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Background Change in short-term (i.e., 10-year) and lifetime risk of cardiovascular disease (CVD) following Roux-en-Y gastric bypass (RYGB) has significant heterogeneity. Objective To identify predictors of change in CVD risk and cardiovascular events following RYGB. Methods Between 2006–2009, 1625 adults without a history of CVD enrolled in a prospective cohort study and underwent RYGB at 1 of 10 U.S. hospitals. Participants were followed annually for a maximum of 7 years. Associations between presurgery characteristics (anthropometric, sociodemographic, physical and mental health, alcohol/drug use, eating behaviors) and 1) pre to postsurgery change in 10 year and lifetime atherosclerotic CVD (ASCVD) risk scores, respectively, and 2) having a CVD event (nonfatal myocardial infarction, stroke, ischemic heart disease, congestive heart failure, angina, percutaneous coronary intervention, coronary artery bypass grafting, or CVD-attributed death) as repeated measures (yr 1–7) were evaluated. Setting Observational cohort study at ten hospitals throughout the United States. Results Presurgery factors independently associated with decreases in both 10-year and lifetime risk scores 1–7 years post-RYGB were higher CVD risk score, female sex, higher household income, and normal kidney function. Additionally, Black race and having diabetes were independently associated with decreases in 10-year risk, while not having diabetes and a higher (better) composite mental health score were independently related to decreases in lifetime risk. A lower (worse) presurgery composite physical health score was associated with a higher CVD event risk (RR = 1.68, per 10 points). Conclusion This study identified multiple presurgery factors that characterize patients who may have more cardiovascular benefit from RYGB, and patients who might require additional support to improve their cardiovascular health.

Introduction and objectives: The prevalence of alcohol, tobacco, and coffee use and association with liver health among North Americans with Chronic Hepatitis B (CHB) infection has not been well described. Materials and methods: The Hepatitis B Research Network includes an observational study of untreated CHB adults enrolled at 21 sites in the United States and Canada. Alcohol use was categorized as none, moderate, and at-risk based on the definition from the National Institute on Alcohol Abuse and Alcoholism; tobacco use as never, current and former; coffee use as none, 1–2 cups/day, and ≥3 cups/day. Linear regression and linear mixed models were used to associate lifestyle behaviors with ALT and FIB-4 values. Results: 1330 participants met eligibility: 53% males, 71% Asian and the median age was 42 years (IQR: 34–52). Median ALT was 33 U/L (IQR: 22–50), 37% had HBV DNA

Rationale & Objective The association between bariatric surgery, type 2 diabetes, and chronic kidney disease (CKD) is poorly understood. We studied whether remission of type 2 diabetes induced by bariatric surgery influences markers of kidney disease, if CKD is associated with remission of diabetes after bariatric surgery, and if baseline levels of gut hormones and peptides modify these associations. Study Design Prospective observational study. Study Participants 737 bariatric surgery patients with type 2 diabetes who participated in a multicenter cohort study for up to 5 years. Predictors Demographics, blood pressure, medications, type of bariatric surgery, anthropometrics, markers of kidney disease, and circulating levels of gut hormones and peptides. Outcomes Estimated glomerular filtration rate (eGFR), urinary albumin excretion, prognostic risk for CKD, and remission of diabetes. Analytical Approach Linear mixed models for eGFR; generalized linear mixed models with logit link for albuminuria, prognostic risk for CKD, and diabetes remission. Results Remission of diabetes at 5 years post–bariatric surgery was not independently associated with eGFR but was associated with lower risk for moderate/severe increase in albuminuria (risk ratio, 0.66; 95% CI, 0.48-0.90) and stabilization in prognostic risk for CKD. These findings were modified by baseline ghrelin level. Lower preoperative eGFR and greater prognostic risk for CKD were independently associated with reduced likelihood of diabetes remission. The association with preoperative GFR was modified by C-peptide level. Higher baseline circulating ghrelin level was independently associated with a lower prognostic risk for CKD. Limitations A minority of participants had baseline CKD; lack of comparison group; no information on duration of diabetes, other clinical end points, or kidney biopsy results. Conclusions Remission of type 2 diabetes 5 years after bariatric surgery was associated with improvements in albuminuria and stabilized prognostic risk for CKD, but not with eGFR. Lower kidney function and greater prognostic risk at the time of bariatric surgery was linked to a lower likelihood of diabetes remission. These results highlight the need to identify the mechanisms through which bariatric surgery may delay the long-term progression of CKD in type 2 diabetes.

Objective Older adults with knee osteoarthritis (OA) and comorbid subsyndromal depressive symptoms are at elevated risk for incidental major depression or anxiety disorders. Using an indicated prevention paradigm, the authors conducted a sequenced multiple assignment randomized trial (SMART) to: 1) evaluate the effect of cognitive behavioral therapy (CBT) and physical therapy (PT), together with the temporal ordering of these interventions, on patient-reported global impression of change (P-GIC), mood, anxiety, and pain; and 2) compare the strategies’ impact on incidence of common psychiatric disorders over 12-months. Methods This intervention development trial compared four adaptive strategies delivered in two stages (each up to 8 weeks), contrasted with enhanced usual care (EUC). The strategies were CBT followed by an increased dose of CBT (CBT-CBT), CBT followed by PT (CBT-PT), PT followed by an increased dose of PT (PT-PT), and PT followed by CBT (PT-CBT). Participants (n = 99) were aged 60 years and older and met clinical criteria for knee OA and subthreshold depression. Response was defined as at least “much better” on the P-GIC. Participants were assessed quarterly for 12 months for incidence of psychiatric disorders. Results Stage 1 response was higher for PT (47.5%) compared to CBT (20.5%). Non-responders receiving an additional dose of the same intervention experienced a response rate of 73%, higher than for switching to a different intervention. All strategies were superior to EUC (5%). Although not powered to detect effects on disorders, neither intervention strategy nor response status affected 12-month incidence of depression and anxiety disorders. Conclusion As response rates were similar for PT-PT and CBT-CBT, it may be dose and not type of these interventions that are necessary for clinical benefit. For non-responders, this finding may guide providers to stay the clinical course for up to 12 weeks before switching. These results support future trials of SMART designs in late-life depression prevention.

Chronic exposure to arsenic via drinking water is a serious public health issue in many countries. Arsenic causes not only cancers but also non-malignant diseases, including asthma. We have previously reported that arsenic exposure increases the risk of Th2-mediated allergic asthma. The serum level of periostin, an extracellular matrix protein activated by Th2 cytokines, is recognized as a biomarker for Th2-mediated eosinophilic asthma and contributes to enhanced airway inflammation and remodeling. However, the role of periostin in arsenic-related asthma is unknown. Therefore, this study was designed to explore the associations of serum periostin levels with arsenic exposure and the features of asthma in 442 individuals in Bangladesh who participated in our previous study. Exposure levels of the participants were determined by measuring the arsenic concentrations in drinking water, hair, and nails through inductively coupled plasma mass spectroscopy. Periostin levels in serum were assessed by immunoassay. In this study, we found that serum periostin levels of the participants were increased with increasing exposure to arsenic. Notably, even the participants with 10.1–50 μg/L arsenic in drinking water had significantly higher levels of periostin than participants with

Objective Testing stepped-care approaches that address both depression and low back pain are needed to optimize outcomes in older adults. Methods This university-based late-life depression research center assessed 227 adults aged ≥ 60 years with chronic low back pain and depression. In Phase 1 participants received 6 weeks of low-dose venlafaxine (≤150 mg/day). Nonresponders were randomized to 10 weeks of high-dose venlafaxine (up to 300 mg/day) plus problem-solving therapy (PST) or high-dose venlafaxine with supportive management. Definition of response was 2 weeks of Patient Health Questionnaire-9 ≤ 5 and ≥30% pain reduction on a numeric rating scale. Function was measured with the Short Physical Performance Battery (SPPB) and Roland Morris Disability Questionnaire (RMDQ). Results Of those who completed Phase 1 (N = 209), 78.5% (N = 164) were nonresponders and 139 proceeded to Phase 2, with 68 randomized to venlafaxine/PST and 71 randomized to venlafaxine/supportive management. Of those in venlafaxine/PST, 41.2% (28/68) responded, and of those in venlafaxine/supportive management, 39.4% (28/71) responded. Cumulative proportion responding over time did not differ across the two arms (hazard ratio: 1.07; 95% confidence interval: 0.63–1.80). We observed clinically significant improvements in physical performance (SPPB) and disability (RMDQ) across both Phase 1 and 2, independent of intervention. Over 12 months of follow-up there was no difference between groups for stability of depression, pain, or disability. Conclusion The combination of antidepressant pharmacotherapy and PST was not superior to antidepressant pharmacotherapy and supportive management. Clinically, the rates of response and stability of response over 1 year observed in both groups suggest that these approaches may have clinical utility in these chronically suffering patients.

Anastomotic leak is one of the most serious complications after Roux-en-Y gastric bypass (RYGB). Our objective was to examine the relationship between technical factors and incidence of clinically relevant anastomotic leak after RYGB in longitudinal assessment of bariatric surgery (LABS). The setting of the study was 11 bariatric centers in the United States, university, and private practice.Patient characteristics, technical factors of surgery, and postoperative outcomes were assessed by trained researchers using standardized protocols. Correlation of surgical factors of patients undergoing RYGB (n = 4444) with the incidence of postoperative anastomotic leak was assessed by univariate χ(2) analysis.Forty-four participants (1.0%, 95% CI .7%-1.3%) experienced a clinically relevant anastomotic leak. Of these, 39 (89%) underwent abdominal reoperation and 3 (7%) died. Technical factors associated with anastomotic leak were open surgery (P.0001), revision surgery (P.0001), and use of an abdominal drain (P = .02). Provocative leak testing, method of gastrojejunostomy, and use of fibrin sealant were not associated with anastomotic leak.Anastomotic leak after RYGB was rare (1.0%). Most cases required reintervention; however, the majority (93%) recovered from this event. Open surgery, revision surgery, and routine drain placement were associated with increased leak rate. Some of these findings may be due to differences in preoperative patient risk.

BACKGROUND & AIMS: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America. METHODS: We collected data from the Hepatitis B Research Network—an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). RESULTS: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th–75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P

The goals were to compare the morbidity and mortality between primary and revisional bariatric surgery and to identify the clinical predictors of adverse outcomes among patients undergoing revisional surgery in the Longitudinal Assessment of Bariatric Surgery consortium. The study was multi-institutional at university hospitals in the United States.Data from the LABS-1 (safety) cohort were analyzed, excluding primary gastric banding patients. A total of 3802 LABS-1 patients were included: 3577 who underwent primary surgery and 225 who underwent revisional surgery. The demographic, clinical, operative, and 30-day outcome data were compared between the 2 groups. A nonlinear mixed effects logit model was used to identify independent risk factors for adverse outcomes (death, deep vein thrombosis, pulmonary embolism, reintubation, reoperation, or discharge after 30 days).Compared with those undergoing revisional surgery, the primary surgery patients were younger (median age 44 versus 49 years, P.0001) and more likely to be male (20.5% versus 12.7%, P = .006) and heavier (median body mass index 47.3 versus 41.2 kg/m(2), P.0001) and to have more co-morbidities (P.0001), including hypertension (56.0% versus 46.0%, P = .0044), diabetes (35.7% versus 20.0%, P.0001), and sleep apnea (50.3% versus 27.2%, P.0001). The operative time for the revisional procedures was longer (median 181 versus 135 min, P.0001) and associated with greater blood loss (median 100 versus50 mL, P.0001). Adverse outcomes were more likely after revisional surgery (15.1% versus 5.3%, P.0001, odds ratio 2.4, 95% confidence interval 1.6-3.6). After adjusting for patient characteristics previously shown to be associated with adverse outcomes, this difference remained statistically significant (odds ratio 2.3, 95% confidence interval 1.5-3.8). The 30-day mortality rate was similar in the 2 groups (.4%).Revisional surgery was performed without substantial mortality but with a greater incidence of adverse outcomes than was primary bariatric surgery.

In two-stage randomization designs, patients are randomized to one or more available therapies upon entry into the study. Depending on the response to the initial treatment (such as complete remission or shrinkage of tumor), patients are then randomized to receive maintenance treatments to maintain the response or salvage treatment to induce response. One goal of such trials is to compare the combinations of initial and maintenance or salvage therapies in the form of treatment strategies. In cases where the endpoint is defined as overall survival, Lunceford et al. [2002. Estimation of survival distributions of treatment policies in two-stage and randomization designs in clinical trials. Biometrics 58, 48–57] used mean survival time and pointwise survival probability to compare treatment strategies. But, mean survival time or survival probability at a specific time may not be a good summary representative of the overall distribution when the data are skewed or contain influential tail observations. In this article, we propose consistent and asymptotic normal estimators for percentiles of survival curves under various treatment strategies and demonstrate the use of percentiles for comparing treatment strategies. Small sample properties of these estimators are investigated using simulation. We demonstrate our methods by applying them to a leukemia clinical trial data set that motivated this research.

Background & Aims T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). Methods We enrolled 200 adults with CHB who participated in the National Institutes of Health−supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. Results Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3 + CD127 − regulatory T cells and CD4 + T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg) + than HBeAg − patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg + than HBeAg − patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. Conclusions HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell−based immune signatures for clinical phenotypes. These findings suggest additional T-cell−independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.