Depressive Symptoms are Associated With C-Reactive Protein in Older Adults With Obesity.

OBJECTIVES: To test the hypothesis that depressive symptoms vary with high-sensitivity C-reactive protein (hs-CRP), among older adults with obesity. METHODS: This was a cross-sectional, secondary analysis of baseline data from two related lifestyle intervention trials. The study sample comprises 148 consecutively recruited, community-dwelling older adults (age >=65 years) without severe psychiatric illness and with body mass index >=30 kg/m2. Logarithmically transformed GDS was analyzed as the dependent variable. Independent variables included log-transformed hs-CRP and covariates: sex, age, and concurrent use of antidepressant medication at baseline. An additional analysis was performed using binary conversion of the GDS scores, wherein a cutoff score of 5 was considered positive for depressive symptoms. RESULTS: Sample mean GDS score was 2.7 (SD 3.0, range 0 - 14). A significant multivariate model of GDS scores (R2 = .089, F = 3.5, P = .010) revealed log-transformed hs-CRP (P = .017) and male sex (P = .012) as associated with depressive symptoms. Supplemental analysis demonstrated associations between depressive symptoms and log-transformed hs-CRP (OR 2.17, P = .001) and between depressive symptoms and male sex (OR 3.78, P = .013). Univariate logistic regression found hs-CRP to be associated with depressive symptoms. CONCLUSIONS: In older adults with obese BMI, male sex and higher hs-CRP are associated with depression, even in a group with relatively minimal depressive symptoms. Hs-CRP may offer clinical utility as a biomarker for depression among older adults with obese BMI, even among those with non-severe psychiatric symptomatology.

Potential for repurposing oral hypertension/diabetes drugs to decrease asthma risk in obesity.

OBJECTIVE: Risk for asthma in the overweight/obese may be mediated by adiponectin and peroxisome proliferator activated receptor pathways and may be reduced by the use of oral drugs impacting these pathways, such as angiotensin converting enzyme inhibitors (ACE-I), thiazolidinediones (TZD), and angiotensin receptor blockers (ARB). Our study objective was to determine whether ACE-I, TZD, and/or ARB use in overweight/obese adults with diabetes mellitus and/or hypertension is associated with a lower risk for incident asthma. METHODS: Using an existing cohort of American veterans, we performed a longitudinal data analysis over 15 years. Exposure was defined by the prescription pickup of ACE-I, TZD, and/or ARB for at least 4 weeks. The outcome, time until new-onset of clinician-diagnosed asthma, was studied using survival analysis. The propensity scoring method controlled for treatment selection bias. RESULTS: 2.83 million eligible veterans, including 77,278 with incident asthma, were studied. As compared to those unexposed, the use of ACE-I alone, TZD alone, or their combinations were each associated with decreased risk for incident asthma (hazard ratios of 0.88, 0.74, and 0.20, respectively; p < 0.001 for all analyses in the fully adjusted statistical models). TZD lowered the risk among racial/ethnic minority subjects more than among White participants (p < 0.001). On the other hand, ARB use alone or in combination with TZD was associated with a higher risk for incident asthma. CONCLUSIONS: Use of ACE-I and/or TZD was associated with a lower risk for incident asthma in overweight/obese patients with diabetes mellitus and/or hypertension.

One-Year Mean A1c of > 7% is Associated with Poor Bone Microarchitecture and Strength in Men with Type 2 Diabetes Mellitus.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is associated with normal or slightly elevated bone mineral density (BMD) but paradoxically increased fracture risk. Although multiple mechanisms have been proposed to explain this observation, one thing is clear from prior studies, T2DM is associated with poor bone quality rather than a defect in bone quantity. The objective of our study is to evaluate the effect of longitudinal glycemic control on bone quality and bone turnover in men with T2DM. METHODS: This was a secondary analysis of baseline data from 169 male participants, aged 35-65 in 3 clinical trials. Participants were grouped according to the average of all their A1C measurements between 9 and 15 months prior to study entry (group 1: no T2DM, group 2: T2DM with A1C ≤ 7%, group 3: T2DM with A1C > 7%). At study entry serum osteocalcin and C-terminal telopeptide of type 1 collagen (CTx) were measured by ELISA, and testosterone and estradiol by liquid-chromatography/mass-spectrometry. Areal BMD, trabecular bone score and body composition were measured by dual-energy X-ray absorptiometry while volumetric BMD, bone microarchitecture, and bone strength were assessed by high-resolution peripheral quantitative computed tomography. RESULTS: At the tibia, trabecular separation was higher and trabecular number was significantly lower in group 3 compared to both groups 2 and 1, even after adjustments for covariates (p = 0.02 for both). Bone strength indices at the tibia such as stiffness and failure load were lowest in group 3, the difference being significant when compared to group 1 (p = 0.01, p = 0.009 respectively) but not to group 2, after adjustments for covariates. Bone turnover markers (osteocalcin and CTx) were significantly lower in group 3 relative to group 1, with CTx also being significantly lower in group 3 compared with group 2 (p < 0.001, p = 0.001 respectively). CONCLUSION: Poor glycemic control over the course of a year in men with T2DM is associated with poorer bone microarchitecture and strength, and reduced bone turnover. Conversely, good glycemic control in the setting of T2DM appears to attenuate this observed impairment in bone quality.

Differential effects of CD20+ B cells and PD-L1+ immune cells on pathologic complete response and outcome: comparison between inflammatory breast cancer and locally advanced breast cancer patients.

PURPOSE: This study evaluated epidemiologic and immune factors associated with pathologic complete response (pCR), breast cancer-specific survival (BCSS) and disease-free survival (DFS) outcomes in inflammatory (IBC) and locally advanced breast cancer (LABC) patients. METHODS: Tumor-infiltrating lymphocytes (TILs) and CD20+ B-cell frequencies (CD20+), and PD-L1 expression on tumor (PD-L1+carcinoma cells) and immune (PD-L1+TILs) cells were analyzed by immunohistochemistry along with clinicopathologic factors as modifiers of pCR and outcomes in 221 IBC and 162 LABC patients. Analysis included Kaplan-Meier curves and Cox proportional hazard models. RESULTS: IBC and LABC display similar levels of TILs, CD20+, and combined CD20+ and PD-L1+TILs (CD20+PD-L1+TILs), while LABC contained more PD-L1+TILs and PD-L1+ carcinoma cells. Absence of lymphovascular involvement, high TILs, PD-L1+ carcinoma cells, and combined CD20+ and PD-L1+ carcinoma cells correlated with pCR in IBC and LABC patients. High PD-L1+TILs correlated with pCR only in LABC; less lymph node involvement at diagnosis, CD20+ and CD20+PD-L1+TILs correlated with pCR only in IBC (P < 0.04, all comparisons). Achievement of pCR in IBC and LABC patients correlated with BCSS and DFS (P < 0.02). In multivariate analyses, pCR remained an independent prognostic factor of improved DFS in IBC and LABC patients, but of BCSS in only LABC. CD20+PD-L1+TILs remained an independent prognostic factor of improved DFS and BCSS only in IBC. CONCLUSION: CD20+PD-L1+TILs are an independent prognostic biomarker of improved outcomes in IBC, but not LABC. Selecting IBC patients by CD20 and PD-L1 status could stratify patients and potentially identify those in whom activating CD20 agents and anti-PD-1/PD-L1 therapy could be explored.

Aerobic or Resistance Exercise, or Both, in Dieting Obese Older Adults.

BACKGROUND: Obesity causes frailty in older adults; however, weight loss might accelerate age-related loss of muscle and bone mass and resultant sarcopenia and osteopenia. METHODS: In this clinical trial involving 160 obese older adults, we evaluated the effectiveness of several exercise modes in reversing frailty and preventing reduction in muscle and bone mass induced by weight loss. Participants were randomly assigned to a weight-management program plus one of three exercise programs - aerobic training, resistance training, or combined aerobic and resistance training - or to a control group (no weight-management or exercise program). The primary outcome was the change in Physical Performance Test score from baseline to 6 months (scores range from 0 to 36 points; higher scores indicate better performance). Secondary outcomes included changes in other frailty measures, body composition, bone mineral density, and physical functions. RESULTS: A total of 141 participants completed the study. The Physical Performance Test score increased more in the combination group than in the aerobic and resistance groups (27.9 to 33.4 points [21% increase] vs. 29.3 to 33.2 points [14% increase] and 28.8 to 32.7 points [14% increase], respectively; P=0.01 and P=0.02 after Bonferroni correction); the scores increased more in all exercise groups than in the control group (P<0.001 for between-group comparisons). Peak oxygen consumption (milliliters per kilogram of body weight per minute) increased more in the combination and aerobic groups (17.2 to 20.3 [17% increase] and 17.6 to 20.9 [18% increase], respectively) than in the resistance group (17.0 to 18.3 [8% increase]) (P<0.001 for both comparisons). Strength increased more in the combination and resistance groups (272 to 320 kg [18% increase] and 288 to 337 kg [19% increase], respectively) than in the aerobic group (265 to 270 kg [4% increase]) (P<0.001 for both comparisons). Body weight decreased by 9% in all exercise groups but did not change significantly in the control group. Lean mass decreased less in the combination and resistance groups than in the aerobic group (56.5 to 54.8 kg [3% decrease] and 58.1 to 57.1 kg [2% decrease], respectively, vs. 55.0 to 52.3 kg [5% decrease]), as did bone mineral density at the total hip (grams per square centimeter; 1.010 to 0.996 [1% decrease] and 1.047 to 1.041 [0.5% decrease], respectively, vs. 1.018 to 0.991 [3% decrease]) (P<0.05 for all comparisons). Exercise-related adverse events included musculoskeletal injuries. CONCLUSIONS: Of the methods tested, weight loss plus combined aerobic and resistance exercise was the most effective in improving functional status of obese older adults. (Funded by the National Institutes of Health; LITOE ClinicalTrials.gov number, NCT01065636 .).

Army and Navy ECHO Pain Telementoring Improves Clinician Opioid Prescribing for Military Patients: an Observational Cohort Study.

BACKGROUND: Opioid overdose deaths occur in civilian and military populations and are the leading cause of accidental death in the USA. OBJECTIVE: To determine whether ECHO Pain telementoring regarding best practices in pain management and safe opioid prescribing yielded significant declines in opioid prescribing. DESIGN: A 4-year observational cohort study at military medical treatment facilities worldwide. PARTICIPANTS: Patients included 54.6% females and 46.4% males whose primary care clinicians (PCCs) opted to participate in ECHO Pain; the comparison group included 39.9% females and 60.1% males whose PCCs opted not to participate in ECHO Pain. INTERVENTION: PCCs attended 2-h weekly Chronic Pain and Opioid Management TeleECHO Clinic (ECHO Pain), which included pain and addiction didactics, case-based learning, and evidence-based recommendations. ECHO Pain sessions were offered 46 weeks per year. Attendance ranged from 1 to 3 sessions (47.7%), 4-19 (32.1%, or > 20 (20.2%). MAIN MEASURES: This study assessed whether clinician participation in Army and Navy Chronic Pain and Opioid Management TeleECHO Clinic (ECHO Pain) resulted in decreased prescription rates of opioid analgesics and co-prescribing of opioids and benzodiazepines. Measures included opioid prescriptions, morphine milligram equivalents (MME), and days of opioid and benzodiazepine co-prescribing per patient per year. KEY RESULTS: PCCs participating in ECHO Pain had greater percent declines than the comparison group in (a) annual opioid prescriptions per patient (- 23% vs. - 9%, P < 0.001), (b) average MME prescribed per patient/year (-28% vs. -7%, p < .02), (c) days of co-prescribed opioid and benzodiazepine per opioid user per year (-53% vs. -1%, p < .001), and (d) the number of opioid users (-20.2% vs. -8%, p < .001). Propensity scoring transformation-adjusted results were consistent with the opioid prescribing and MME results. CONCLUSIONS: Patients treated by PCCs who opted to participate in ECHO Pain had greater declines in opioid-related prescriptions than patients whose PCCs opted not to participate.

Effect of prenatal EPA and DHA on maternal and cord blood insulin sensitivity: a secondary analysis of the mothers, omega 3, and mental health study.

BACKGROUND: We sought to determine whether prenatal supplementation with the omega-3 fatty acids eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) would increase markers of insulin sensitivity in maternal or cord blood compared with placebo supplementation. A secondary aim was to evaluate the association of serum EPA and DHA fractions with adiponectin, leptin and the adiponectin:leptin ratio (ALR). We hypothesized that omega-3 fatty acid supplementation would increase markers of insulin sensitivity in maternal and umbilical cord plasma. METHODS: We analyzed stored plasma samples collected from a prior 3-arm prospective, double-blinded, randomized controlled trial in which 126 women with singleton pregnancies between 12- and 20-weeks' gestation were randomized to receive: 1) an EPA-rich fish oil supplement, 2) a DHA-rich fish oil supplement, or 3) a soy oil placebo. Maternal venous blood samples were collected at 12-20 weeks gestation (before supplementation) and at 34-36 weeks gestation. At delivery, cord blood was collected. Samples were analyzed using sandwich enzyme-linked immunosorbent assay kits to quantify leptin and adiponectin levels which were utilized to calculate the ALR, a proxy measure for insulin sensitivity. RESULTS: We found no difference in adiponectin, leptin, and the ALR between the treatment and placebo groups at baseline, after supplementation, or in umbilical cord blood. In regression analyses, higher maternal serum DHA fraction was associated with increased ALR before (p = 0.01) and after (p = 0.04) DHA supplementation. There was no association of EPA fraction with any measure of insulin sensitivity. Cord blood DHA fraction was significantly associated with cord plasma leptin (p = 0.02). Early pregnancy BMI was significantly associated with maternal leptin levels at baseline and in late pregnancy (p < 0.001) and was inversely associated with the ALR (p < 0.001). The ALR decreased significantly between the early and late pregnancy visits (p < 0.001). Pregnancy weight gain was inversely associated with the ALR (P. < 0.02). CONCLUSIONS: EPA- and DHA- rich fish oil supplementation had no effect on plasma markers of insulin sensitivity. However, maternal serum DHA fraction was significantly associated with markers of insulin sensitivity. TRIAL REGISTRATION: https://clinicaltrials.gov/, registration number NCT00711971, 7/7/2008.

Progression of atherosclerosis versus arterial stiffness with age within and between arteries in systemic lupus erythematosus.

The progression of atherosclerosis versus arterial stiffness with age within and between arteries has not been defined. Systemic lupus erythematosus (SLE) is a human model of accelerated arterial disease that may permit this determination. 76 SLE patients (69 women, age 37 ± 12 years) and 26 age-and-sex-matched controls (22 women, age 34 ± 11 years) underwent transesophageal echocardiography and carotid ultrasonography for assessment of atherosclerosis [plaques and intima-media thickening (IMT)] and arterial stiffness [increased pressure-strain elastic modulus (PSEM)] of the descending thoracic aorta and carotid arteries. Since IMT is highly associated with plaques, IMT was used as a marker of atherosclerosis to assess its progression in relation with age and PSEM. Aortic and carotid plaques, IMT, and PSEM were greater in patients than in controls (all p ≤ 0.05). Within the aorta and within the carotid arteries, the average percent increases per decade of age for IMT versus PSEM were similar in patients (8.55% versus 9.33% and 3.39% versus 2.46%, respectively) and controls (5.53% versus 6.60% and 4.75% versus 3.49%, respectively) (all p ≥ 0.58). However, in SLE patients, the average percent increases per decade of age for IMT and PSEM were higher in the aorta than in the carotid arteries (8.55% and 9.33% versus 3.39% and 2.46%, respectively, both p ≤ 0.03). In patients with SLE, atherosclerosis and arterial stiffness progress with age parallel to each other within arteries, but divergently between arteries with different anatomy and hemodynamics.

ENDO ECHO IMPROVES PRIMARY CARE PROVIDER AND COMMUNITY HEALTH WORKER SELF-EFFICACY IN COMPLEX DIABETES MANAGEMENT IN MEDICALLY UNDERSERVED COMMUNITIES.

OBJECTIVE: To determine whether participation in a multidisciplinary telementorship model of healthcare delivery improves primary care provider (PCP) and community health worker (CHW) confidence in managing patients with complex diabetes in medically underserved regions. METHODS: We applied a well-established healthcare delivery model, Project ECHO (Extension for Community Healthcare Outcomes), to the management of complex diabetes (Endo ECHO) in medically underserved communities. A multidisciplinary team at Project ECHO connected with PCPs and CHWs at 10 health centers across New Mexico for weekly videoconferencing virtual clinics. Participating PCPs and CHWs presented de-identified patients and received best practice guidance and mentor-ship from Project ECHO specialists and network peers. A robust curriculum was developed around clinical practice guidelines and presented by weekly didactics over the ECHO network. After 2 years of participation in Endo ECHO, PCPs and CHWs completed self-efficacy surveys comparing confidence in complex diabetes management to baseline. RESULTS: PCPs and CHWs in rural New Mexico reported significant improvement in self-efficacy in all measures of complex diabetes management, including PCP ability to serve as a local resource for other healthcare providers seeking assistance in diabetes care. Overall self-efficacy improved by 130% in CHWs ( P<.0001) and by 60% in PCPs ( P<.0001), with an overall large Cohen's effect size. CONCLUSION: Among PCPs and CHWS in rural, medically underserved communities, participation in Endo ECHO for 2 years significantly improved confidence in complex diabetes management. Application of the ECHO model to complex diabetes care may be useful in resource-poor communities with limited access to diabetes specialist services. ABBREVIATIONS: CHW = community health worker; CME = Continuing Medical Education; ECHO = Extension for Community Healthcare Outcomes; FQHC = federally qualified health center; PCP = primary care provider.

Effect of prenatal EPA and DHA on maternal and umbilical cord blood cytokines.

BACKGROUND: Investigators have hypothesized that omega-3 fatty acid supplementation may modulate the immune response. However, available evidence is conflicting. We performed this study to investigate the effect of prenatal eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-rich fish oil supplementation on maternal and fetal cytokine production. METHODS: This study is a secondary analysis of a randomized controlled trial designed to assess whether prenatal EPA- or DHA-rich fish oil supplementation would prevent perinatal depressive symptoms among women at risk. Enrolled participants received EPA-rich fish oil (1060 mg EPA plus 274 mg DHA), DHA-rich fish oil (900 mg DHA plus 180 mg EPA) or soy oil placebo. Maternal venous blood was collected at enrollment (12-20 weeks gestation) and after supplementation (34-36 weeks gestation). Umbilical cord blood was collected at delivery. We analyzed stored plasma specimens for 16 human cytokines using multiplex immunoassays. Maternal and cord blood cytokine levels were compared among the treatment groups. Associations of serum DHA and EPA with maternal and cord blood cytokines were explored via regression analysis. RESULTS: We enrolled 126 women, of whom 118 completed the trial. Prenatal supplementation with EPA-rich fish oil significantly lowered maternal IL6, IL15, and TNFα concentrations. However, supplementation with DHA-rich fish oil had no significant effect on maternal cytokine profiles. Maternal serum DHA fraction was significantly associated with IL1α, and maternal serum DHA and EPA fractions were significantly associated with IL 10 concentrations after supplementation. Compared with placebo, supplementation with EPA- or DHA-rich fish oils had no significant effect on cord blood cytokine concentrations. CONCLUSIONS: Prenatal supplementation with EPA-rich fish oil significantly reduced levels of several inflammatory cytokines in maternal plasma, while prenatal DHA-rich fish oil had no significant effect on cytokine concentrations. Supplementation with EPA- and DHA- rich fish oil had no significant effect on umbilical cord blood cytokine concentrations. TRIAL REGISTRATION: Clinical Trial Registration: registration number NCT00711971 7/7/2008.

Correlation of neurocognitive function and brain lesion load on magnetic resonance imaging in systemic lupus erythematosus.

Neurocognitive dysfunction and brain injury on magnetic resonance imaging (MRI) are common in patients with systemic lupus erythematosus (SLE) and are associated with increased morbidity and mortality. However, brain MRI is expensive, is restricted by payers, and requires high expertise. Neurocognitive assessment is an easily available, safe, and inexpensive clinical tool that may select patients needing brain MRI. In this cross-sectional and controlled study, 76 SLE patients (69 women, age 37 ± 12 years) and 26 age and gender-matched healthy subjects (22 women, age 34 ± 11 years) underwent assessment of attention, memory, processing speed, executive function, motor function, and global neurocognitive function. All subjects underwent brain MRI with T1-weighted, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging. Hemispheric and whole brain lesion load in cm3 were determined using semi-automated methods. Neurocognitive z-scores in all clinical domains were significantly lower and whole brain and right and left hemispheres brain lesion load were significantly greater in patients than in controls (all p ≤ 0.02). There was significant correlation between neurocognitive z-scores in all domains and whole brain lesion load: processing speed (r = - 0.46; p < 0.0001), attention (r = - 0.42; p < 0.001), memory (r = - 0.40; p = 0.0004), executive function (r = - 0.25; p = 0.03), motor function (r = - 0.25; p = 0.05), and global neurocognitive function (r = - 0.38; p = 0.006). Similar correlations were found for brain hemisphere lesion loads (all p ≤ 0.05). These correlations were strengthened when adjusted for glucocorticoid therapy and SLE disease activity index. Finally, global neurocognitive z-score and erythrosedimentation rate were the only independent predictors of whole brain lesion load (both p ≤ 0.007). Neurocognitive measures and brain lesion load are worse in SLE patients than in controls. In SLE patients, neurocognitive z-scores correlate negatively with and independently predict brain lesion load. Therefore, neurocognitive testing may be an effective clinical tool to select patients needing brain MRI.

Rapid decline in lung function is temporally associated with greater metabolically active adiposity in a longitudinal study of healthy adults.

RATIONALE: Adiposity is associated with low lung function, but the longitudinal relationship between lung function and adiposity is inadequately studied. OBJECTIVE: To examine the bidirectional longitudinal associations between rapid decline in lung function and adiposity phenotypes in healthy adults. METHODS: This secondary analysis used a 25-year longitudinal dataset from the Coronary Artery Risk Development in Young Adults (CARDIA) study that enrolled 5115 participants. MEASUREMENTS: In the first analysis, metabolic syndrome at or before CARDIA year (Y) 10 (Y10) was the predictor, and subsequent rapid decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1) between Y10 and Y20 was the outcome. In the second analysis, rapid decline was the predictor, and incident metabolic syndrome at Y20 and/or Y25 was the outcome. In the third analysis, rapid decline was the predictor, and subsequent CT-assessed regional fat depots at Y25 were the outcome. RESULTS: Metabolic syndrome at or before Y10 is temporally associated with rapid decline in FVC between Y10 and Y20 (adjusted p=0.04), but this association was explained by body mass index (BMI) at Y10. Rapid decline in FVC or FEV1 is temporally associated with greater incident metabolic syndrome at Y20 and/or Y25 (adjusted OR 2.10 (1.69, 2.61); p<0.001, and 1.56 (1.26, 1.94); p<0.001, respectively) and greater CT-assessed intrathoracic visceral adiposity at Y25 (adjusted standardised ß 0.09; p<0.001 for both analyses). These associations were not explained by BMI levels prior to the outcome measurement. CONCLUSIONS: Healthy adults with rapid decline in lung function are at risk for developing metabolic syndrome and for disproportionate accumulation of intrathoracic visceral fat. Metabolic abnormalities may be an early extrapulmonary manifestation of lung impairment that may be preventable by improving lung health.

Hypogonadal Men with Higher Body Mass Index have Higher Bone Density and Better Bone Quality but Reduced Muscle Density.

Although hypogonadism is a risk factor for bone loss and fractures, the different etiopathophysiology and hormonal profile of classical and obesity-induced hypogonadism may lead to differences in musculoskeletal profile. This is a cross-sectional study of hypogonadal men between 40 and 74 years old. Our outcomes include: areal bone mineral density (aBMD) and body composition by dual-energy X-ray absorptiometry; volumetric BMD (vBMD) and soft tissue composition of the tibia by peripheral quantitative computed tomography. Fracture risk assessment tool (FRAX) scores were evaluated. Testosterone, estradiol, luteinizing hormone, follicle stimulating hormone, sex hormone-binding globulin, C-telopeptide, osteocalcin, and sclerostin were measured. We divided the population into subgroups of BMI: group 1: BMI < 30; group 2: BMI ≥30 to <35 and group 3: BMI ≥ 35 kg/m2. One-hundred five men were enrolled. Spine and hip aBMD, and total and trabecular vBMD at the 4% tibia significantly increased with increasing BMI. Cortical thickness (330.7 ± 53.2, 343.3 ± 35.4, and 358.7 ± 38.2 mm, p = 0.04; groups 1, 2 and 3, respectively) and cortical area (5.3 ± 0.7, 5.5 ± 0.6, and 5.7 ± 0.6 mm, p = 0.01; groups 1, 2 and 3, respectively) at 38% tibia increased with increasing BMI. While absolute lean mass increased with increasing BMI, % lean mass and muscle density (70.2 ± 5.0, 71.3 ± 6.4, and 67.1 ± 5.1 mg/cm3; groups 1, 2 and 3, respectively) were lowest in group 3. Although severely obese hypogondal men have better BMD and bone quality, they have reduced muscle density, the significance of which remains to be determined.

Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible airflow limitation in response to inhalation of noxious stimuli, such as cigarette smoke. However, only 15-20 % smokers manifest COPD, suggesting a role for genetic predisposition. Although genome-wide association studies have identified common genetic variants that are associated with susceptibility to COPD, effect sizes of the identified variants are modest, as is the total heritability accounted for by these variants. In this study, an extreme phenotype exome sequencing study was combined with in vitro modeling to identify COPD candidate genes. RESULTS: We performed whole exome sequencing of 62 highly susceptible smokers and 30 exceptionally resistant smokers to identify rare variants that may contribute to disease risk or resistance to COPD. This was a cross-sectional case-control study without therapeutic intervention or longitudinal follow-up information. We identified candidate genes based on rare variant analyses and evaluated exonic variants to pinpoint individual genes whose function was computationally established to be significantly different between susceptible and resistant smokers. Top scoring candidate genes from these analyses were further filtered by requiring that each gene be expressed in human bronchial epithelial cells (HBECs). A total of 81 candidate genes were thus selected for in vitro functional testing in cigarette smoke extract (CSE)-exposed HBECs. Using small interfering RNA (siRNA)-mediated gene silencing experiments, we showed that silencing of several candidate genes augmented CSE-induced cytotoxicity in vitro. CONCLUSIONS: Our integrative analysis through both genetic and functional approaches identified two candidate genes (TACC2 and MYO1E) that augment cigarette smoke (CS)-induced cytotoxicity and, potentially, COPD susceptibility.

A model for conditional male trimorphisms.

Conditional dimorphisms are widespread in color, morphology, behavior, and life history. Such traits have been successfully modeled in game theory as conditional strategies, and in quantitative genetics as threshold traits. Conditional trimorphisms have recently been unveiled, and here we combine the rock-paper-scissors (RPS) model of game theory and the environmental threshold (ET) model of quantitative genetics to model trimorphisms that are environmentally induced and result from the expression of two thresholds. We investigated the tactic fitness structure for maintenance of alternative reproductive tactics in scarab dung beetles that constitute the first known examples of conditional male trimorphism. We parameterized a novel ternary fitness landscape that explains how conditional male trimorphism in these beetles can be maintained. We tracked changes in tactic frequencies in a wild population of Phanaeus triangularis and detected fitness intransitivity consistent with RPS dynamics. Quantitative predictions of our model compare favorably with corresponding observed parameters. The ternary landscape further reveals how geographic populations of these beetles can evolve between conditional trimorphism and dimorphism. The ternary model also suggests that polyphenic systems could potentially evolve between conditional and purely genetic mediation.

Sexual function changes during pregnancy.

INTRODUCTION AND HYPOTHESIS: We describe changes in sexual activity and function among pregnant nulliparous women. METHODS: This secondary analysis evaluated sexual activity and function with the Female Sexual Function Index (FSFI) at baseline in the first (T1), second (T2) and early third (T3) trimester. Evaluation was repeated in T3 after 36 completed weeks of gestation. Data were assigned to the trimester in which they were collected and compared across trimesters. FSFI items were dichotomized into favorable and unfavorable responses. ANOVA and logistic regression models were used to compare values across trimesters, taking into account repeated measurements. Pair-wise comparisons of trimesters were done when there were significant overall differences. Significance was set at p < 0.05. We adjusted for baseline differences. RESULTS: Of 627 women, four did not give sexual function data. Baseline data were collected in 124 women in T1, 403 in T2, and 96 in early T3. Of these 623 women, 496 (80 %) gave data again in T3. The participants' mean age was 24.2 ± 5.1 years and 44.5 % were Hispanic. Rates of sexual activity (T1 94 %, T2 90 %, T3 77 %; p < 0.001) and mean FSFI scores decreased as pregnancy progressed (T1 26.5 ± 7.7, T2 25.6 ± 9.0, T3 21.5 ± 10.3; T1/T2 vs. T3, p < 0.001). Using the FSFI cut-off score for sexual dysfunction of 26.55, women in T3 were more likely to report dysfunction than women in T2 (57 % vs. 37 %, p < 0.001). For specific FSFI questions, the proportions of women reporting favorable responses did not change between T1 and T2 (all p > 0.05) and the proportions of women with a favorable response decreased for all questions between T2 and T3. CONCLUSIONS: As pregnancy progresses, women report poorer sexual function.

Pelvic floor symptoms and quality of life changes during first pregnancy: a prospective cohort study.

INTRODUCTION AND HYPOTHESIS: We describe pelvic floor function in nulliparous pregnant women. MATERIALS AND METHODS: Nulliparous midwifery patients completed the Incontinence Severity Index (ISI), Pelvic Floor Impact Questionnaire (PFIQ-7), Wexner Fecal Incontinence Scale (W), and answered questions about sexual activity and perineal pain at baseline during the first (T1), second (T2), or third trimester (T3) and repeated in late T3. They also underwent a Pelvic Organ Prolapse Quantification (POP-Q) exam at their baseline visit. Data were compared across trimesters. Analysis of variance (ANOVA) and logistic regression accounted for repeated measures and was controlled for age and education. RESULTS: We recruited 627 women. In T1, 124 women gave baseline data and completed questionnaires; in T2, 403; and in early T3, 96 (496 repeated questionnaires in later T3). Besides an increase in genital hiatus and perineal body (all adjusted p < .05), physical exam measures did not differ between trimesters. As pregnancy progressed, urinary incontinence (UI) (T1 = 33, T2 = 44, T3 = 69% women with ISI >0, all comparisons p < .02) and Incontinence Impact Questionnaire (IIQ-7) scores increased. Fecal incontinence (FI) increased (T1 = 8, T2 = 15, T3 = 16% from T2 to T3, p = .04); the Colorectal-Anal Impact Questionnaire (CRAIQ-7) scores did not. Perineal pain increased (T1 = 17, T2 = 18 and T3 = 40%, all adjusted p < .001), and sexual activity decreased (T1 = 94, T2 = 90, T3 = 77% sexually active, T1 vs T3 and T2 vs T3, p < .001) as pregnancy progressed. CONCLUSIONS: During pregnancy, women experience worsening UI, FI, and perineal pain. UI symptoms are associated with a negative impact on quality of life (QoL). Sexual activity decreased and POP-Q stage did not change.

Connective Tissue Growth Factor Promotes Pulmonary Epithelial Cell Senescence and Is Associated with COPD Severity.

The purpose of this study was to determine whether expression of connective tissue growth factor (CTGF) protein in chronic obstructive pulmonary disease (COPD) is consistent in humans and animal models of COPD and to investigate the role of this protein in lung epithelial cells. CTGF in lung epithelial cells of ex-smokers with COPD was compared with ex-smokers without COPD by immunofluorescence. A total of twenty C57Bl/6 mice and sixteen non-human primates (NHPs) were exposed to cigarette smoke (CS) for 4 weeks. Ten mice of these CS-exposed mice and eight of the CS-exposed NHPs were infected with H3N2 influenza A virus (IAV), while the remaining ten mice and eight NHPs were mock-infected with vehicle as control. Both mRNA and protein expression of CTGF in lung epithelial cells of mice and NHPs were determined. The effects of CTGF overexpression on cell proliferation, p16 protein, and senescence-associated ß-galactosidase (SA-ß-gal) activity were examined in cultured human bronchial epithelial cells (HBECs). In humans, CTGF expression increased with increasing COPD severity. We found that protein expression of CTGF was upregulated in lung epithelial cells in both mice and NHPs exposed to CS and infected with IAV compared to those exposed to CS only. When overexpressed in HBECs, CTGF accelerated cellular senescence accompanied by p16 accumulation. Both CTGF and p16 protein expression in lung epithelia are positively associated with the severity of COPD in ex-smokers. These findings show that CTGF is consistently expressed in epithelial cells of COPD lungs. By accelerating lung epithelial senescence, CTGF may block regeneration relative to epithelial cell loss and lead to emphysema.

The FTO gene is associated with a paradoxically favorable cardiometabolic risk profile in frail, obese older adults.

OBJECTIVE: Fat mass and obesity-associated (FTO) gene polymorphisms have been reported to be associated with differences in BMI, obesity, and type 2 diabetes. However, previous studies have been predominantly conducted in younger individuals across a spectrum of body weights, whereas little information is available on the older population. We examined the association of FTO gene polymorphisms with cardiometabolic risks among adults who were both obese (BMI≥30 kg/m) and older (age≥65 years). METHODS: A total of 165 frail, obese older adults were genotyped for FTO (rs9939609 and rs8050136) single nucleotide polymorphisms and studied for associations with body weight and body composition, components and prevalence of the metabolic syndrome, insulin response to an oral glucose tolerance test, and levels of adipocytokines (e.g. leptin) and vitamin D. RESULTS: Carriers of the A allele (CA/AA) of the FTO single nucleotide polymorphism rs8050136 had lower body weight, BMI, body fat, and trunk fat than those without the A allele (CC genotype; all P's<0.05). Moreover, genotype CA/AA was associated with lower levels of triglycerides and higher levels of high-density lipoprotein-cholesterol and carriers of this genotype showed a trend toward a lower waist circumference, resulting in a lower prevalence of metabolic syndrome than in CC genotype carriers. The insulin area under the curve during the oral glucose tolerance test was lower for genotype CA/AA. Despite the lower insulin levels, the glucose area under the curve was unchanged, resulting in a higher insulin sensitivity index. Leptin levels were also lower and adiponectin and 25-hydroxyvitamin levels tended to be higher for genotype CA/AA than for genotype CC. No differences were observed for rs9939609. CONCLUSION: Unlike the results from studies in younger individuals, the risk A allele may confer a favorable cardiometabolic risk profile in obese older adults, suggesting selective survival of obese adults into old age. If confirmed in a larger sample of surviving obese older adults, these findings may have implications in the clinical approach to obesity in this population.