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Quantile residual lifetime (QRL) is of significant interest in many clinical studies as an easily interpretable quantity compared to other summary measures of survival distributions. In cancer or other chronic diseases, treatments are often compared based on the distributions or quantiles of the residual lifetime. Thus a common problem of interest is to test the equality of the QRL between two populations. In this paper, we propose two classes of tests to compare two QRLs; one class is based on the difference between two estimated QRLs, and the other is based on the estimating function of the QRL, where the estimated QRL from one sample is plugged into the QRL-estimating-function of the other sample. We outline the asymptotic properties of these test statistics. Simulation studies demonstrate that the proposed tests produced Type I errors closer to the nominal level and are superior to some existing tests based on both Type I error and power. Our proposed test statistics are also computationally less intensive and more straightforward compared to tests based on the confidence intervals. We applied the proposed methods to a randomized multicenter phase III trial for breast cancer patients.

Liver injury may persist in patients with HBV receiving antiviral therapy who have ongoing transcription and translation. We sought to assess ongoing HBV transcription by serum HBV RNA, translation by serum hepatitis B core related antigen (HBcrAg), and their associations with hepatic HBsAg and HBcAg staining in patients coinfected with HBV and HIV.This is a cross-sectional study of 110 adults coinfected with HBV and HIV who underwent clinical assessment and liver biopsy. Immunohistochemistry (IHC) was performed for HBsAg and HBcAg. Viral biomarkers included quantitative HBsAg, HBV RNA, and HBcrAg.Participants' median age was 49 years (male, 93%; Black, 51%; HBeAg+, 65%), with suppressed HBV DNA (79%) and undetectable HIV RNA (77%) on dually active antiretroviral therapy. Overall, HBV RNA and HBcrAg were quantifiable in 81% and 83%, respectively (96% and 100% in HBeAg+, respectively). HBcAg staining was detected in 60% and HBsAg in 79%. Higher HBV RNA was associated with higher HBcAg and HBsAg IHC grades (both p 0.0001). The HBsAg membranous staining pattern was significantly associated with higher HBV-RNA and HBcrAg levels.HBcAg and HBsAg IHC staining persisted despite viral suppression, and IHC grades and staining patterns correlated with markers of transcription (HBV RNA) and translation (HBcrAg). These data indicate that apparent HBV suppression is associated with residual transcription and translation that could contribute to liver pathology. Additional antiviral strategies directed to HBV protein expression may be useful to ameliorate liver injury.

Number of children ever born to women of reproductive age forms a core component of fertility and is vital to the population dynamics in any country. Using Bangladesh Multiple Indicator Cluster Survey 2019 data, we fitted a novel weighted Bayesian Poisson regression model to identify multi-level individual, household, regional and societal factors of the number of children ever born among married women of reproductive age in Bangladesh. We explored the robustness of our results using multiple prior distributions, and presented the Metropolis algorithm for posterior realizations. The method is compared with regular Bayesian Poisson regression model using a Weighted Bayesian Information Criterion. Factors identified emphasize the need to revisit and strengthen the existing fertility-reduction programs and policies in Bangladesh.The online version contains supplementary material available at 10.1007/s44199-022-00044-2.

Hepatitis B surface antigen (HBsAg) loss is associated with improved long-term outcomes of patients with chronic hepatitis B but is infrequently achieved with current monotherapies. We assessed whether combination strategies that included treatment withdrawal enhanced HBsAg loss.A randomized (1:1) trial of tenofovir disoproxil fumarate (TDF) for 192 weeks with or without peginterferon (PegIFN) alfa-2a for the first 24 weeks, followed by withdrawal of TDF at week 192 with 48 weeks of off-treatment follow-up to week 240. The primary end point was HBsAg loss at week 240.Of 201 participants (52% HBeAg positive, 12%/6% genotype A/A2, 7% cirrhosis) randomized to TDF + PegIFN (n = 102) or TDF alone (n = 99), 6 participants had lost HBsAg at the end of the treatment phase (week 192), 5 (5.3%) in the combination group, and 1 (1.0%) in the TDF alone group (P = 0.09). By week 240, 9 participants had cleared HBsAg, 5.3% in combination, and 4.1% in monotherapy arms (P = 0.73). HBsAg decline and loss occurred earlier with TDF + PegIFN than TDF, with a ≥1-logIU/mL qHBsAg decline by week 24 in 28% in TDF + PegIFN compared with 6% in TDF (P = 0.04). HBsAg loss occurred in 7 of 12 (58%) with hepatitis B virus subgenotype A2 (all HBeAg positive) compared with only 2 of 189 (1%) with other hepatitis B virus genotypes and in 8 of 93 (8.6%) HBeAg positive vs 1 of 87 (1.1%) HBeAg negative.PegIFN combined TDF followed by protocolized TDF withdrawal led to earlier but not higher percentages of HBsAg clearance. Pretreatment HBeAg positivity and subgenotype A2 were strongly associated with HBsAg clearance.

A sequential multiple assignment randomized trial (SMART) facilitates the comparison of multiple adaptive treatment strategies (ATSs) simultaneously. Previous studies have established a framework to test the homogeneity of multiple ATSs by a global Wald test through inverse probability weighting. SMARTs are generally lengthier than classical clinical trials due to the sequential nature of treatment randomization in multiple stages. Thus, it would be beneficial to add interim analyses allowing for an early stop if overwhelming efficacy is observed. We introduce group sequential methods to SMARTs to facilitate interim monitoring based on the multivariate chi-square distribution. Simulation studies demonstrate that the proposed interim monitoring in SMART (IM-SMART) maintains the desired type I error and power with reduced expected sample size compared to the classical SMART. Finally, we illustrate our method by reanalyzing a SMART assessing the effects of cognitive behavioral and physical therapies in patients with knee osteoarthritis and comorbid subsyndromal depressive symptoms.

BACKGROUND: Acute hepatitis B virus (aHBV) is thought to be self-limited with clearance of HBsAg within 6 months. There are limited reports of the presenting features and outcomes of adults with symptomatic aHBV in the U.S. PATIENTS AND METHODS: Demographics, clinical features and 12-month outcomes of patients with adjudicated aHBV were captured prospectively and compared to a contemporaneous cohort of chronic HBV (cHBV) cases enrolled in the Hepatitis B Research Network. RESULTS: Between 2011 and 2018, 60 adjudicated aHBV were compared to 1534 cHBV untreated controls. Although similar in age, other features were dissimilar: aHBV subjects were more often male (72% vs. 51%), single (72% vs. 30%), non-Hispanic whites or blacks (75% vs. 24%). They also were frequently genotype A(2) (65% vs. 9%) having different risk factors: sexual exposure (75% vs. 16%) or injection drug use (10% vs. 2%), compared to the cHBV controls. In addition to higher serum aminotransferase and bilirubin levels, acute cases had higher HBV DNA levels (4.8 vs. 3.6 log(10) IU/mL) while quantitative HBeAg levels were lower (1.4 vs. 3.0 log(10) IU/mL) despite higher rates of HBeAg (73% vs. 25%). The median time to HBsAg clearance was 27 weeks and to anti-HBs appearance, 41 weeks. CONCLUSIONS: In the current era, Caucasian men infected with genotype A(2) as a result of sexual exposure or injection drug use were the predominant group in aHBV, suggesting a potential strategy for adult vaccination in North America. Strikingly, only an estimated 36% of subjects cleared HBsAg by month 6; the definition of resolution in acute hepatitis B may need to be modified. ClinicalTirals.gov number NCT01263587

Summary Sequential multiple assignment randomized trials (SMARTs) are systematic and efficient media for comparing dynamic treatment regimes (DTRs), where each patient is involved in multiple stages of treatment with the randomization at each stage depending on the patient’s previous treatment history and interim outcomes. Generally, patients enrolled in SMARTs are randomized equally to ethically acceptable treatment options regardless of how effective those treatments were during the previous stages, which results in some undesirable consequences in practice, such as low recruitment, less retention, and lower treatment adherence. In this article, we propose a response-adaptive SMART (RA-SMART) design where the allocation probabilities are imbalanced in favor of more promising treatments based on the accumulated information on treatment efficacy from previous patients and stages. The operating characteristics of the RA-SMART design relative to SMART design, including the consistency and efficiency of estimated response rate under each DTR, the power of identifying the optimal DTR, and the number of patients treated with the optimal and the worst DTRs, are assessed through extensive simulation studies. Some practical suggestions are discussed in the conclusion.

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

The estimated average treatment effect in observational studies is biased if the assumptions of ignorability and overlap are not satisfied. To deal with this potential problem when propensity score weights are used in the estimation of the treatment effects, in this paper we propose a bootstrap bias correction estimator for the average treatment effect (ATE) obtained with the inverse propensity score (BBC-IPS) estimator. We show in simulations that the BBC-IPC performs well when we have misspecifications of the propensity score (PS) due to: omitted variables (ignorability property may not be satisfied), overlap (imbalances in distribution between treatment and control groups) and confounding effects between observables and unobservables (endogeneity). Further refinements in bias reductions of the ATE estimates in smaller samples are attained by iterating the BBC-IPS estimator.

BACKGROUND: Patient-reported outcomes such as health-related quality of life and symptoms associated with chronic hepatitis B viral (HBV) infection have not been well-described in North American cohorts. AIMS: Evaluate several patient-reported outcomes and associations with HBV disease activity markers. METHODS: Cross-sectional analysis including 876 adults who completed patient-reported outcome measures during the Hepatitis B Research Network Adult Cohort Study. Participants on HBV treatment were excluded. Outcomes included: health-related quality of life using the SF-36 Mental Component Summary and Physical Component Summary scores; Symptom Burden using a 10-item Total Symptom Checklist; and fatigue using an instrument from the Patient-Reported Outcomes Measurement Information System®. Covariates included laboratory markers of disease severity, virological status, comorbidities and medications. RESULTS: Median age was 42 (range: 19–79), 51% were female, 73% Asian, 19% HBeAg (+), 2% had AST-platelet-ratio index (APRI) ≥ 1.5 and 74% without comorbidities. Mean Mental Component Summary T-score=52, Physical Component Summary T-score=54, and PROMIS fatigue T-score=47. On a scale from 0 (none) to 40 (extreme), the mean Symptom Checklist score=3 and 25% reported no symptoms. The most frequent symptoms were fatigue (60%), irritability (32%) and itching (32%). Most symptoms were “a little bit” bothersome. In multivariable regressions, APRI ≥ 1.50 and more comorbidities were associated with worse patient-reported outcomes; virological markers were not. Adding the Total Symptom Checklist score to original regression models increased explanation of variation in the Mental Component Summary Score from 4% to 44% and the Physical Component Summary Score from 17% to 34%. CONCLUSIONS: Untreated North American HBV patients with mild liver disease report favorable health-related quality of life and minimal symptoms. HBV does not impact health-related quality of life unless advanced liver disease or comorbidities are present. High symptom burden explains substantial variation in health-related quality of life. (CT.gov identifier: ).

Mortality due to opioid misuse and overdose has increased substantially in the United States over the past two decades. The study objective was to describe the causes of death among persons with opioid-related hospitalizations and examine survival by Hepatitis C virus (HCV) or HIV. Opioid-related hospitalization records in Pennsylvania from 2000 to 2010 were linked to death registry files to assess cause of death, and survival from first hospital discharge date to death date, or December 31, 2010. Accelerated failure time models were used to compare survival between persons with and without HCV or HIV diagnoses. Among the 136,416 individuals with an opioid-related hospitalization, 13.0% died over a median of 56 months of follow-up; the most common causes of death were circulatory diseases (26.4%) and drug overdose (23.5%). There were 27,122 (19.9%) and 3662 (2.7%) persons who had an HCV and HIV diagnosis, respectively. Among patients aged ≥20 years, those with HCV had shorter survival time compared to those without HCV, with discrepancies more pronounced at older ages. Patients with HIV also had shorter survival time (time ratio: 0.29 [95% CI: 0.26, 0.34]) compared to without HIV. These findings show that in a cohort of patients with opioid-related hospitalizations, those with HCV or HIV diagnoses have shorter survival. This has public health implications, providing further evidence that medical providers should educate patients who use opioids about the risks of HCV and HIV infection and focus prevention and treatment to decrease mortality among patients hospitalized for opioid use.

Achieving HBsAg loss is an important landmark in the natural history of chronic hepatitis B (CHB). A more personalized approach to prediction of HBsAg loss is relevant in counseling patients. This study sought to develop and validate a prediction model for HBsAg loss based on quantitative HBsAg levels (qHBsAg) and other baseline characteristics.The Hepatitis B Research Network (HBRN) is a prospective cohort including 1240 untreated HBeAg-negative patients (1150 adults, 90 children) with median follow-up of 5.5 years. Incidence rates of HBsAg loss and hepatitis B surface antibody (anti-HBs) acquisition were determined, and a predictor score of HBsAg loss using readily available variables was developed and externally validated.Crude incidence rates of HBsAg loss and anti-HBs acquisition were 1.6 and 1.1 per 100 person-years (PY); 67 achieved sustained HBsAg loss for an incidence rate of 1.2 per 100 PY. Increased HBsAg loss was significantly associated with older age, non-Asian race, HBV phenotype (inactive CHB vs. others), HBV genotype A, lower HBV-DNA levels, and lower and greater change in qHBsAg. The HBRN-SQuARe (sex,∆quantHBsAg, age, race) score predicted HBsAg loss over time with area under the receiver operating characteristic curve (AUROC) (95% CIs) at 1 and 3 years of 0.99 (95% CI: 0.987-1.00) and 0.95 (95% CI 0.91-1.00), respectively. In validation in another cohort of 1253 HBeAg-negative patients with median follow-up of 3.1 years, HBRN SQuARe predicted HBsAg loss at 1 and 3 years with AUROC values of 0.99 (0.98-1.00) and 0.88 (0.77-0.99), respectively.HBsAg loss in predominantly untreated patients with HBeAg-negative CHB can be accurately predicted over a 3-year horizon using a simple validated score (HBRN SQuARe). This prognostication tool can be used to support patient care and counseling.

OBJECTIVE: To report C-reactive protein (CRP) following Roux-en-Y gastric bypass surgery (RYGB). BACKGROUND: Long-term change in CRP is not well characterized in the context of Roux-en-Y gastric bypass (RYGB). METHODS: Between 2006–2009, 1770 adults enrolled in a US multi-center prospective cohort study (Longitudinal Assessment of Bariatric Surgery) underwent RYGB. Research assessments were conducted pre-surgery and annually post-surgery up to 7 years. This study included those with high-sensitivity CRP assessed pre-surgery and one or more follow up assessments (n=1180). RESULTS: Pre-surgery, participants’ median age was 46 years and median body mass index (BMI) was 46 kg/m(2); 80% were female. At pre-surgery, mean (95% CI) CRP (mg/L) was the highest of all time points (1.01 [0.95–1.08]); it then decreased to a nadir of 0.18 (0.15–0.22) at 2 years post-surgery (P1 mg/dL) 7 years post-surgery versus 32.9% (95% CI, 30.2–35.3) pre-surgery (P

BACKGROUND AND AIMS: Histological and clinical outcomes in HBV-HIV coinfection in the era of combination antiretroviral therapy (cART) are poorly defined. APPROACH AND RESULTS: Adult patients co-infected with HBV-HIV from eight North American sites were enrolled in this National Institutes of Health (NIH)–funded prospective observational study (n = 139). Demographic, clinical, serological, and virological data were collected at entry and every 24 weeks for ≤ 192 weeks. Paired liver biopsies were obtained at study entry and at ≥ 3 years of follow-up. Biopsies were assessed by a central pathology committee using the modified Ishak scoring system. Clinical outcome rate and changes in histology are reported. Among participants with follow-up data (n = 114), median age was 49 years, 91% were male, 51% were non-Hispanic Black, and 13% had at-risk alcohol use, with a median infection of 20 years. At entry, 95% were on anti-HBV cART. Median CD4 count was 562 cells/mm(3) and 93% had HIV < 400 copies/mL. HBeAg was positive in 61%, and HBV DNA was below the limit of quantification (< 20 IU/mL) in 61% and < 1,000 IU/mL in 80%. Clinical events were uncommon across follow-up: one hepatic decompensation, two HCC, no liver transplants, and one HBV-related deaths, with a composite endpoint rate of 0.61/100 person-years. Incident cirrhosis (n = 1), alanine aminotransferase flare (n = 2), and HBeAg loss (n = 13) rates were 0.40, 0.65, and 6.86 per 100 person-years, respectively. No participants had HBsAg loss. Paired biopsy (n = 62; median 3.6 years apart) revealed minimal improvement in Histologic Activity Index (median [interquartile range]: 3 [2–4] to 3 [1–3]; P = 0.02) and no significant change in fibrosis score (1 [1–2] to 1 [0–3]; P = 0.58). CONCLUSIONS: In a North American cohort of adults with HBV-HIV on cART with virological suppression, clinical outcomes and worsening histological disease were uncommon. (Hepatology 2021;74:1174–1189).

Effect measure modification is often evaluated using parametric models. These models, although efficient when correctly specified, make strong parametric assumptions. While nonparametric models avoid important functional form assumptions, they often require larger samples to achieve a given accuracy. We conducted a simulation study to evaluate performance tradeoffs between correctly specified parametric and nonparametric models to detect effect modification of a binary exposure by both binary and continuous modifiers. We evaluated generalized linear models and doubly robust (DR) estimators, with and without sample splitting. Continuous modifiers were modeled with cubic splines, fractional polynomials, and nonparametric DR-learner. For binary modifiers, generalized linear models showed the greatest power to detect effect modification, ranging from 0.42 to 1.00 in the worst and best scenario, respectively. Augmented inverse probability weighting had the lowest power, with an increase of 23% when using sample splitting. For continuous modifiers, the DR-learner was comparable to flexible parametric models in capturing quadratic and nonlinear monotonic functions. However, for nonlinear, nonmonotonic functions, the DR-learner had lower integrated bias than splines and fractional polynomials, with values of 141.3, 251.7, and 209.0, respectively. Our findings suggest comparable performance between nonparametric and correctly specified parametric models in evaluating effect modification.

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

Background Symptoms of chronic hepatitis B (CHB) are not well characterized. Aims To evaluate CHB symptoms and associations with disease activity and clinical outcomes. Methods Longitudinal data from 1,576 participants in the Hepatitis B Research Network Cohort Study who completed symptom assessments were analyzed. A composite symptom score was calculated using a Symptom Checklist (0=none to 40=extreme). Multivariable mixed models assessed variables associated with symptom change over time. Latent class symptom trajectories were evaluated. The cumulative probability of long-term clinical outcomes (new onset cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplantation, death) was examined by baseline symptom groups. Results Participants median age was 42 (range:18-80), 51% were male, 75% Asian, (68% of whom were born outside North America) with a median follow-up of 4.2 years. On average, symptoms did not significantly change over time. The multivariable model identified several variables associated with higher symptoms during follow-up: being female, non-Asian, born in the US/Canada, lower education, higher AST, lower platelets, and more comorbidities. Two patient subgroups were identified based on longitudinal symptom trajectories: a low symptom group (92%, n=1,451) with symptom scores averaging 2.4 over time and a moderate symptom group (8%, n=125) with symptom scores averaging 11.5. During follow-up, 7.3% in the moderate symptom group, but only 3.2% of the low symptom group, developed adverse outcomes (p=0.02). Conclusions In this large cohort of CHB patients, symptoms were generally mild and stable over time. However, in some patients with moderate symptoms at baseline, deleterious clinical outcomes were more frequent in follow-up.

Studies of human hepatitis B virus (HBV) immune pathogenesis are hampered by limited access to liver tissues and technologies for detailed analyses. Here, utilizing imaging mass cytometry (IMC) to simultaneously detect 30 immune, viral, and structural markers in liver biopsies from patients with hepatitis B e antigen+ (HBeAg+) chronic hepatitis B, we provide potentially novel comprehensive visualization, quantitation, and phenotypic characterizations of hepatic adaptive and innate immune subsets that correlated with hepatocellular injury, histological fibrosis, and age. We further show marked correlations between adaptive and innate immune cell frequencies and phenotype, highlighting complex immune interactions within the hepatic microenvironment with relevance to HBV pathogenesis.

Many medical conditions are marked by a sequence of events in association with continuous changes in biomarkers. Few works have evaluated the overall accuracy of a biomarker in predicting disease progression. We thus extend the concept of receiver operating characteristic (ROC) surface and the volume under the surface (VUS) from multi-category outcomes to ordinal competing-risk outcomes that are also subject to noninformative censoring. Two VUS estimators are considered. One is based on the definition of the ROC surface and obtained by integrating the estimated ROC surface. The other is an inverse probability weighted U estimator that is built upon the equivalence of the VUS to the concordance probability between the marker and sequential outcomes. Both estimators have nice asymptotic results that can be derived using counting process techniques and U-statistics theory. We illustrate their good practical performances through simulations and applications to two studies of cognition and a transplant dataset.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) precore (PC) and dual basal core promoter (BCP) mutations halt and down-regulate hepatitis B e antigen (HBeAg) production respectively. PC mutation is rarely associated with HBV genotype A. We sought to examine the association of these variants with HBV genotypes, age, and HBeAg status in a racially diverse population in North America. Prospective study included 1,036 (808 adults, 228 children) participants in the Hepatitis B Research Network. PC and BCP variants were determined by Sanger sequencing, and dominant HBV species (>50%) were reported. APPROACH AND RESULTS: Median age was 36.3 years (range, 2–80), 44.6% HBeAg(+), 74.2% Asians, 13.3% black, and 9.7% white. The dominant PC variant was present in 29.4% participants, including 20 with subgenotype A1 or A2. Seventeen of 20 participants with genotype A and PC had a compensatory C1858T mutation. In the HBeAg(+) cohort, the prevalence of PC and/or BCP variants increased from 14.4% in the first two decades to 51% after 40 years of age. Among those aged 2–18, 52% and 83% with dominant PC and BCP variants were HBeAg(+) compared to 3.8% and 29% in the >40 years age group. HBeAg clearance rates were significantly higher for those with dominant PC or BCP variants: 24.4 and 15.0 per 100 person-years compared to 6.0 in wild-type HBV (P < 0.0001). CONCLUSIONS: PC variants can be present in HBV genotype A and are usually associated with C1858T, which preserves the pregenome encapsidation sequence. Selection of PC and BCP variants occurred at a young age, with increasing prevalence across age groups. HBeAg(+) participants with dominant PC and BCP variants progressed to the HBeAg(−) phase of chronic HBV infection significantly faster. This finding has potential clinical and therapeutic implications.

OBJECTIVE The study objective was to empirically identify subgroups of patients with obesity and investigate their association with postoperative weight change. METHODS A longitudinal analysis of 2,458 adults in the Longitudinal Assessment of Bariatric Surgery (LABS) study was used. Baseline data were used to identify subgroups. The outcome was 3-year weight change after bariatric surgery. RESULTS We identified four classes (subtypes) of obesity, which could be characterized as diabetes with low rates of high-density lipoprotein (Class 1), disordered eating (Class 2), mixed (Class 3), and extreme obesity with early onset (Class 4). Approximately 98% of participants in Class 1 had diabetes compared with < 40% in the other classes. There were high rates of binge eating in Class 2, and more than 92% of those in this class reported eating when not hungry. Class 4 was characterized by a higher BMI at baseline. Adults in Class 4 lost an average of 25.0% (males) and 30.3% (females) of their baseline weight over 3 years. In contrast with participants in Class 1, those in Classes 2 and 3 had significantly larger 3-year weight losses than their peers in Class 4. CONCLUSIONS Obesity is a heterogeneous disease. Bariatric surgery may be most beneficial for adults with disordered eating.

Certain conditions and illnesses may necessitate multiple stages of treatment and thus require unique study designs to compare the efficacy of these interventions. Such studies are characterized by two or more stages of treatment punctuated by decision points where intermediate outcomes inform the choice for the next stage of treatment. The algorithm that dictates what treatments to take based on intermediate outcomes is referred to as a dynamic regime. This paper describes an efficient method of building double robust estimators of the treatment effect of different regimes. A double robust estimator utilizes both modeling of the outcome and weighting based on the modeled probability of receiving treatment in such a way that the resulting estimator is a consistent estimate of the desired population parameter under the condition that at least one of those models is correct. This new and more efficient double robust estimator is compared to another double robust estimator as well as classical regression and inverse probability weighted estimators. The methods are applied to estimate the regime effects in the STAR*D anti-depression treatment trial.

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.

Jiang, Z (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. zhen.jiang@fda.hhs.gov

The product limit or Kaplan-Meier (KM) estimator is commonly used to estimate the survival function in the presence of incomplete time to event. Application of this method assumes inherently that the occurrence of an event is known with certainty. However, the clinical diagnosis of an event is often subject to misclassification due to assay error or adjudication error, by which the event is assessed with some uncertainty. In the presence of such errors, the true distribution of the time to first event would not be estimated accurately using the KM method. We develop a method to estimate the true survival distribution by incorporating negative predictive values and positive predictive values, into a KM-like method of estimation. This allows us to quantify the bias in the KM survival estimates due to the presence of misclassified events in the observed data. We present an unbiased estimator of the true survival function and its variance. Asymptotic properties of the proposed estimators are provided, and these properties are examined through simulations. We demonstrate our methods using data from the Viral Resistance to Antiviral Therapy of Hepatitis C study.

Two-stage longitudinal studies are common in the treatment of mental diseases, such as chronic forms of major depressive disorders. Outcomes in such studies often consist of repeated measurements of scores, such as the 24-item Hamilton Rating Scale for Depression, throughout the duration of therapy. Two issues that make the analysis of data from such two-stage studies different from standard longitudinal data are: (1) the randomization in the second stage for patients who fail to respond in the first stage; and (2) the drop-out of patients which sometimes occurs before the second stage. In this article, we show how the weighted generalized estimating equations can be used to draw inference for treatment regimes from two-stage studies. Specifically, we show how to construct weights and use them in the generalized estimating equations to derive consistent estimators of regime effects, and compare them. Large-sample properties of the proposed estimators are derived analytically, and examined through simulations. We demonstrate our methods by applying them to a depression data set.

Modeling of correlated biomarkers jointly has been shown to improve the efficiency of parameter estimates, leading to better clinical decisions. In this paper, we employ a joint modeling approach to a unique diabetes dataset, where blood glucose (continuous) and urine glucose (ordinal) measures of disease severity for diabetes are known to be correlated. The postulated joint model assumes that the outcomes are from distributions that are in the exponential family and hence modeled as multivariate generalized linear mixed effects model associated through correlated and/or shared random effects. The Markov chain Monte Carlo Bayesian approach is used to approximate posterior distribution and draw inference on the parameters. This proposed methodology provides a flexible framework to account for the hierarchical structure of the highly unbalanced data as well as the association between the 2 outcomes. The results indicate improved efficiency of parameter estimates when blood glucose and urine glucose are modeled jointly. Moreover, the simulation studies show that estimates obtained from the joint model are consistently less biased and more efficient than those in the separate models.

Patients with hepatitis B early antigen (HBeAg)-negative chronic hepatitis B (CHB) and low-level viremia are a heterogeneous group. Identifying those at risk of developing active CHB requiring antiviral therapy is important. In this study, we prospectively characterize incidence rates and predictors of transitioning from inactive to active CHB in a North American adult cohort.Participants in the multicenter National Institute of Diabetes and Digestive and Kidney Diseases Hepatitis B Research Network cohort who were HBeAg negative with baseline hepatitis B virus (HBV) DNA ≤ 10,000 IU/mL were included in the study. Cox regression models were used to estimate the proportion of individuals in 3 baseline HBV DNA categories (≤100, 101 to ≤2,000, and 2,001 to ≤10,000 IU/mL) who developed phase transition defined by HBV DNA10,000 IU/mL and alanine aminotransferase (ALT)2× upper limit of normal or initiated treatment during follow-up.Of 970 participants meeting inclusion criteria, 15% experienced phase transition or initiated treatment over a median follow-up of 4 years: 9% of those with baseline HBV DNA ≤ 100 IU/mL, 14% with HBV DNA 101 to ≤2,000 IU/mL, and 24% with HBV DNA 2,001 to ≤10,000 IU/mL (P0.001). The overall rate of phase transition or treatment initiation was 7.6 per 100 person-years: 4.6 in those with HBV DNA ≤ 100 IU/mL, 6.8 in those with HBV DNA 101 to ≤2,000 IU/mL, and 12.2 in those with HBV DNA 2,001 to ≤10,000 IU/mL (P0.001). Factors independently associated with higher rate of phase transition or treatment initiation included HBV genotype B or C, higher baseline ALT and HBV DNA levels, lower platelet count, quantitative hepatitis B surface antigen1,000 IU/mL, and hyperlipidemia. Only higher ALT, higher HBV DNA, and lower platelets were associated with phase transition when patients starting treatment were censored.Most adults in this North American cohort with HBeAg-negative CHB and low-level viremia remained inactive and off treatment over 4 years. Transition from inactive to active CHB is infrequent and predominantly associated with viral rather than host factors.

Noninvasive biomarkers are used increasingly to assess fibrosis in patients with chronic liver disease. We determined the utility of dual cutoffs for noninvasive biomarkers to exclude and confirm advanced fibrosis in hepatitis B virus (HBV)-human immunodeficiency virus (HIV) co-infected patients receiving combined antiretroviral therapy. Participants were anti-HIV/hepatitis B surface antigen-positive adults from eight clinical sites in the United States and Canada of the Hepatitis B Research Network. Fibrosis was staged by a central pathology committee using the Ishak fibrosis score (F). Clinical, laboratory, and vibration-controlled transient elastography (VCTE) data were collected at each site. Dual cutoffs for three noninvasive biomarkers (aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 index [FIB-4], and liver stiffness by VCTE) with the best accuracy to exclude or confirm advanced fibrosis (F ≥ 3) were determined using established methodology. Of the 139 enrolled participants, 108 with a liver biopsy and having at least one noninvasive biomarker were included: 22% had advanced fibrosis and 54% had normal alanine aminotransferase. The median (interquartile range) of APRI (n = 106), FIB-4 (n = 106), and VCTE (n = 63) were 0.34 (0.26-0.56), 1.35 (0.99-1.89), and 4.9 (3.8-6.8) kPa, respectively. The area under the curve for advanced fibrosis was 0.69 for APRI, 0.66 for FIB-4, and 0.87 for VCTE. VCTE cutoffs of 5.0 kPa or less (to exclude) and 8.8 kPa or greater (to confirm) advanced fibrosis had a sensitivity of 92.3% and specificity of 96.0%, respectively, and accounted for 65.1% of participants. Among the 34.9% with values between the cutoffs, 26.1% had advanced fibrosis. Considering APRI or FIB-4 jointly with VCTE did not improve the discriminatory capacity. Conclusion: VCTE is a better biomarker of advanced fibrosis compared with APRI or FIB-4 in HBV/HIV co-infected adults on combined antiretroviral therapy. Using VCTE dual cutoffs, approximately two-thirds of patients could avoid biopsy to determine advanced fibrosis.

BACKGROUND: Because most HBV/HIV co-infected patients on combination antiretroviral therapy (cART) have suppressed HBV DNA and normal liver enzymes, the histologic spectrum of liver disease in HBV/HIV coinfection is poorly defined. To address this gap in knowledge, we conducted a prospective study to comprehensively characterize liver disease severity assessed by liver biopsy in a well-defined cohort of HBV/HIV patients in North America receiving cART. METHODS: Adult HIV/HBsAg positive patients on stable cART were recruited. Demographic, clinical, serological, and virological data were collected. Liver histology was assessed by a central pathology committee. The association of demographic, clinical, serologic, and virologic characteristics with liver histology was assessed using logistic regression. RESULTS: In this cross-sectional analysis, the mean age of the cohort (N = 139) was 49 years; 92% were male, 51% were non-Hispanic black, 7% had at-risk alcohol use with a median duration of infections of 14 years. The median ALT was 28 IU/L and CD4 count was 568 cells/mm(3). Almost all (99%) were on cART. Three-fourths (75%) had undetectable HIV RNA (

Background Opioid abuse is associated with substantial morbidity and often results in hospitalization. Despite this, patient-level factors associated with opioid-related hospitalizations are not well understood. Methods We used the Pennsylvania Health Care Cost Containment Council dataset (2000–2014) to identify opioid-related hospitalizations using primary and/or secondary ICD-9-CM hospital discharge codes for opioid use disorder (OUD), opioid poisoning, and heroin poisoning. Latent class analyses (LCA) of patient-level factors including sociodemographic characteristics, pregnancy, alcohol, tobacco, other substance use, and psychiatric disorders were used to identify common patterns within hospitalizations. Results Among 28,538,499 hospitalizations, 430,569 (1.5%) were opioid-related. LCA identified five latent class (LC) patient groups associated with opioid-related hospitalizations: pregnant women with OUD (LC1); women over 65 with opioid overdose (LC2); OUD, polysubstance use and co-occurring psychiatric disorders (LC3); patients with opioid overdose without co-occurring polysubstance use (LC4); and African American patients with OUD and co-occurring cocaine use (LC5). LC3 was the largest latent class (58.2%) with annual hospitalizations doubling over time. Discussion Among patients with opioid-related discharges, we identified five subpopulations among this sample. These findings suggest increased outpatient OUD treatment, mental health service support for patients with co-occurring psychiatric disorders and polysubstance use to prevent overdose and hospitalization.

The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease and may be a treatment for NASH due to its antioxidant properties. We aimed to assess the safety and efficacy of higher than customary doses of silymarin in non-cirrhotic patients with NASH. This exploratory randomized double-blind placebo controlled multicenter Phase II trial tested a proprietary standardized silymarin preparation (Legalon®, Rottapharm|Madaus, Mylan) and was conducted at 5 medical centers in the United States. Eligible adult patients had liver biopsy within 12 months showing NASH without cirrhosis with NAFLD Activity Score (NAS) ≥4 per site pathologist's assessment. Participants were randomized to Legalon® 420 mg, 700 mg, or placebo t.i.d. for 48 weeks. The primary endpoint was histological improvement ≥2 points in NAS. Of 116 patients screened, 78 were randomized. There were no significant differences in adverse events among the treatment groups. After 48-50 weeks, 4/27 (15%) in the 700 mg dose, 5/26 (19%) participants randomized to 420 mg, and 3/25 (12%) of placebo recipients reached the primary endpoint (p = 0.79) among all randomized participants, indicating no benefit from silymarin in the intention to treat analysis Review by a central pathologist demonstrated that a substantial number of participants (49, 63%) did not meet histological entry criteria and that fibrosis stage improved most in the placebo treated group, although not significantly different from other groups. Silymarin (Legalon®) at the higher than customary doses tested in this study is safe and well tolerated. The effect of silymarin in patients with NASH remains inconclusive due to the substantial number of patients who entered the study but did not meet entry histological criteria, the lack of a statistically significant improvement in NAS of silymarin treated patients, and the unanticipated effect of placebo on fibrosis indicate the need for additional clinical trials. Trial Registration: clinicaltrials.gov, Identifier: NCT00680407.

BackgroundFatigue is a common symptom of liver disease but not well characterized in patients with chronic hepatitis B virus (HBV).AimsWe assessed the rate of fatigue using a validated instrument in patients with HBV and identified demographic, virologic, and clinical features associated with fatigue in a cross-sectional cohort study from the Hepatitis B Research Network.MethodsParticipants were English- and Spanish-speaking adults with chronic HBV who were not pregnant nor on treatment. Fatigue was measured using the PROMIS® Fatigue 7-item Short Form.ResultsThe sample included 948 adults: median age 42; 51 % female; 71 % Asian; 74 % college educated; 77 % employed; 41 % inactive HBV carriers; 36 % with active chronic disease; and 2 % with advanced fibrosis, defined as AST-platelet ratio index (APRI) > 1.50. Patients with chronic HBV had a mean fatigue T-score of 46.8 ± SD = 7.9, compared to a mean fatigue T-score of 50.0 ± 10 in the US general population (p < .0001). In univariate analyses, greater fatigue was associated with demographic and clinical features such as female sex, lower income, more comorbidities, higher APRI score, and poorer mental health (p < 0.05). In multivariate analysis, female sex (p < .001), poorer mental health (p < .001), APRI score (p = .005), and history of diabetes (p = .039) were the strongest independent predictors.ConclusionsThe frequency of fatigue in this large cohort of North American chronic HBV patients may be equal to or lower than that reported in the US general population. Patients with advanced fibrosis, more comorbidities, and poorer mental health report worse fatigue.

Missing data mechanisms, methods of handling missing data, and the potential impact of missing data on study results are usually not taught until graduate school. However, the appropriate handling of missing data is fundamental to biomedical research and should be introduced earlier on in a student's education. The Summer Institute for Training in Biostatistics (SIBS) provides practical experience to motivate trainees to pursue graduate training and biomedical research. Since 2010, SIBS Pittsburgh has demonstrated the feasibility of introducing missing data concepts to trainees in a small-group project-based setting that involves both simulation and data analysis. After learning about missing data mechanisms and statistical techniques, trainees apply what they have learned to a NIDDK/NIH-funded Hepatitis C treatment study, to examine how various hypothesized missing data patterns can affect results. A simulation is also used to examine the bias and precision of these methods under each missing data pattern. Our experience shows that under such project-based training, advanced topics, such as missing data, can be presented to trainees with limited statistical preparation, and ultimately, can further their statistical literacy and reasoning. The tools presented here are provided in the Appendix.

The study objective was to empirically identify subgroups of patients with obesity and investigate their association with postoperative weight change.A longitudinal analysis of 2,458 adults in the Longitudinal Assessment of Bariatric Surgery (LABS) study was used. Baseline data were used to identify subgroups. The outcome was 3-year weight change after bariatric surgery.We identified four classes (subtypes) of obesity, which could be characterized as diabetes with low rates of high-density lipoprotein (Class 1), disordered eating (Class 2), mixed (Class 3), and extreme obesity with early onset (Class 4). Approximately 98% of participants in Class 1 had diabetes compared with40% in the other classes. There were high rates of binge eating in Class 2, and more than 92% of those in this class reported eating when not hungry. Class 4 was characterized by a higher BMI at baseline. Adults in Class 4 lost an average of 25.0% (males) and 30.3% (females) of their baseline weight over 3 years. In contrast with participants in Class 1, those in Classes 2 and 3 had significantly larger 3-year weight losses than their peers in Class 4.Obesity is a heterogeneous disease. Bariatric surgery may be most beneficial for adults with disordered eating.

Summary Recently dynamic treatment regimens (DTRs) have drawn considerable attention, as an effective tool for personalizing medicine. Sequential Multiple Assignment Randomized Trials (SMARTs) are often used to gather data for making inference on DTRs. In this article, we focus on regression analysis of DTRs from a two-stage SMART for competing risk outcomes based on cumulative incidence functions (CIFs). Even though there are extensive works on the regression problem for DTRs, no research has been done on modeling the CIF for SMART trials. We extend existing CIF regression models to handle covariate effects for DTRs. Asymptotic properties are established for our proposed estimators. The models can be implemented using existing software by an augmented-data approximation. We show the improvement provided by our proposed methods by simulation and illustrate its practical utility through an analysis of a SMART neuroblastoma study, where disease progression cannot be observed after death.

Importance Estimates of weight regain following bariatric surgery vary widely. Objective To describe weight regain after reaching nadir weight following Roux-en-Y gastric bypass (RYGB) surgery and compare weight regain measures for association with outcomes. Design, Setting, and Participants Prospective cohort study of 2458 adults who underwent bariatric surgery at 10 hospitals in 6 US cities between March 2006 and April 2009. Assessments were conducted within 30 days’ presurgery, at 6 months’ postsurgery, and then annually until January 2015. Of the 1703 participants who underwent RYGB surgery, 1406 (83%) were followed up for 5 years or longer and had 5 or more weight measurements (excluding those who died or underwent surgical reversal). Exposures Weight regain assessed by 5 continuous measures (weight in kilograms, body mass index [BMI], percentage of presurgery weight, percentage of nadir weight, and percentage of maximum weight lost) and 8 dichotomous measures (per established thresholds) were compared in relation to clinical outcomes based on statistical significance, magnitude of association, and model fit. Main Outcomes and Measures Progression of diabetes, hyperlipidemia, and hypertension and declines in physical and mental health–related quality of life and satisfaction with surgery. Results Among the 1406 participants who underwent RYGB surgery, the median age was 47 years (25th-75th percentile, 38-55 years) and the median BMI was 46.3 (25th-75th percentile, 42.3-51.8) prior to surgery. Most participants were female (80.3%) and white (85.6%). The median follow-up was 6.6 years (25th-75th percentile, 5.9-7.0 years). The median percentage of maximum weight loss was 37.4% (25th-75th percentile, 31.6%-43.3%) of presurgery weight and occurred a median of 2.0 years after RYGB surgery (25th-75th percentile, 1.0-3.2 years). The rate of weight regain was highest during the first year after reaching nadir weight, but weight regain continued to increase throughout follow-up (range, a median of 9.5% of maximum weight lost [25th-75th percentile, 4.7%-17.2%] to 26.8% of maximum weight lost [25th-75th percentile, 16.7%-41.5%] 1 to 5 years after reaching nadir weight). The percentage of participants who regained weight depended on threshold (eg, 5 years after nadir weight, 43.6% regained ≥5 BMI points; 50.2% regained ≥15% of nadir weight; and 67.3% regained ≥20% of maximum weight lost). Compared with other continuous weight regain measures, the percentage of maximum weight lost had the strongest association and best model fit for all outcomes except hyperlipidemia, which had a slightly stronger association with BMI. Of the dichotomous measures, 20% or greater of maximum weight lost performed better or similarly with most of the outcomes, and was the second best measure for hyperlipidemia (after ≥10 kg of weight) and hypertension (after ≥10% of maximum weight lost). Conclusions and Relevance Among a large cohort of adults who underwent RYGB surgery, weight regain quantified as percentage of maximum weight lost performed better for association with most clinical outcomes than the alternatives examined. These findings may inform standardizing the measurement of weight regain in studies of bariatric surgery.

Hepatitis B virus (HBV) persists with global and virus-specific T-cell dysfunction, without T-cell based correlates of outcomes. To determine if γδT-cells are altered in HBV infection relative to clinical status, we examined the frequency, phenotype and function of peripheral blood Vδ1(+) and Vδ2(+)γδT-cells by multi-parameter cytometry in a clinically diverse North American cohort of chronic hepatitis B (CHB), acute hepatitis B (AHB) and uninfected control subjects. We show that circulating γδT-cells were comprised predominantly of CD3(hi)CD4(-) Vδ2(+)γδT-cells with frequencies that were 2–3 fold higher among Asian than non-Asian Americans and inversely correlated with age, but without differences between CHB, AHB and control subjects. However, compared to control subjects, CHB was associated with increased Tbet(hi)Eomes(dim) phenotype in Vδ2(+)γδT-cells whereas AHB was associated with increased Tbet(hi)Eomes(dim) phenotype in Vδ1(+)γδT-cells, with significant correlations between Tbet/Eomes expression in γδT-cells with their expression of NK and T-cell activation and regulatory markers. As for effector functions, IFNγ/TNF responses to phosphoantigens or PMA/Ionomycin in Vδ2(+)γδT-cells were weaker in AHB but preserved in CHB, without significant differences for Vδ1(+)γδT-cells. Furthermore, early IFNγ/TNF responses in Vδ2(+) γδT-cells to brief PMA/Ionomycin stimulation correlated inversely with serum ALT but not HBV DNA. Accordingly, IFNγ/TNF responses in Vδ2(+)γδT-cells were weaker in patients with CHB with hepatitis flare compared to those without hepatitis flares, and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating γδT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes.