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The development of new modes of diagnosis and targeted therapy for lung cancer is dependent on the identification of unique cell surface features on cancer cells and isolation of reagents that bind with high affinity and specificity to these biomarkers. We recently isolated a 20-mer peptide which binds to the lung adenocarcinoma cell line, H2009, from a phage-displayed peptide library. We show here that the cellular receptor for this peptide, TP H2009.1, is the uniquely expressed integrin, αvβ6, and the peptide binding to lung cancer cell lines correlates to integrin expression. The peptide is able to mediate cell-specific uptake of a fluorescent nanoparticle via this receptor. Expression of αvβ6 was assessed on 311 human lung cancer samples. The expression of this integrin is widespread in early-stage nonsmall cell lung carcinoma (NSCLC). Log-rank test and Cox regression analyses show that expression of this integrin is significantly associated with poor patient outcome. Preferential expression is observed in the tumors compared with the surrounding normal lung tissue. Our data indicate that αvβ6 is a prognostic biomarker for NSCLC and may serve as a receptor for targeted therapies. Thus, cell-specific peptides isolated from phage biopanning can be used for the discovery of cell surface biomarkers, emphasizing the utility of peptide libraries to probe the surface of a cell. [Cancer Res 2007;67(12):5889–95]

Supplementary Figure 1 from RASSF1A Polymorphism A133S Is Associated with Early Onset Breast Cancer in BRCA1/2 Mutation Carriers

Supplementary Figures 1-6 from A Peptide Selected by Biopanning Identifies the Integrin αvβ6 as a Prognostic Biomarker for Nonsmall Cell Lung Cancer

The tumor suppressor gene RASSF1A regulates cell cycle progression, apoptosis, and microtubule stability and is inactivated by promoter methylation in ∼50% of breast cancers. It has been shown previously that the polymorphism A133S in RASSF1A reduces its ability to regulate cell cycle progression and this polymorphism is associated with an increased risk of breast cancer. We analyzed the frequency of RASSF1A A133S in 190 Caucasian women without breast cancer and 653 patients with breast cancer including 138 BRCA1 and BRCA2 (BRCA1/2) mutation carriers, 395 non–BRCA1/2 mutations carriers, and 120 untested for BRCA1/2 mutations. Patients with breast cancer had a higher frequency of A133S than the controls [P = 0.017; odds ratios (OR), 1.71; 95% confidence intervals (95% CI), 1.10–2.66]. There is also a higher frequency of A133S in patients with higher familial breast cancer risk (P = 0.029; OR, 1.76; 95% CI, 1.06–2.92) and patients carrying BRCA1/2 mutations (P = 0.037, OR, 1.82; 95% CI, 1.04–3.18). Importantly, we found that the co-occurrence of a BRCA1 or BRCA2 mutation and A133S in RASSF1A was associated with earlier onset of breast cancer compared with those individuals with either a BRCA1/2 mutation or the A133S polymorphism alone (36.0 versus 42.0 years old, P = 0.002). Our data suggest that the presence of the RASSF1A A133S polymorphism is associated with breast cancer pathogenesis in general and modifies breast cancer age of onset in BRCA1/2 mutations carriers. Our results warrant a large-scale study to examine the effect of the A133S polymorphism in the development of breast and other types of cancers. [Cancer Res 2008;68(1):22–5]

Supplementary Figure Legends 1-6 from A Peptide Selected by Biopanning Identifies the Integrin αvβ6 as a Prognostic Biomarker for Nonsmall Cell Lung Cancer

BackgroundRacial inequities exist in retention in human immunodeficiency virus (HIV) care and multilevel analyses are needed to contextualize and address these differences. Leveraging data from a multisite clinical cohort of people with HIV (PWH), we assessed the relationships between patient race and residential characteristics with missed HIV care visits.MethodsMedical record and patient-reported outcome (PRO; including mental health and substance-use measures) data were drawn from 7 participating Center for AIDS Research Network of Integrated Clinical Systems (CNICS) sites including N = 20 807 PWH from January 2010 through December 2015. Generalized estimating equations were used to account for nesting within individuals and within census tracts in multivariable models assessing the relationship between race and missed HIV care visits, controlling for individual demographic and health characteristics and census tract characteristics.ResultsBlack PWH resided in more disadvantaged census tracts, on average. Black PWH residing in census tracts with higher proportion of Black residents were more likely to miss an HIV care visit. Non-Black PWH were less likely to miss a visit regardless of where they lived. These relationships were attenuated when PRO data were included.ConclusionsResidential racial segregation and disadvantage may create inequities between Black PWH and non-Black PWH in retention in HIV care. Multilevel approaches are needed to retain PWH in HIV care, accounting for community, healthcare setting, and individual needs and resources.

Social support is a modifiable social determinant of health that shapes breastfeeding outcomes and may contribute to racial and ethnic breastfeeding disparities. This study characterizes the relationship between social support and early breastfeeding.This is a cross-sectional analysis of baseline data collected in 2019-2021 for an RCT. Social support was measured using the Enhancing Recovery in Coronary Heart Disease Social Support Instrument. Outcomes, collected by self-report, included (1) early breastfeeding within the first 21 days of life, (2) planned breastfeeding duration, and (3) confidence in meeting breastfeeding goals. Each outcome was modeled using proportional odds regression, adjusting for covariates. Analysis was conducted in 2021-2022.Self-reported race and ethnicity among 883 mothers were 50% Hispanic, 17% Black, 23% White, and 10% other. A large proportion (88%) of mothers were breastfeeding. Most breastfeeding mothers (82%) planned to breastfeed for at least 6 months, with more than half (58%) planning to continue for 12 months or more. Most women (65%) were confident or very confident in meeting their breastfeeding duration goal. In adjusted models, perceived social support was associated with planned breastfeeding duration (p=0.042) but not with early breastfeeding (p=0.873) or confidence in meeting breastfeeding goals (p=0.427). Among the covariates, maternal depressive symptoms were associated with lower breastfeeding confidence (p0.001).The associations between perceived social support and breastfeeding outcomes are nuanced. In this sample of racially and ethnically diverse mothers, social support was associated with longer planned breastfeeding duration but not with early breastfeeding or breastfeeding confidence.

Electronic health record (EHR) data are increasingly used for biomedical research, but these data have recognized data quality challenges. Data validation is necessary to use EHR data with confidence, but limited resources typically make complete data validation impossible. Using EHR data, we illustrate prospective, multiwave, two-phase validation sampling to estimate the association between maternal weight gain during pregnancy and the risks of her child developing obesity or asthma. The optimal validation sampling design depends on the unknown efficient influence functions of regression coefficients of interest. In the first wave of our multiwave validation design, we estimate the influence function using the unvalidated (phase 1) data to determine our validation sample; then in subsequent waves, we re-estimate the influence function using validated (phase 2) data and update our sampling. For efficiency, estimation combines obesity and asthma sampling frames while calibrating sampling weights using generalized raking. We validated 996 of 10,335 mother-child EHR dyads in six sampling waves. Estimated associations between childhood obesity/asthma and maternal weight gain, as well as other covariates, are compared to naïve estimates that only use unvalidated data. In some cases, estimates markedly differ, underscoring the importance of efficient validation sampling to obtain accurate estimates incorporating validated data.

We compared mortality between HIV-positive and HIV-negative South African adults with drug-resistant tuberculosis (DR-TB) and high incidence of acquired second-line drug resistance.We performed a retrospective review of DR-TB patients with serial second-line TB drug susceptibility tests (2008-2015) who were hospitalized at a specialized TB hospital. We used Kaplan-Meier analysis and Cox models to examine associations with mortality.Of 245 patients, the median age was 33 years, 54% were male and 40% were HIV-positive, 96% of whom had ever received antiretroviral therapy (ART). At initial drug resistance detection, 99% of patients had resistance to at least rifampicin and isoniazid, and 18% had second-line drug resistance (fluoroquinolones and/or injectable drugs). At later testing, 88% of patients had acquired additional second-line drug resistance. Patient-initiated treatment interruptions (gt; 2 months) occurred in 47%. Mortality was 79%. Those with HIV had a shorter time to death (p = 0.02; log-rank): median survival time from DR-TB treatment initiation was 2.44 years [95% confidence interval (CI): 2.09-3.15] versus 3.99 years (95% CI: 3.12-4.75) for HIV-negative patients. HIV-positive patients who received ART within 6 months before DR-TB treatment had a higher mortality hazard than HIV-negative patients [adjusted hazard ratio (aHR) ratio = 1.82, 95% CI: 1.21-2.74]. By contrast, HIV-positive patients who did not receive ART within 6 months before DR-TB treatment did not have a significantly higher mortality hazard than HIV-negative patients (aHR = 1.09; 95% CI: 0.72-1.65), although those on ART had lower median CD4 counts than those not on ART (157 vs. 281 cells/μL, respectively; p = 0.02).A very high incidence of acquired second-line drug resistance and high overall mortality were observed, reinforcing the need to reduce the risk of acquired resistance and for more effective treatment.

BACKGROUND: Effective type 2 diabetes care remains a challenge for patients including those receiving primary care in safety net settings. OBJECTIVE: The Partnership to Improve Diabetes Education (PRIDE) trial team and leaders from a regional department of health evaluated approaches to improve care for vulnerable patients. DESIGN: Cluster randomized controlled trial. PATIENTS: Adults with uncontrolled type 2 diabetes seeking care across 10 unblinded, randomly assigned safety net clinics in Middle TN. INTERVENTIONS: A literacy-sensitive, provider-focused, health communication intervention (PRIDE; 5 clinics) vs. standard diabetes education (5 clinics). MAIN MEASURES: Participant-level primary outcome was glycemic control [A1c] at 12 months. Secondary outcomes included select health behaviors and psychosocial aspects of care at 12 and 24 months. Adjusted mixed effects regression models were used to examine the comparative effectiveness of each approach to care. KEY RESULTS: Of 410 patients enrolled, 364 (89%) were included in analyses. Median age was 51 years; Black and Hispanic patients represented 18% and 25%; 96% were uninsured, and 82% had low annual income level (

Background: Self-rated health (SRH) and the surprise question (SQ) capture perceptions of health and are independent risk factors for poor outcomes. Little is known about their association with physiologic and functional decline. Objective: Determine the association of SRH and SQ with frailty and functional status in older adults with chronic kidney disease (CKD) and their utility as screening tools. Design: Prospective cohort study. Setting/Subjects: Two hundred seventy-two adults, age ≥60 years, with advanced CKD seen in nephrology clinic. Measurements: Patients completed SRH and were evaluated for frailty (Fried criteria and Clinical Frailty Scale [CFS]) and functional status (Katz and Lawton indices of activities of daily living [ADLs] and instrumental ADLs [iADLs]). Providers completed the SQ. Correlations were evaluated using Spearman's rho. Results: Fifteen percent of patients were frail, 8% had ≥1 ADL deficit, and 29% had ≥1 iADL deficit. SRH and SQ were moderately correlated with frailty and iADLs. A SRH of excellent, very good, or good was predictive of nonfrail status (Fried negative predictive value [NPV]: 0.92; CFS NPV: 0.92) and preserved ADL function (NPV for ≥1 deficit: 0.96). A SQ response of 5, 4, or 3 (i.e., surprised) was predictive of nonfrail status and preserved ADL function (CFS NPV: 0.90; ADL ≥1 deficit NPV: 0.95). A SQ response of 1 or 2 had a positive predictive value of 0.64 for ≥1 iADL deficit. Conclusions: Subjective health measures may be useful screening tools for frailty and functional status.

BackgroundIndependent of CD4 cell count, low CD4/CD8 ratio in people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the USA and Canada.MethodsWe examined all cancer-free PWH with one or more CD4/CD8 values from NA-ACCORD observational cohorts with validated cancer diagnoses between 1998-2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines.Models were adjusted for age, sex, race/ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness.ResultsAmong 83,893 PWH, there were 5,628 incident cancers, including lung cancer (n=755), Kaposi sarcoma (KS, n=501), non-Hodgkin lymphoma (NHL, n=497), and anal cancer (n=439). Median age at cohort entry was 43 years, 87% were male, and 43% were white. Overall median six-month lagged CD4/CD8 ratio was 0.52 (interquartile range: 0.30-0.82). Compared with six-month lagged CD4/CD8=0.80, CD4/CD8=0.30 was associated with increased risk of any incident cancer (adjusted hazard ratio = 1.24 [95% confidence interval: 1.14-1.35]). CD4/CD8 ratio was also inversely associated with NHL, KS, lung cancer, anal cancer, and colorectal cancer in adjusted analyses (all pConclusionsLow CD4/CD8 ratio up to 24 months prior to cancer diagnosis was independently associated with increased cancer risk in PWH and may serve as a clinical biomarker.

Background Identifying individuals at high risk of missing HIV care provider visits could support proactive intervention. Previous prediction models for missed visits have not incorporated data beyond the individual level. Methods We developed prediction models for missed visits among people with HIV (PWH) with ≥1 follow-up visit in the Center for AIDS Research Network of Integrated Clinical Systems from 2010 to 2016. Individual-level (medical record data and patient-reported outcomes), community-level (American Community Survey), HIV care site–level (standardized clinic leadership survey), and structural-level (HIV criminalization laws, Medicaid expansion, and state AIDS Drug Assistance Program budget) predictors were included. Models were developed using random forests with 10-fold cross-validation; candidate models with the highest area under the curve (AUC) were identified. Results Data from 382 432 visits among 20 807 PWH followed for a median of 3.8 years were included; the median age was 44 years, 81% were male, 37% were Black, 15% reported injection drug use, and 57% reported male-to-male sexual contact. The highest AUC was 0.76, and the strongest predictors were at the individual level (prior visit adherence, age, CD4+ count) and community level (proportion living in poverty, unemployed, and of Black race). A simplified model, including readily accessible variables available in a web-based calculator, had a slightly lower AUC of .700. Conclusions Prediction models validated using multilevel data had a similar AUC to previous models developed using only individual-level data. The strongest predictors were individual-level variables, particularly prior visit adherence, though community-level variables were also predictive. Absent additional data, PWH with previous missed visits should be prioritized by interventions to improve visit adherence., We developed a simple, point-of-care model, available via a web-based calculator with strong discriminatory power for predicting missed HIV care visits. Strongest predictors were individual-level variables, particularly prior visit adherence, though community-level variables were also predictive.

BACKGROUND AND OBJECTIVES:Children who become overweight by age 2 have greater risk of long-term obesity and health problems. The study aim was to assess the effectiveness of a primary care–based intervention on the prevalence of overweight at age 24 months.METHODS:In a cluster-randomized trial, sites were randomly assigned to the Greenlight intervention or an attention-control arm. Across 4 pediatric residency clinics, we enrolled infant–caregiver dyads at the 2-month well-child visit. Inclusion criteria included parent English- or Spanish-speaking and birth weight ≥1500 g. Designed with health-literacy principles, the intervention included a parent toolkit at each well-child visit, augmented by provider training in clear-health communication. The primary outcome was proportion of children overweight (BMI ≥85th percentile) at age 24 months. Secondary outcomes included weight status (BMI z score).RESULTS:A total of 459 intervention and 406 control dyads were enrolled. In total, 49% of all children were overweight at 24 months. Adjusted odds for overweight at 24 months (treatment versus control) was 1.02 (95% confidence interval [CI]: 0.63 to 1.64). Adjusted mean BMI z score differences (treatment minus control) were −0.04 (95% CI: −0.07 to −0.01), −0.09 (95% CI: −0.14 to −0.03), −0.19 (−0.33 to −0.05), −0.20 (−0.36 to −0.03), −0.16 (95% CI: −0.34 to 0.01), and 0.00 (95% CI −0.21 to 0.21) at 4, 6, 12, 15, 18, and 24 months, respectively.CONCLUSIONS:The intervention resulted in less weight gain through age 18 months, which was not sustained through 24 months. Clinic-based interventions may be beneficial for early weight gain, but greater intervention intensity may be needed to maintain positive effects.

Objective This study examines the development of active television (TV) watching behaviors across the first 2 years of life in a racially and ethnically diverse, low-income cohort and identifies caregiver and child predictors of early TV watching. Methods We used longitudinal data from infants enrolled in the active control group (N = 235; 39% Latino; 29% Black; 15% White) of Greenlight, a cluster randomized multisite trial to prevent childhood obesity. At preventive health visits from 2 months to 2 years, caregivers were asked: "How much time does [child's first name] spend watching television each day?" Proportional odds models and linear regression analyses were used to assess associations among TV introduction age, active TV watching amount at 2 years, and sociodemographic factors. Results Sixty-eight percent of children watched TV by 6 months, and 88% by 2 years. Age of TV introduction predicted amount of daily active TV watching at 2 years, with a mean time of 93 minutes if starting at 2 months; 64 minutes if starting at 4 or 6 months; and 42 minutes if starting after 6 months. Factors predicting earlier introduction included lower income, fewer children in household, care away from home, male sex, and non-Latino ethnicity of child. Conclusions Many caregivers report that their infants actively watch TV in the first 6 months of life. Earlier TV watching is related to sociodemographic factors yet predicts more daily TV watching at 2 years even controlling those factors. Interventions to limit early TV watching should be initiated in infancy.

Background Integrase strand transfer inhibitor (INSTI)–based combination antiretroviral therapy (cART) is associated with greater weight gain among persons with human immunodeficiency virus (HIV), though metabolic consequences, such as diabetes mellitus (DM), are unclear. We examined the impact of initial cART regimen and weight on incident DM in a large North American HIV cohort (NA-ACCORD). Methods cART-naive adults (≥18 years) initiating INSTI-, protease inhibitor (PI)–, or nonnucleoside reverse transcriptase inhibitor (NNRTI)–based regimens from January 2007 through December 2017 who had weight measured 12 (±6) months after treatment initiation contributed time until clinical DM, virologic failure, cART regimen switch, administrative close, death, or loss to follow-up. Multivariable Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DM by cART class. Mediation analyses, with 12-month weight as mediator, similarly adjusted for all covariates. Results Among 22 884 eligible individuals, 47% started NNRTI-, 30% PI-, and 23% INSTI-based cART with median follow-up of 3.0, 2.3, and 1.6 years, respectively. Overall, 722 (3%) developed DM. Persons starting INSTIs vs NNRTIs had incident DM risk (HR, 1.17 [95% CI, .92–1.48]), similar to PI vs NNRTI initiators (HR, 1.27 [95% CI, 1.07–1.51]). This effect was most pronounced for raltegravir (HR, 1.42 [95% CI, 1.06–1.91]) vs NNRTI initiators. The INSTI–DM association was attenuated (HR, 1.03 [95% CI, .71–1.49] vs NNRTIs) when accounting for 12-month weight. Conclusions Initiating first cART regimens with INSTIs or PIs vs NNRTIs may confer greater risk of DM, likely mediated through weight gain.

Background: Older adults with advanced non-dialysis-dependent chronic kidney disease (NDD-CKD) face a high risk of hospitalization and related adverse events. Methods: This prospective cohort study followed nephrology clinic patients ≥60 years old with NDD-CKD stages 4-5. After an eligible patient’s office visit, study staff asked the patient’s provider to rate the patient’s risk of death within the next year using the surprise question (“Would you be surprised if this patient died in the next 12 months?”) with a 5-point Likert scale response (1, “definitely not surprised” to 5, “very surprised”). We used a statewide database to ascertain hospitalization during follow-up. Results: There were 488 patients (median age 72 years, 51% female, 17% black) with median estimated glomerular filtration rate 22 mL/min/1.73 m2. Over a median follow-up of 2.1 years, the rates of hospitalization per 100 person-years in the respective response groups were 41 (95% confidence interval [CI]: 34–50), “very surprised”; 65 (95% CI: 55–76), “surprised”; 98 (95% CI: 85–113), “neutral”; 125 (95% CI: 107–144), “not surprised”; and 120 (95% CI: 94–151), “definitely not surprised.” In a fully adjusted cumulative probability ordinal regression model for proportion of follow-up time spent hospitalized, patients whose providers indicated that they would be “definitely not surprised” if they died spent a greater proportion of follow-up time hospitalized compared with those whose providers indicated that they would be “very surprised” (odds ratio 2.4, 95% CI: 1.0–5.7). There was a similar association for time to first hospitalization. Conclusion: Nephrology providers’ responses to the surprise question for older patients with advanced NDD-CKD were independently associated with proportion of future time spent hospitalized and time to first hospitalization. Additional studies should examine how to use this information to provide patients with anticipatory guidance on their possible clinical trajectory and to target potentially preventable hospitalizations.

Background Older adults with advanced CKD have significant pain, other symptoms, and disability. To help ensure that care is consistent with patients’ values, nephrology providers should understand their patients’ priorities when they make clinical recommendations. Methods Patients aged ≥60 years with advanced (stage 4 or 5) non–dialysis-dependent CKD receiving care at a CKD clinic completed a validated health outcome prioritization tool to ascertain their health outcome priorities. For each patient, the nephrology provider completed the same health outcome prioritization tool. Patients also answered questions to self-rate their health and completed an end-of-life scenarios instrument. We examined the associations between priorities and self-reported health status and between priorities and acceptance of common end-of-life scenarios, and also measured concordance between patients’ priorities and providers’ perceptions of priorities. Results Among 271 patients (median age 71 years), the top health outcome priority was maintaining independence (49%), followed by staying alive (35%), reducing pain (9%), and reducing other symptoms (6%). Nearly half of patients ranked staying alive as their third or fourth priority. There was no relationship between patients’ self-rated health status and top priority, but acceptance of some end-of-life scenarios differed significantly between groups with different top priorities. Providers’ perceptions about patients’ top health outcome priorities were correct only 35% of the time. Patient-provider concordance for any individual health outcome ranking was similarly poor. Conclusions Nearly half of older adults with advanced CKD ranked maintaining independence as their top heath outcome priority. Almost as many ranked being alive as their last or second-to-last priority. Nephrology providers demonstrated limited knowledge of their patients’ priorities.

CKD is steadily increasing along with obesity worldwide. Furthermore, obesity is a proinflammatory risk factor for progression of CKD and cardiovascular disease. We tested the hypothesis that implementation of caloric restriction and aerobic exercise is feasible and can improve the proinflammatory metabolic milieu in patients with moderate to severe CKD through a pilot, randomized, 2×2 factorial design trial. Of 122 participants consented, 111 were randomized to receive caloric restriction and aerobic exercise, caloric restriction alone, aerobic exercise alone, or usual care. Of those randomized, 42% were women, 25% were diabetic, and 91% were hypertensive; 104 started intervention, and 92 completed the 4-month study. Primary outcomes were a change from baseline in absolute fat mass, body weight, plasma F 2 -isoprostane concentrations, and peak oxygen uptake (VO 2 peak ). Compared with usual care, the combined intervention led to statistically significant decreases in body weight and body fat percentage. Caloric restriction alone also led to significant decreases in these measures, but aerobic exercise alone did not. The combined intervention and each independent intervention also led to significant decreases in F 2 -isoprostane and IL-6 concentrations. No intervention produced significant changes in VO 2 peak , kidney function, or urine albumin-to-creatinine ratio. In conclusion, 4-month dietary calorie restriction and aerobic exercise had significant, albeit clinically modest, benefits on body weight, fat mass, and markers of oxidative stress and inflammatory response in patients with moderate to severe CKD. These results suggest healthy lifestyle interventions as a nonpharmacologic strategy to improve markers of metabolic health in these patients.

Background and objectives Prognostic uncertainty is one barrier that impedes providers in engaging patients with CKD in shared decision making and advance care planning. The surprise question has been shown to identify patients at increased risk of dying. Design, setting, participants, & measurements In our prospective observational study, 488 patients ≥60 years of age with CKD stage 4 or 5 were enrolled. Binary surprise question (i.e., “Would you be surprised if this patient died in the next 12 months?”) responses were recorded, and dialysis planning preferences, presence of advance care planning documentation, and care preceding death were abstracted. Results The median patient age was 71 (65–77) years old. Providers responded no and yes to the surprise question for 171 (35%) and 317 (65%) patients, respectively. Median follow-up was 1.9 (1.5–2.1) years, during which 18% of patients died (33% of surprise question no, 10% of surprise question yes; P Conclusions Nephrologists’ prognostic perceptions were associated with modest changes in care, highlighting a critical gap in conservative management discussions, advance care planning, and end of life care among older adults with CKD stages 4 and 5 and high-risk clinical characteristics. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_09_18_CJASNPodcast_17_11.mp3

Patient-provider communication is modifiable and is linked to diabetes outcomes. The association of communication quality with medical mistrust is unknown. We examined these factors within the context of a low-literacy/numeracy-focused intervention to improve diabetes care, using baseline data from diverse patients enrolled in a randomized trial of a health communication intervention. Demographics, measures of health communication (Communication Assessment Tool [CAT], Interpersonal Processes of Care survey [IPC-18]), health literacy (Short Test of Functional Health Literacy in Adults), depression, medical mistrust, and glycemic control were ascertained. Adjusted proportional odds models were used to test the association of mistrust with patient-reported communication quality. The interaction effect of health literacy on mistrust and communication quality was also assessed. A total of 410 patients were analyzed. High levels of mistrust were observed. In multivariable modeling, patients with higher mistrust had lower adjusted odds of reporting a higher CAT score (adjusted odds ratio [AOR] = 0.67, 95% confidence interval [CI] [0.52, 0.86], p = .003) and higher scores on the Communication (AOR = 0.69, 95% CI [0.55, 0.88], p = .008), Decided Together (AOR = 0.74, 95% CI [0.59, 0.93], p = .02), and Interpersonal Style (AOR = 0.69, 95% CI [0.53, 0.90], p = .015) subscales of the IPC-18. We observed evidence of an interaction effect of health literacy for the association between mistrust and the Decided Together subscale of the IPC-18 such that patients with higher mistrust and lower literacy perceived worse communication relative to mistrustful patients with higher literacy. In conclusion, medical mistrust was associated with poorer communication with providers in this public health setting. Patients' health literacy level may vary the effect of mistrust on interactional aspects of communication. Providers should consider the impact of mistrust on communication with vulnerable diabetes populations and focus efforts on mitigating its influence.

Background and Objectives Protein energy wasting and systemic inflammation are prevalent in maintenance hemodialysis (MHD) patients. Omega-3 (ω-3) fatty acids have anti-inflammatory properties and have been shown to improve protein homeostasis. We hypothesized that administration of high-dose (2.9 g/d) ω-3 would be associated with decreased muscle protein breakdown in MHD patients with systemic inflammation. Design, setting, participants & measurements This is a substudy from a randomized, placebo-controlled study (NCT00655525). Patients were recruited between September 2008 and June 2011. Primary inclusion criteria included signs of chronic inflammation (average C-reactive protein of ≥5 mg/L over three consecutive measurements), lack of active infectious or inflammatory disease, no hospitalization within 1 month prior to the study, and not receiving steroids (>5 mg/d) and/or immunosuppressive agents. The primary outcomes were forearm muscle and whole body protein breakdown and synthesis before and after the intervention. The patients received ω-3 (n=11) versus placebo (n=9) for 12 weeks. Analysis of covariance was used to compare outcome variables at 12 weeks. Models were adjusted for a propensity score that was derived from age, sex, race, baseline high sensitivity C-reactive protein, diabetes mellitus, and fat mass because the groups were not balanced for several characteristics. Results Compared with placebo, ω-3 supplementation was significantly associated with decreased muscle protein breakdown at 12 weeks (−31, [interquartile range, −98–−13] versus 26 [interquartile range, 13–87] µg/100 ml per min; P=0.01), which remained significant after multivariate adjustment (−46, [95% confidence interval, −102 to −1] µg/100 ml per min). ω-3 Supplementation resulted in decreased forearm muscle protein synthesis while the rate in the placebo group increased; however, there is no longer a statistically significant difference in skeletal muscle protein synthesis or in net protein balance after multivariate adjustment. There was no statistically significant effect of ω-3 supplementation on whole body protein synthesis or breakdown. Conclusions High-dose ω-3 supplementation over 12 weeks in MHD patients with systemic inflammation was associated with attenuation of forearm muscle protein breakdown but did not influence skeletal muscle protein synthesis, skeletal muscle net protein balance or any component of the whole-body protein balance. These results should be interpreted cautiously given the imbalance in the two groups and the short duration of the intervention.

Background: Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle and cardiac dysfunction. While skeletal muscle dysfunction precedes cardiomyopathy, the relationship between the progressive decline in skeletal and cardiac muscle function is unclear. This relationship is especially important given that the myocardial effects of many developing DMD therapies are largely unknown. Objective: Our objective was to assess the relationship between progression of skeletal muscle weakness and onset of cardiac dysfunction in DMD. Methods: A total of 77 DMD subjects treated at a single referral center were included. Demographic information, quantitative muscle testing (QMT), subjective muscle strength, cardiac function, and current and retrospective medications were collected. A Spearman rank correlation was used to evaluate for an association between subjective strength and fractional shortening. The effects of total QMT and arm QMT on fractional shortening were examined in generalized least square with and without adjustments for age, ambulatory status, and duration of corticosteroids and cardiac specific medications. Results: We found a significant correlation between maintained subjective skeletal muscle arm and leg strength and maintained cardiac function as defined by fractional shortening (rho = 0.47, p = 0.004 and rho = 0.48, p = 0.003, respectively). We also found a significant association between QMT and fractional shortening among non-ambulatory DMD subjects (p = 0.03), while this association was not significant in ambulatory subjects. Conclusions: Our findings allow us to conclude that in this population, there exists a significant relationship between skeletal muscle and cardiac function in non-ambulatory DMD patients. While this does not imply a causal relationship, a possible association between skeletal and cardiac muscle function suggests that researchers should carefully monitor cardiac function, even when the primary outcome measures are not cardiac in nature.

Maintenance hemodialysis (MHD) patients display significant nutritional abnormalities. Insulin is an anabolic hormone with direct effects on skeletal muscle (SM). We examined the anabolic actions of insulin, whole-body (WB), and SM protein turnover in 33 MHD patients and 17 participants without kidney disease using hyperinsulinemic-euglycemic-euaminoacidemic (dual) clamp. Gluteal muscle biopsies were obtained before and after the dual clamp. At baseline, WB protein synthesis and breakdown rates were similar in MHD patients. During dual clamp, controls had a higher increase in WB protein synthesis and a higher suppression of WB protein breakdown compared with MHD patients, resulting in statistically significantly more positive WB protein net balance [2.02 (interquartile range [IQR]: 1.79 and 2.36) vs. 1.68 (IQR: 1.46 and 1.91) mg·kg fat-free mass−1·min−1 for controls vs. for MHD patients, respectively, P < 0.001]. At baseline, SM protein synthesis and breakdown rates were higher in MHD patients versus controls, but SM net protein balance was similar between groups. During dual clamp, SM protein synthesis increased statistically significantly more in controls compared with MHD patients ( P = 0.03), whereas SM protein breakdown decreased comparably between groups. SM net protein balance was statistically significantly more positive in controls compared with MHD patients [67.3 (IQR: 46.4 and 97.1) vs. 15.4 (IQR: −83.7 and 64.7) μg·100 ml−1·min−1 for controls and MHD patients, respectively, P = 0.03]. Human SM biopsy showed a positive correlation between glucose and leucine disposal rates, phosphorylated AKT to AKT ratio, and muscle mitochondrial markers in controls but not in MHD patients. Diminished response to anabolic actions of insulin in the stimulated setting could lead to muscle wasting in MHD patients.

Background and Aims Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) reduce cardiovascular events in the general population. Maintenance hemodialysis (MHD) patients are at high cardiovascular risk but few studies have directly addressed the comparative efficacy of these drugs. MHD disrupts the normally atheroprotective actions of high density lipoprotein (HDL), therefore, we compared ACEI or ARB treatment on HDL functions in MHD. Methods and Results HDL was isolated at the starting point (pre) and 3–6 months later (post) in 30 MHD randomly assigned to placebo, ramipril or valsartan. Outcomes included cholesterol efflux, inflammatory cytokine response, effects on Toll-like receptors (TLR), superoxide production, methylarginine and serum amyloid A (SAA) levels. HDL from ARB- or ACEI-treated subjects was more effective in maintaining efflux than HDL of placebo. HDL from ARB- or ACEI-treated subjects but not placebo lessened cellular superoxide production. In contrast, neither ARB nor ACEI improved HDL anti-inflammatory effect. Indeed, HDL of ACEI-treated subjects potentiated the cytokine responses in association with activation of TLR but did not alter the HDL content of methylarginines or SAA. Conclusion Both ACEI and ARB stabilized HDL cholesterol acceptor function and sustained cellular anti-oxidative effects but not anti-inflammatory effects, and ACEI-treatment instead amplified the HDL inflammatory response. The findings reveal possible utility of antagonizing angiotensin actions in MDH and suggest a possible mechanism for superiority of ARB vs ACEI in the setting of advanced kidney disease.

Background Integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) has been implicated in greater weight gain than other regimens among people with HIV, but there is little evidence about its role in serious clinical outcomes proximal to weight gain. We therefore examined the impact of initial ART regimen class/drug on incident diabetes mellitus (DM) in a large North American HIV cohort. Methods Treatment-naïve adults (≥18 years) initiating INSTI-, protease inhibitor (PI)-, or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART from January 2007 to December 2016 in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included. Individuals were followed until date of incident DM (HgA1c >6.5%, diabetes-specific medication, DM diagnosis along with diabetes-related medication, or random glucose measure ≥200 mg/dL), virologic failure, regimen core switch, cohort close (through December 2016), death date, or loss to follow-up (≥12 months with no contact before cohort close). Cox regression stratified by site and adjusting for age, sex, race, HIV transmission risk, year of ART initiation, and baseline weight, CD4+ cell count, and HIV-1 RNA yielded adjusted hazard ratios (HR) and 95% confidence intervals (CI) for incident DM by ART class and INSTI drug. Results Among 21,516 eligible ART initiators, 10,553 (49%) started NNRTIs, 6,677 (31%) PIs, and 4,286 (20%) INSTIs, with median follow-up of 3.0, 2.4, and 1.6 years, respectively. Among INSTI initiators, 21% started dolutegravir (DTG), 28% raltegravir (RAL), and 51% elvitegravir (EVG). Overall, 669 (3%) developed DM. Patients differed by all characteristics except baseline body mass index and HIV-1 RNA. Those starting INSTIs vs. NNRTIs had increased risk of incident DM (HR = 1.22; CI: 0.95–1.57) similar in magnitude as for PI vs. NNRTI initiators (HR = 1.25; CI: 1.05–1.49) (figure). Among INSTIs, starting RAL- vs. NNRTI-based ART was associated with a 50% increased risk of DM (HR = 1.50, CI: 1.11–2.03). Conclusion Initiating ART with INSTI- or PI- vs. NNRTI-based regimens may confer increased risk of incident DM, though risk is heterogeneous among INSTIs. Further research is needed to determine whether this elevated risk can be attributed to weight gain. Disclosures Kassem Bourgi, MD, Gilead Sciences (Grant/Research Support), Joseph J. Eron, MD, Gilead Sciences (Consultant, Grant/Research Support), Janssen (Grant/Research Support), Merck (Consultant), ViiV Healthcare (Consultant, Grant/Research Support), M. John Gill, MB, ChB, MSc, Gilead (Board Member), Merck (Board Member), Viiv (Board Member), Michael Silverberg, PhD, MPH, Gilead (Grant/Research Support). Other Authors: No reported disclosures.

Background and objectives Electronic health record (EHR) patient portals allow individuals to access their medical information with the intent of patient empowerment. However, little is known about portal use in nephrology patients. We addressed this gap by characterizing adoption of an EHR portal, assessing secular trends, and examining the association of portal adoption and BP control ( Design, setting, participants, & measurements Patients seen between January 1, 2010, and December 31, 2012, at any of four university-affiliated nephrology offices who had at least one additional nephrology follow-up visit before June 30, 2013, were included. Sociodemographic characteristics, comorbidities, clinical measurements, and office visits were abstracted from the EHR. Neighborhood median household income was obtained from the American Community Survey 2012. Results Of 2803 patients, 1098 (39%) accessed the portal. Over 87% of users reviewed laboratory results, 85% reviewed their medical information (e.g., medical history), 85% reviewed or altered appointments, 77% reviewed medications, 65% requested medication refills, and 31% requested medical advice from their renal provider. In adjusted models, older age, African-American race (odds ratio [OR], 0.50; 95% confidence interval [95% CI], 0.39 to 0.64), Medicaid status (OR, 0.53; 95% CI, 0.36 to 0.77), and lower neighborhood median household income were associated with not accessing the portal. Portal adoption increased over time (2011 versus 2010: OR, 1.38 [95% CI, 1.09 to 1.75]; 2012 versus 2010: OR, 1.95 [95% CI, 1.44 to 2.64]). Portal adoption was correlated with BP control in patients with a diagnosis of hypertension; however, in the fully adjusted model this was somewhat attenuated and no longer statistically significant (OR, 1.11; 95% CI, 0.99 to 1.24). Conclusion While portal adoption appears to be increasing, greater attention is needed to understand why vulnerable populations do not access it. Future research should examine barriers to the use of e-health technologies in underserved patients with CKD, interventions to address them, and their potential to improve outcomes.

Aims Food insecurity is the ‘limited or uncertain availability of nutritionally adequate and safe foods’. Our objective was to examine the association between food insecurity, diabetes self-care and glycaemic control. Methods We conducted a cross-sectional analysis of baseline data from adult patients with Type 2 diabetes who were enrolled in a randomized trial evaluating a health literacy-focused diabetes intervention in safety net primary care clinics in middle Tennessee. Food insecurity was assessed with three items from the U.S. Household Food Security Survey. Diabetes self-care behaviours were assessed with the Summary of Diabetes Self-Care Activities Scale, Personal Diabetes Questionnaire and Adherence to Refills and Medication Scale. Glycaemic control was assessed with HbA1c. Results The sample consisted of 401 participants, 73% of whom reported some level of food insecurity. Food insecurity was significantly associated with self-care behaviours including less adherence to a general diet [Adjusted Odds Ratio (AOR) 0.9, P = 0.02], less physical activity (AOR 0.9, P = 0.04) and with a greater occurrence of medication non-adherence (AOR 1.2, P = 0.002) and calorie restriction (AOR 1.1, P = 0.02). Food insecurity was also associated with worse glycaemic control (adjusted β = 0.1, P = 0.03). None of the self-care behaviours were significantly associated with HbA1c, limiting the ability to test for self-care as a mechanism linking food insecurity to glycaemic control. Conclusions There was a high rate of food insecurity in a sample of patients with Type 2 diabetes who were of low socio-economic status. Food insecurity was associated with less adherence to recommended self-care behaviours and worse glycaemic control.

Objectives Our aim was to determine if chronic kidney disease (CKD) occurring in childhood impairs the normally vasoprotective functions of high-density lipoproteins (HDLs). Materials and methods HDLs were isolated from children with end-stage renal disease on dialysis (ESRD), children with moderate CKD and controls with normal kidney function. Macrophage response to HDLs was studied as expression of inflammatory markers (MCP-1, TNF-α, IL-1β) and chemotaxis. Human umbilical vein endothelial cells were used for expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and adhesion. Cellular proliferation, apoptosis, and necrosis of endothelial cells were measured by MTS/PMS reagent-based assay, flow cytometry, and ELISA. Cholesterol efflux was assessed by gas chromatographic measurements of cholesterol in macrophages exposed to HDLs. Results Compared with HDL Control , HDL CKD and HDL ESRD heightened the cytokine response and disrupted macrophage chemotaxis. HDL Control reduced endothelial expression of ICAM-1, VCAM-1, E-selectin, whereas HDL CKD and HDL ESRD were less effective and showed reduced capacity to protect endothelial cells against monocyte adhesion. Compared with a dramatically enhanced endothelial proliferation following injurious stimulus by HDL Control , neither HDL CKD nor HDL ESRD caused proliferative effects. HDLs of all three groups were equally protective against apoptosis assessed by flow cytometry and cleaved caspase-3 activity. Compared to HDL Control , HDL CKD and HDL ESRD trended toward reduced capacity as cholesterol acceptors. Conclusion CKD in children impairs HDL function. Even in the absence of long-standing and concomitant risk factors, CKD alters specific HDL functions linked to control of inflammation and endothelial responses.

The efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in preventing recurrence of atrial fibrillation (AF) is controversial and their effects on inflammation and oxidative stress in this population are not known. This study examined the effects of high-dose marine n-3 PUFAs added to conventional therapy on the recurrence of AF and on markers of inflammation and oxidative stress. Patients with paroxysmal or persistent AF were randomized to n-3 PUFAs (4 g/day; n = 126) or placebo (n = 64) in a 2:1 ratio in a prospective, double-blind, placebo-controlled, parallel group study. The primary outcome was time to recurrence of AF. Secondary outcomes were changes in biomarkers of inflammation (serum interleukin [IL]-6, IL-8, IL-10, tissue necrosis factor alpha, monocyte chemoattractant protein-1, and vascular endothelial growth factor), N-terminal-pro-brain-type natriuretic peptide, and oxidative stress (urinary F2-isoprostanes). AF recurred in 74 patients (58.7%) randomized to n-3 PUFAs and in 30 patients (46.9%) who received placebo; time to recurrence of AF did not differ significantly in the 2 groups (hazard ratio 1.20; 95% confidence interval 0.76 to 1.90, adjusted p = 0.438). Compared with placebo, n-3 PUFAs did not result in clinically meaningful changes in concentrations of inflammatory markers, N-terminal-pro-brain-type natriuretic peptide or F2-isoprostanes. In conclusion, in patients with paroxysmal or persistent AF, treatment with n-3 PUFAs 4 g/day did not reduce the recurrence of AF, nor was it associated with clinically important effects on concentrations of markers of inflammation and oxidative stress. (Clinical trial registration number, NCT 00552084.).

BACKGROUND. Systemic inflammation and muscle wasting are highly prevalent and coexist in patients on maintenance hemodialysis (MHD). We aimed to determine the effects of systemic inflammation on skeletal muscle protein metabolism in MHD patients. METHODS. Whole body and skeletal muscle protein turnover were assessed by stable isotope kinetic studies. We incorporated expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue from integrin β1 gene KO CKD mice models. RESULTS. Among 129 patients with mean (± SD) age 47 ± 12 years, 74% were African American, 73% were male, and 22% had diabetes mellitus. Median high-sensitivity C-reactive protein (hs-CRP) concentration was 13 (interquartile range 0.8, 33) mg/l. There were statistically significant associations between hs-CRP and forearm skeletal muscle protein synthesis, degradation, and net forearm skeletal muscle protein balance (P < 0.001 for all). The associations remained statistically significant after adjustment for clinical and demographic confounders, as well as in sensitivity analysis, excluding patients with diabetes mellitus. In attempting to identify potential mechanisms involved in this correlation, we show increased expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue obtained from an animal model of chronic kidney disease. CONCLUSION. These data suggest that systemic inflammation is a strong and independent determinant of skeletal muscle protein homeostasis in MHD patients, providing rationale for further studies using anticytokine therapies in patients with underlying systemic inflammation. FUNDING. This study was in part supported by NIH grants R01 DK45604 and 1K24 DK62849, the Clinical Translational Science Award UL1-TR000445 from the National Center for Advancing Translational Sciences, the Veterans Administration Merit Award I01 {"type":"entrez-nucleotide","attrs":{"text":"CX000414","term_id":"56271831","term_text":"CX000414"}}CX000414, the SatelliteHealth Normon Coplon Extramural Grant Program, and the FDA grant 000943.

Objective Sarcopenic obesity (SO), a combination of low muscle mass and high fat mass, is considered as risk factor for mortality in general population. It is unclear if SO affects mortality in maintenance hemodialysis (MHD) patients. In this study, we aimed to determine whether body composition as assessed by currently available SO definitions is related to all-cause mortality in MHD subjects. We also examined the impact of applying different definitions on the prevalence of SO in our MHD database. Design Retrospective analysis. Subjects Adult patients on MHD for at least 3 months with no acute illness studied in the clinical research center between 2003 and 2011. Intervention Assessment of body composition was performed using dual energy x-ray absorptiometry. SO (appendicular skeletal mass: arm lean mass + leg lean mass and fat mass) was defined according to Baumgartner definition, Janssen criteria 1, and Janssen criteria 2. Main Outcome Measure All-cause mortality and prevalence of SO. Patient deaths were ascertained from medical records and United States social security death index. Results Of 122 participants, 62% were male; mean age was 46 years (interquartile range: 40, 54) in men and 50 years (44, 61) in women. Prevalence of SO ranged from 12% to 62% in men and 2% to 74% in female according to different definitions. SO prevalence was lowest using the Baumgartner criteria (all: 8%, men 12%, women: 2%) and highest according to the Janssen criteria 2 (all: 57%, men 46%, women 74%). There were 45 deaths during a median follow-up period of 44 (20, 76) months. SO by any definition was not statistically significantly associated with mortality during follow-up. Conclusions The current SO definitions are not applicable to predict increased risk of death in MHD patients. We found high degree of variation in the rates of SO when using different definitions. Future studies should focus on establishing MHD population-specific thresholds of muscle mass and adiposity for accurate prognostication.

Acute kidney injury (AKI) is associated with subsequent chronic kidney disease (CKD), but the mechanism is unclear. To clarify this, we examined the association of AKI and new-onset or worsening proteinuria during the 12 months following hospitalization in a national retrospective cohort of United States Veterans hospitalized between 2004-2012. Patients with and without AKI were matched using baseline demographics, comorbidities, proteinuria, estimated glomerular filtration rate, blood pressure, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (ACEI/ARB) use, and inpatient exposures linked to AKI. The distribution of proteinuria over one year post-discharge in the matched cohort was compared using inverse probability sampling weights. Subgroup analyses were based on diabetes, pre-admission ACEI/ARB use, and AKI severity. Among the 90,614 matched AKI and non-AKI pairs, the median estimated glomerular filtration rate was 62 mL/min/1.73m2. The prevalence of diabetes and hypertension were 48% and 78%, respectively. The odds of having one plus or greater dipstick proteinuria was significantly higher during each month of follow-up in patients with AKI than in patients without AKI (odds ratio range 1.20-1.39). Odds were higher in patients with Stage II or III AKI (odds ratios 1.32-1.81) than in Stage I AKI (odds ratios 1.18-1.32), using non-AKI as the reference group. Results were consistent regardless of diabetes status or baseline ACEI/ARB use. Thus, AKI is a risk factor for incident or worsening proteinuria, suggesting a possible mechanism linking AKI and future CKD. The type of proteinuria, physiology, and clinical significance warrant further study as a potentially modifiable risk factor in the pathway from AKI to CKD.

Biomarker studies for early detection of acute kidney injury (AKI) have been limited by non-selective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), Interleukin-18 (IL-18), and Kidney Injury Moledule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category free net reclassification index improved with urine L-FABP [total net reclassification index for non-events 31.0%] and urine NGAL [total net reclassification index for events 33.3%]. However, only urine L-FABP significantly improved the integrated discriminative index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP providing independent and additive prognostic information when combined with clinical predictors.

To quantify the combined effect of maternal prepregnancy obesity and maternal gestational weight gain (GWG) on the shape of infant growth throughout the first year of life.A retrospective cohort of mother-child dyads with children born between January 2007 and May 2012 was identified in a linked electronic medical record. Data were abstracted to define the primary exposures of maternal prepregnancy body mass index (BMI) and GWG, and the primary outcome of infant growth trajectory.We included 499 mother-child dyads. The average maternal age was 28.2 years; 55% of mothers were overweight or obese before pregnancy, and 42% of mothers had excess GWG, as defined by the Institute of Medicine. Maternal prepregnancy BMI (P.001) and the interaction between prepregnancy BMI and maternal GWG (P = .02) showed significant association with infant growth trajectory through the first year of life after controlling for breast-feeding and other covariates, while GWG alone did not reach statistical significance (P = .38). Among infants of mothers with excess GWG, a prepregnancy BMI of 40 kg/m(2) versus 25 kg/m(2) resulted in a 13.6% (95% confidence interval 5.8, 21.5; P.001) increase in 3-month infant weight/length percentile that persisted at 12 months (8.4%, 95% confidence interval 0.2, 16.5; P = .04).The combined effect of excess maternal GWG and prepregnancy obesity resulted in higher infant birth weight, rapid weight gain in the first 3 months of life, with a sustained weight elevation throughout the first year of life. These findings highlight the importance of the preconception and prenatal periods for pediatric obesity prevention.

Objective To examine the hypothesis that improving insulin sensitivity improves vascular function in rheumatoid arthritis (RA). Methods We performed a 20-week, single center, randomized, double-blind, placebo-controlled crossover study. Patients with RA (n = 34) with moderate disease activity who were receiving stable disease-modifying antirheumatic drug therapy were randomized to drug sequence, receiving either pioglitazone 45 mg/day or matching placebo for 8 weeks, followed by a 4-week washout period and the alternative treatment for 8 weeks. We measured changes in vascular stiffness (augmentation index and aortic pulse wave velocity [PWV]), endothelial function (reactive hyperemia index), and blood pressure. High-sensitivity C-reactive protein levels and the homeostatic model assessment of insulin resistance were also measured. The treatment effect of pioglitazone on outcomes was analyzed using linear mixed-effects models. Results Pioglitazone treatment resulted in a change in augmentation index of −4.7% units (95% confidence interval [95% CI] −7.9, −1.5) (P = 0.004) and in diastolic blood pressure of −3.0 mm Hg (95% CI −5.7, −0.2) (P = 0.03), but did not significantly change aortic PWV (P = 0.33) or reactive hyperemia index (P = 0.46). The improvements in augmentation index and diastolic blood pressure were not mediated by the effect of pioglitazone on insulin resistance or inflammation. Conclusion Our findings indicate that pioglitazone improves some indices of vascular function, including augmentation index and diastolic blood pressure, in patients with RA. This is not mediated by improved insulin sensitivity.

Objective Depression is common in patients with type 2 diabetes and associated with poor diabetes-related outcomes. We evaluated the factors associated with antidepressant use in a low-income, racially and ethnically diverse sample of patients with type 2 diabetes. Research design and methods We performed a cross-sectional study of baseline data from participants in a cluster randomized trial evaluating a health literacy intervention for diabetes care in safety net clinics. Depressive symptoms were measured by the Center for Epidemiological Studies Depression Scale (CES-D); antidepressant use was abstracted from medication lists. Multivariable mixed effects logistic regression was used to evaluate the relationship between antidepressant use and race/ethnicity adjusting for depressive symptoms, age, gender, income, and health literacy. Results Of 403 participants, 58% were non-Hispanic White, 18% were non-Hispanic Black, and 24% were Hispanic. Median age was 51 years old; 60% were female, 52% of participants had a positive screen for depression, and 18% were on antidepressants. Black and Hispanic participants were significantly less likely to be on an antidepressant compared with white participants, adjusted odds ratios 0.31(95% CI: 0.12 to 0.80) and 0.26 (95% CI: 0.10 to 0.74), respectively. Conclusions In this vulnerable population with type 2 diabetes, we found a high prevalence of depressive symptoms, and a small proportion of participants were on an antidepressant. Black and Hispanic participants were significantly less likely to be treated with an antidepressant. Our findings suggest depression may be inadequately treated in low-income, uninsured patients with type 2 diabetes, especially racial and ethnic minorities.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease associated with increased prevalence of early cardiovascular disease (1, 2), a major cause of mortality (3). Additionally, the prevalence of insulin resistance and metabolic syndrome, important risk factors for cardiovascular disease, are increased in patients with RA (4). However, the cause of accelerated atherosclerosis in RA is unclear and the prevalence of cardiovascular disease remains higher than that of the general population after consideration of traditional cardiovascular risk factors (1). One potential contributor may be visceral adiposity, particularly epicardial adipose tissue (EAT). Patients with RA are more likely to have central obesity, or visceral adiposity, than control subjects of similar BMI (5). Adipose tissue, particularly visceral adipose tissue, is strongly related to cardiometabolic risk factors such as insulin resistance, hypertension and dyslipidemia in the general population and in RA patients (6, 7). EAT, a fat layer between the myocardium and visceral pericardium, is a type of visceral fat that is emerging as an important cardiovascular risk factor (8, 9). This may be because of local inflammation and paracrine effects resulting from the proximity of EAT to coronary vessels and a shared microcirculation with the myocardium (10–14). In the general population, EAT volume is independently associated with obstructive coronary artery plaque and non-calcified atherosclerotic lesions (15), and is an independent predictor of ischemia (16). EAT is associated with insulin resistance (17, 18), and is considered a marker of metabolic syndrome in other populations (19–21). Because it is a rich source of bioactive molecules like inflammatory cytokines and adipokines, EAT is regarded as a potential therapeutic target for treatment of the metabolic syndrome (22, 23). There is little information about EAT in RA. We hypothesized that EAT is a marker of insulin resistance and the metabolic syndrome, as well as a risk factor for coronary atherosclerosis in patients with RA. Thus, the purpose of this study was to measure EAT volume in patients with RA and control subjects and determine its relationship with markers of cardiometabolic risk and coronary artery calcium in RA.

Summary Background and objectives The impact of AKI on adverse drug events and therapeutic failures and the medication errors leading to these events have not been well described. Design, setting, participants, & measurements A single-center observational study of 396 hospitalized patients with a minimum 0.5 mg/dl change in serum creatinine who were prescribed a nephrotoxic or renally eliminated medication was conducted. The population was stratified into two groups by the direction of their initial serum creatinine change: AKI and AKI recovery. Adverse drug events, potential adverse drug events, therapeutic failures, and potential therapeutic failures for 148 drugs and 46 outcomes were retrospectively measured. Events were classified for preventability and severity by expert adjudication. Multivariable analysis identified medication classes predisposing AKI patients to adverse drug events. Results Forty-three percent of patients experienced a potential adverse drug event, adverse drug event, therapeutic failure, or potential therapeutic failure; 66% of study events were preventable. Failure to adjust for kidney function (63%) and use of nephrotoxic medications during AKI (28%) were the most common potential adverse drug events. Worsening AKI and hypotension were the most common preventable adverse drug events. Most adverse drug events were considered serious (63%) or life-threatening (31%), with one fatal adverse drug event. Among AKI patients, administration of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, antibiotics, and antithrombotics was most strongly associated with the development of an adverse drug event or potential adverse drug event. Conclusions Adverse drug events and potential therapeutic failures are common and frequently severe in patients with AKI exposed to nephrotoxic or renally eliminated medications.

Background Greater adipose tissue is associated with increased circulating high-sensitivity C-reactive protein (hsCRP) levels in HIV-infected adults on antiretroviral therapy (ART), but the relationship between adiposity and other inflammation biomarkers is not well-characterized. Methods We measured total and regional adipose tissue deposits using dual energy X-ray absorptiometry (DXA) and serum levels of interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) receptor 1 and 2, macrophage inflammatory protein-1α (MIP-1α), macrophage chemotactic protein-1 (MCP-1), soluble CD14 and hsCRP in a cohort of adults on long-term ART. Regression models were adjusted for age, sex, CD4+ T-cell count, smoking status, protease-inhibitor-use and daily use of either non-steroidal anti-inflammatory drugs or aspirin. Results The majority (77%) of the 85 study participants were male, median CD4+ T-cell count was 500 cells/ml (IQR 315-734) and median BMI was 25.1 kg/m2 (IQR 22.7-28.1). DXA measurements of total fat mass were positively associated with serum hsCRP (β =1.82, PConclusions Total and regional adiposity was associated with serum hsCRP, but not other inflammatory cytokines shown to predict morbidity and mortality in treated HIV. Greater adiposity is associated with higher MIP-1α and lower soluble CD14 levels, possibly reflecting an important role for cells of the monocyte/macrophage lineage.

Decreased nitric oxide bioavailability has an important role in the initiation and progression of diabetic nephropathy, but the underlying mechanisms remain unclear. Here, we found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression levels increased in the kidneys of both endothelial nitric oxide synthase (eNOS)-knockout and eNOS-knockout diabetic (Lepr(db/db)) mice as early as at 8 weeks of age. Further increases in expression were only seen in eNOS-knockout diabetic mice and paralleled the progression of glomerulopathy. HB-EGF expression increased in endothelium, podocytes, and tubular epithelial cells. In cultured glomerular endothelial cells, the nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) or L-N5-(1-iminoethyl) ornithine increased HB-EGF protein expression. Administration of L-NAME dramatically increased renal HB-EGF expression and urinary HB-EGF excretion in diabetic mice. On the other hand, replenishing nitric oxide with sodium nitrate in eNOS-knockout diabetic mice reduced urinary HB-EGF excretion and inhibited the progression of diabetic nephropathy. Furthermore, specific deletion of HB-EGF expression in the endothelium attenuated renal injury in diabetic eNOS-knockout mice. Thus, our results suggest that decreased nitric oxide bioavailability leads to increased HB-EGF expression, which may be an important mediator of the resulting progressive diabetic nephropathy in eNOS-knockout diabetic mice.

Background Endothelial dysfunction is an important precursor to the development of atherosclerosis, and has been suggested to play a role in the increased cardiovascular risk in patients with end stage renal disease. Endothelial function improves rapidly following post kidney transplantation, but the long term change remains unclear. Hypothesizing that endothelial function would remain improved long term post kidney transplantation, we evaluated the longitudinal change of endothelial function, measured by flow-mediated dilation (FMD) of the brachial artery, from months 1 to 24 post transplantation. Given the previously reported association of fibroblast growth factor 23 (FGF-23) with endothelial dysfunction, we also examined changes in the association between FGF-23 levels and the change in FMD following kidney transplantation. Methods We performed a prospective cohort study of 149 kidney transplant recipients, measuring endothelial function by FMD at months 1, 12, and 24 post-transplant. FGF-23 levels were measured at months 1 and 24 post-transplant. Linear mixed effects models were used to assess both the unadjusted and adjusted outcomes. Results The cohort (mean age 49 ± 13 years) was 74 % male and 75 % white. The median FMD was 6.3 % (IQR: 3.4, 10.2), 5.4 % (IQR: 3.1, 8.5), and 5.6 % (IQR: 3.5, 9.1) at 1, 12, and 24 months, respectively. After adjustment for covariates, compared to month 1, no change occurred in FMD at 12 months (−0.66 %; 95 % CI: −1.81 %, 0.49 %; P = 0.262) or 24 months (−0.25 %; 95%CI: −1.76 %, 1.26 %; P = 0.746). FGF-23 decreased significantly over time (P = 0.024), but there was no significant association between FGF-23 and FMD (P = 0.799). Conclusion Endothelial function remained stable at 12 and 24 months from 1 month post-kidney transplant, indicating that the improved endothelial function seen with transplant is maintained up to 2 years post transplantation. There was also no significant association between FGF-23 and endothelial function following kidney transplantation.

BACKGROUND: Protein energy wasting (PEW) is common in patients undergoing maintenance hemodialysis (MHD) and closely associated with poor outcomes. Insulin resistance and associated alterations in amino acid metabolism are potential pathways leading to PEW. We hypothesized that the measurement of leucine disposal during a hyperinsulinemic- euglycemic-euaminoacidemic clamp (HEAC) procedure would accurately measure the sensitivity to insulin for its actions on concomitant carbohydrate and protein metabolism in MHD patients. METHODS: We examined 35 MHD patients and 17 control subjects with normal kidney function by hyperinsulinemic-euglycemic clamp (HEGC) followed by HEAC clamp procedure to obtain leucine disposal rate (LDR) along with isotope tracer methodology to assess whole body protein turnover. RESULTS: The glucose disposal rate (GDR) by HEGC was 5.1 ± 2.1 mg/kg/min for the MHD patients compared to 6.3 ± 3.9 mg/kg/min for the controls (p = 0.38). The LDR during HEAC was 0.09 ± 0.03 mg/kg/min for the MHD patients compared to 0.11 ± 0.05 mg/kg/min for the controls (p = 0.009). The LDR level was correlated with whole body protein synthesis (r = 0.25; p = 0.08), with whole body protein breakdown (r = −0.38 p = 0.01) and net protein balance (r = 0.85; p