened for the presence of Ad-36 antibodies to ascertain if natural Ad-36 infection predicted improved glycemic control. RESULTS: Ad-36 increased glucose uptake by adipose tissue explants obtained from nondiabetic and diabetic subjects. Without insulin stimulation, Ad-36 upregulated expressions of several proadipogenic genes, adiponectin, and fatty acid synthase and reduced the expression of inflammatory cytokine macrophage chemoattractant protein-1 in a phosphotidylinositol 3-kinase (PI3K)-dependent manner. In turn, the activation of PI3K by Ad-36 was independent of insulin receptor signaling but dependent on Ras signaling recruited by Ad-36. Ad-2 was nonadipogenic and did not increase glucose uptake. Natural Ad-36 infection in nondiabetic and diabetic subjects was associated with significantly lower fasting glucose levels and A1C, respectively. CONCLUSIONS: Ad-36 proteins may provide novel therapeutic targets that remodel human adipose tissue to a more metabolically favorable profile.

Quantifying genomic variation at the individual level: putting the "person" in personalized medicine.

This project evaluates how the Rasch measurement framework can be used 1) to construct and interpret individualized genomic measures and fit statistics from nominal single nucleotide polymorphism (SNP) data and 2) to identify interaction patterns that are relevant to person-specific disease risk assessment, case management, and prevention.

Effect of endothelin 1 genotype on blood pressure is dependent on physical activity or fitness levels.

Contributions of the DNA sequence variation at the endothelin 1 locus to the risk of hypertension and to endurance training-induced changes in blood pressure were investigated in the Aerobics Center Longitudinal Study and the Health, Risk Factors, Exercise Training and Genetics Family Study cohorts. We identified 586 normotensive control subjects and 607 incident hypertensive case subjects from the Aerobics Center Longitudinal Study cohort (all whites) who were normotensive and healthy at their first clinic visit. The case subjects were diagnosed with hypertension during an average follow-up of 9.5 years, whereas the control subjects remained normotensive. The allele and genotype frequencies of 5 endothelin 1 haplotype tagging single nucleotide polymorphisms did not differ significantly between the case and control subjects. However, we observed a significant (P=0.0025) interaction between the endothelin 1 rs5370 (G/T; Lys198Asn) genotype and cardiorespiratory fitness level on the risk of hypertension: among low-fit subjects, the rs5370 minor allele (T; 198Asn) was associated with higher risk of hypertension (odds ratio: 1.95; 95% CI: 1.36 to 2.81; P=0.0003), whereas the risk did not differ among genotypes in high-fit subjects. In the white Health, Risk Factors, Exercise Training and Genetics subjects (N=480), the rs5370 T allele was associated with blunted systolic blood pressure (P=0.0046) and pulse pressure (P=0.0016) responses to a 20-week endurance training program. The Lys198Asn variant of the endothelin 1 locus is associated with blood pressure phenotypes in whites. However, the expression of the genotype effect is modulated by physical activity or cardiorespiratory fitness level. Our study provides an illustrative example of how physical activity and fitness level modifies the associations between a candidate gene and outcome phenotype.

Hereditary evaluation of multiple developmental abnormalities in the Havanese dog breed.

The Havanese is a toy breed that presents with a wide range of developmental abnormalities. Skeletal defects, particularly osteochondrodysplasia (OCD), are the most frequently observed anomalies. Cataracts, liver shunts, heart murmurs, and missing incisors are also common in this breed. Estimates of heritability and complex segregation analyses were carried out to evaluate modes of transmission for these abnormalities. A moderate heritability was identified and evidence for a single major locus was found. Novel statistical analysis methods were used to identify four traits that co-segregate: cataracts, hepatic abnormalities, OCD, and cardiac abnormalities. A canine-specific microarray was used to identify changes in gene expression in the liver that accompany the aforementioned developmental problems. One hundred and thirteen genes were found to be differentially regulated in the Havanese.

Human adenovirus 36 induces adiposity, increases insulin sensitivity, and alters hypothalamic monoamines in rats.

OBJECTIVE: Human adenovirus 36 (Ad-36) increases adiposity and reduces serum lipids in chicken, mouse, and non-human primate models, and it is linked to obesity in sero-epidemiological studies in humans. Involvement of the central nervous system (CNS) or adipose tissue in the mechanism of Ad-36-induced adiposity is unknown. The effects of Ad-36 on adiposity and on the neuroendocrine system were investigated in a rat model. RESEARCH METHODS AND PROCEDURES: Five-week-old male Wistar rats were inoculated intraperitoneally with Ad-36 or medium. RESULTS: Despite similar food intakes, infected rats attained significantly greater body weight and fat pad weight by 30 weeks post-inoculation. Epididymal-inguinal, retroperitoneal, and visceral fat pad weights of the infected group were greater by 60%, 46%, and 86%, respectively (p < 0.00001). The fasting serum insulin level and homeostasis model assessment index indicated greater insulin sensitivity in the infected group. Visceral adipose tissue expression of glycerol 3-phosphate dehydrogenase, peroxisome proliferator-activated receptor gamma, and CCAAT/enhancer-binding protein alpha and beta was markedly increased in the infected animals compared with controls. Ad-36 decreased norepinephrine levels significantly in the paraventricular nucleus in infected vs. control rats (mean +/- standard error, 8.9 +/- 1.1 vs. 12.8 +/- 1.2 pg/microg protein; p < 0.05). Ad-36 markedly decreased serum corticosterone in infected vs. control rats (mean +/- standard error, 97 +/- 41.0 vs. 221 +/- 111 ng/mL; p < 0.005). DISCUSSION: The results suggest that the pro-adipogenic effect of Ad-36 may involve peripheral as well as central effects. The male Wistar rat is a good model for the elucidation of metabolic and molecular mechanisms of Ad-36-induced adiposity.