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In medical studies, some therapeutic decisions could lead to dependent censoring for the survival outcome of interest. This is exemplified by a study of paediatric acute liver failure, where death was subject to dependent censoring due to liver transplantation. Existing methods for assessing the predictive performance of biomarkers often pose the independent censoring assumption and are thus not applicable. In this work, we propose to tackle the dependence between the failure event and dependent censoring event using auxiliary information in multiple longitudinal risk factors. We propose estimators of sensitivity, specificity and area under curve, to discern the predictive power of biomarkers for the failure event by removing the disturbance of dependent censoring. Point estimation and inferential procedures were developed by adopting the joint modelling framework. The proposed methods performed satisfactorily in extensive simulation studies. We applied them to examine the predictive value of various biomarkers and risk scores for mortality in the motivating example.

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.

To examine associations of objectively-measured free-living physical activity (PA) with changes in depressive symptoms and mental and physical health-related quality of life (HRQoL) over 7 years after Roux-en-Y gastric bypass surgery (RYGB).The contributions of PA to improvements in mental and physical health after RYGB, independent of weight loss, are unclear.Adults undergoing RYGB in a US multi-center cohort study wore an activity monitor and completed the Beck depression inventory (BDI) and 36-Item Short Form Health Survey (SF-36) annually ≤7 years (N = 646; 78% female, median age 47 years, median body mass index 46kg/m 2 ). Linear mixed models estimated associations of quartiles of steps, sedentary behavior (SB), and moderate-to-vigorous intensity physical activity (MVPA), respectively, with pre-to-post-surgery changes in the BDI and SF-36 mental component summary and physical component summary scores, respectively, over 1-7 years post-surgery, with adjustment for sex, age, race, pre-surgerybody mass index, the respective pre-surgery score, treatment for depression (time-varying) and pre-to-post-surgery weight change (time-varying).There were dose-response associations between steps, SB (inverse) and MVPA quartiles, respectively, with improvements in each score. Across follow-up, mean improvements in the BDI, Mental Component Summary and physical component summary scores, were 1.9 [95% confidence interval (CI), 1.0-2.8], 3.1 (95% CI, 1.5-4.7), and 4.0 (95% CI, 2.7-5.4) points higher, respectively, in the highest versus lowest steps quartile.Among adults who underwent RYGB, multiple objective PA measures were associated with decreases in depressive symptoms and improvements in mental and physical HRQoL throughout 7 years, independent of weight loss, indicating PA is a modifiable behavior to augment outcomes.

Introduction and objectives Universal vaccination at birth and in infancy is key to the elimination of chronic hepatitis B infection. We aimed to assess hepatitis B immune-prophylaxis and perinatal transmission knowledge, in a large and ethnically diverse cohort of previously pregnant North American women, chronically infected with hepatitis B. Materials and methods The Hepatitis B Research Network (HBRN) is comprised of 28 Clinical Centers in the United States and Canada. Female cohort participants were administered a questionnaire to assess: (1) their assertion of knowledge regarding HBV prophylaxis at birth, testing, and diagnosis of hepatitis B in their children, and (2) the percentage of affirmative to negative responses for each of the HBV-related interventions her child may have received. The relationship between asserted knowledge, actions taken and maternal demographics were assessed. Results A total of 351 mothers with 627 children born in or after 1992 were included. Median age at enrollment was 39.8 years. Mothers were mostly foreign-born with the largest percentage from Asia (73.4%) and Africa (11.7%). Of the 627 children, 94.5% had mothers who asserted that they knew whether their child had received HBIG or HBV vaccine at birth, for 88.8% of the children, their mothers indicated that they knew if their child was tested for HBV and for 84.5% of children, their mothers knew if the child was diagnosed with HBV infection. Among children whose mothers asserted knowledge of their HBV management, 95.3% were reported to have received HBIG or HBV vaccine, 83.4% of children were said to have been tested for HBV, and 4.8% of children were said to have been diagnosed with HBV. Younger maternal age was the only factor significantly associated with higher percentage of children for whom mothers reported knowledge of testing (p = 0.02) or diagnosis of HBV (p = 0.02). Conclusions While high percentages of North American children had mothers asserting knowledge of HBV prophylaxis and testing, knowledge gaps remain, with mothers of 5.5–15.5% of children lacking knowledge of key components of the HBV prevention and diagnosis in the perinatal setting. Targeted education of HBsAg-positive mothers may aid in closing this gap and reducing vertical transmission.

OBJECTIVE To evaluate smoking history and change in smoking behavior, from 1 year before through 7 years after Roux-en-Y gastric bypass (RYGB) surgery, and to identify risk factors for post-surgery smoking. BACKGROUND Smoking behavior in the context of bariatric surgery is poorly described. METHODS Adults undergoing RYGB surgery entered a prospective cohort study between 2006 and 2009 and were followed up to 7 years until ≤2015. Participants (N = 1770; 80% female, median age 45 years, median body mass index 47 kg/m) self-reported smoking history pre-surgery, and current smoking behavior annually. RESULTS Almost half of participants (45.2%) reported a pre-surgery history of smoking. Modeled prevalence of current smoking decreased in the year before surgery from 13.7% [95% confidence interval (CI) = 12.1-15.4] to 2.2% (95% CI = 1.5-2.9) at surgery, then increased to 9.6% (95% CI = 8.1-11.2) 1-year post-surgery and continued to increase to 14.0% (95% CI = 11.8-16.0) 7-years post-surgery. Among smokers, mean packs/day was 0.60 (95% CI = 0.44-0.77) at surgery, 0.70 (95% CI = 0.62-0.78) 1-year post-surgery and 0.77 (95% CI = 0.68-0.88) 7-years post-surgery. At 7-years, smoking was reported by 61.7% (95% CI = 51.9-70.8) of participants who smoked 1-year pre-surgery (n = 221), 12.3% (95% CI = 8.5-15.7) of participants who formerly smoked but quit >1 year pre-surgery (n = 507), and 3.8% (95% CI = 2.1-4.9) of participants who reported no smoking history (n = 887). Along with smoking history (ie, less time since smoked), younger age, household income

Background Patients having bariatric surgery have lower mortality compared with those with similar body mass index who do not undergo surgery. It is unclear whether mortality post–bariatric surgery is similar to the general population. The benefit of bariatric surgery would be highlighted should people previously at high risk for premature death have comparable, or better, mortality as the general population. Objective To compare mortality after bariatric surgery to the general U.S. population of the same age, sex, and race. Setting The Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) prospective cohort of 2458 adults who underwent bariatric surgery at 10 U.S. hospitals between 2006 and 2009. Methods Deaths were identified via LABS-2 follow-up and the National Death Index. Standardized mortality ratios (SMR) of post–bariatric surgery mortality observed in LABS-2 versus age-, sex-, race-, and year-adjusted expected mortality in the general U.S. population were calculated and compared with 1, which results when the number of observed and expected deaths are equal. Results LABS-2 median follow-up was 6.6 (interquartile range: 5.9–7.0) years postsurgery. Seventy-six deaths were observed over 15,616 person-years (PY) of observation (4.9 deaths/1000 PY). The rate expected in the general U.S. population with the same age, sex, race, and year distribution was 4.8 deaths per 1000 PY (SMR = 1.02, 95% confidence interval [CI]: .80–1.27). There were no significant differences between observed and expected mortality by surgical procedure. Compared with expected mortality in the general U.S. population, people 35–44 years old at time of surgery had significantly more deaths (SMR = 2.06, 95% CI: 1.22–3.25), while people at least 55 years of age had significantly fewer (SMR = .63, 95% CI: .42–.92). Significantly more deaths than expected occurred in the perioperative period and 5–7 years after surgery. Conclusions Mortality within 7 years of bariatric surgery is comparable to the general U.S. population, which is likely to have better survival than people with severe obesity. However, more deaths than expected were identified 5–7 years after surgery.

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.

Background Postbariatric hypoglycemia (PBH) can be a devastating complication for which current therapies are often incompletely effective. More information is needed regarding frequency, incidence, and risk factors for PBH. Objectives To examine hypoglycemia symptoms following Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) and baseline and in-study risk factors. Setting Multicenter, at 10 US hospitals in 6 geographically diverse clinical centers. Methods A prospective, longitudinal cohort study of adults undergoing RYGB or LAGB as part of clinical care between 2006 and 2009 were recruited and followed until January 31, 2015, with baseline and annual postoperative research assessments. We analyzed baseline prevalence and post-operative incidence and frequency of self-reported hypoglycemia symptoms as well as potential preoperative risk factors. Results In all groups, postoperative prevalence of hypoglycemia symptoms was 38.5%. Symptom prevalence increased postoperatively from 2.8%–36.4% after RYGB in patients without preoperative diabetes (T2D), with similar patterns in prediabetes (4.9%–29.1%). Individuals with T2D had higher baseline hypoglycemia symptoms (28.9%), increasing after RYGB (57.9%). Hypoglycemia symptoms were lower after LAGB, with 39.1% reported hypoglycemia symptoms at only 1 postoperative visit with few (4.0%) having persistent symptoms at 6 or more annual visits. Timing of symptoms was not restricted to the postprandial state. Symptoms of severe hypoglycemia were reported in 2.6–3.6% after RYGB. The dominant risk factor for postoperative symptoms was preoperative symptoms; additionally, baseline selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitor use was also associated with increased risk in multivariable analysis. Weight loss and regain were not related to hypoglycemia symptom reporting. Conclusion Hypoglycemia symptoms increase over time after RYGB, particularly in patients without diabetes. In a small percentage, symptoms can be persistent or severe and require hospitalization. Preoperative hypoglycemia symptoms and SSRI/SNRI use in RYGB patients without diabetes is associated with increased risk of symptoms.

To examine associations of objectively-measured physical activity (PA) with changes in weight after roux-en-Y gastric bypass (RYGB) over 7 years.The contribution of free-living PA to surgery-induced weight loss and subsequent weight regain is not well understood.Participants of a multi-center prospective cohort study of bariatric surgery were followed annually ≥7 years. Of 807 participants who underwent RYGB and were given an activity monitor, 649 (80%) had sufficient data for this report (78% female; median age 47 years; median body mass index 46 kg/m2). Mean daily steps, hours/day in SB and minutes/week in moderate-to-vigorous physical activity (MVPA) were determined at each assessment. Mixed models tested associations between PA measures and weight outcomes, controlling for sociodemographics, health status, and eating behaviors.Across follow-up, mean pre to postsurgery changes in PA were small, and mean postsurgery PA level was below PA recommendations for health (eg, 101 MVPA min/week 7 years postsurgery versus the ≥150 MVPA min/week recommendation). There was a dose-response association between more steps, less SB and more MVPA with greater weight loss. Steps and SB, but not MVPA, were also associated with weight regain. For example, participants in the highest versus lowest steps quartile lost 2.9% (95% confidence interval, 1.8-4.1) more of their presurgery weight and regained 5.4% (95% confidence interval, 2.4-8.3) less of their maximum weight lost across follow-up.Despite only small increases in objectively-measured PA level after RYGB, PA level was independently associated with weight outcomes of bariatric surgery throughout 7 years of follow-up.Reprints will not be available from the authors.

BACKGROUND AND AIMS: Outcomes of persons with chronic hepatitis B virus (HBV) infection in the era of antiviral therapy (AVT) are not well characterized. We determined the incidence and factors associated with clinical outcomes in a multiethnic, North American cohort of adults with chronic HBV infection, who were not on AVT at enrollment. APPROACH AND RESULTS: Adults with chronic HBV infection, not receiving AVT, and without a history of decompensation, HCC, or liver transplantation (LT), were prospectively followed. Participants with known human immunodeficiency virus (HIV), hepatitis C virus, or hepatitis D virus (HDV) coinfection were excluded. During follow-up, treatment could be initiated per standard of care. Clinical outcomes included: incident cirrhosis, decompensation, HCC, OLT, and HBV-related death. Among 1,418 participants analyzed, 51.5% were women, median age was 41.1 years, 75% were Asian, 10% White, 13% Black, 24% HBeAg(+), and 1.5% cirrhosis at baseline. During the study, 274 started treatment, 83 had an alanine aminotransferase flare, 118 of 330 initially HBeAg(+) became HBeAg(−), and 90 of 1,329 became HBsAg(−). After 6,641 person-years follow-up, 8 participants (4 of 21 with baseline cirrhosis) had 12 clinical outcomes (2 decompensation, 5 HCC, 2 OLT, and 3 HBV-related deaths) and 19 of 1,397 had incident cirrhosis. Twenty-one of 26 participants had first outcome before treatment, none had become HBsAg(−), whereas 5/9 HBeAg(+) had become HBeAg(−) at time of first outcome. Cumulative percentage of clinical outcomes was 16% at year 4 in participants with baseline cirrhosis and 2% (including incident cirrhosis) at year 7 in those without. CONCLUSIONS: Incidence of adverse outcomes was low in this closely monitored, large cohort of North American adults with predominantly inactive, chronic HBV without cirrhosis. Our data highlight the benefits of HBsAg loss and the importance of early diagnosis and treatment to prevent cirrhosis and other complications of chronic HBV infection.

To evaluate smoking history and change in smoking behavior, from 1 year before through 7 years after Roux-en-Y gastric bypass (RYGB) surgery, and to identify risk factors for post-surgery smoking.Smoking behavior in the context of bariatric surgery is poorly described.Adults undergoing RYGB surgery entered a prospective cohort study between 2006 and 2009 and were followed up to 7 years until ≤2015. Participants (N = 1770; 80% female, median age 45 years, median body mass index 47 kg/m2) self-reported smoking history pre-surgery, and current smoking behavior annually.Almost half of participants (45.2%) reported a pre-surgery history of smoking. Modeled prevalence of current smoking decreased in the year before surgery from 13.7% [95% confidence interval (CI) = 12.1-15.4] to 2.2% (95% CI = 1.5-2.9) at surgery, then increased to 9.6% (95% CI = 8.1-11.2) 1-year post-surgery and continued to increase to 14.0% (95% CI = 11.8-16.0) 7-years post-surgery. Among smokers, mean packs/day was 0.60 (95% CI = 0.44-0.77) at surgery, 0.70 (95% CI = 0.62-0.78) 1-year post-surgery and 0.77 (95% CI = 0.68-0.88) 7-years post-surgery. At 7-years, smoking was reported by 61.7% (95% CI = 51.9-70.8) of participants who smoked 1-year pre-surgery (n = 221), 12.3% (95% CI = 8.5-15.7) of participants who formerly smoked but quit1 year pre-surgery (n = 507), and 3.8% (95% CI = 2.1-4.9) of participants who reported no smoking history (n = 887). Along with smoking history (ie, less time since smoked), younger age, household income$25,000, being married or living as married, and illicit drug use were independently associated with increased risk of post-surgery smoking.Although most adults who smoked 1-year before RYGB quit pre-surgery, smoking prevalence rebounded across 7-years, primarily due to relapse.

Background Data from a US multicenter longitudinal study of bariatric surgery were used to compare weight change (primary outcome) and comorbidities (secondary outcome) in patients who underwent sleeve gastrectomy versus Roux-en-Y gastric bypass. Methods This study includes participants who underwent sleeve gastrectomy and matched participants who underwent Roux-en-Y gastric bypass from the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) study. Adults undergoing initial bariatric surgical procedures between 2006 and 2009 were enrolled. Participants who underwent sleeve gastrectomy were high-risk or superobese and intended to have a second-stage procedure. Mixed models were used to evaluate percent weight change from baseline through 7 years, and diabetes, dyslipidemia, and hypertension prevalence through 5 years. Results Fifty-seven of 59 participants who underwent sleeve gastrectomy were matched one to one. Most were female (68%) and white (81%), and had a median age of 49 (37–56) years and median body mass index of 56.4 (35.5–76.8) kg/m2 presurgery. Weight loss was significantly less 1 to 7 years after sleeve gastrectomy versus matched Roux-en-Y gastric bypass (eg, year 7 mean weight loss was 23.6% vs 30.4%, respectively; P = .001). For both surgical groups, prevalence of diabetes, low high-density lipoprotein, and hypertension were significantly (P Conclusion Higher-risk or super-obese participants after sleeve gastrectomy lost less weight than did matched Roux-en-Y gastric bypass counterparts throughout 7 years. Both groups exhibited improvements in comorbidities from presurgery through 5 years.

Background Limited evidence suggests bariatric surgery may not reduce opioid analgesic use, despite improvements in pain. Objective To determine if use of prescribed opioid analgesics changes in the short and long term after bariatric surgery and to identify factors associated with continued and postsurgery initiated use. Setting Ten U.S. hospitals. Methods The Longitudinal Assessment of Bariatric Surgery-2 is an observational cohort study. Assessments were conducted presurgery, 6 months postsurgery, and annually postsurgery for up to 7 years until January 2015. Opioid use was defined as self-reported daily, weekly, or "as needed" use of a prescribed medication classified as an opioid analgesic. Results Of 2258 participants with baseline data, 2218 completed follow-up assessment(s) (78.7% were female, median body mass index: 46; 70.6% underwent Roux-en-Y gastric bypass). Prevalence of opioid use decreased after surgery from 14.7% (95% CI: 13.3–16.2) at baseline to 12.9% (95% CI: 11.5–14.4) at month 6 but then increased to 20.3%, above baseline levels, as time progressed (95% CI: 18.2–22.5) at year 7. Among participants without baseline opioid use (n = 1892), opioid use prevalence increased from 5.8% (95% CI: 4.7–6.9) at month 6 to 14.2% (95% CI: 12.2–16.3) at year 7. Public versus private health insurance, more pain presurgery, undergoing subsequent surgeries, worsening or less improvement in pain, and starting or continuing nonopioid analgesics postsurgery were significantly associated with higher risk of postsurgery initiated opioid use. Conclusion After bariatric surgery, prevalence of prescribed opioid analgesic use initially decreased but then increased to surpass baseline prevalence, suggesting the need for alternative methods of pain management in this population.

Background Pediatric acute liver failure (PALF) is a public heath burden, often requiring prolonged hospitalization and liver transplantation. Hepatic encephalopathy (HE) is a complication of PALF with limited diagnostic tools to predict outcomes. Serum neurological markers (neuron-specific enolase, S100β, and myelin basic protein) can be elevated in traumatic or ischemic brain injury. We hypothesized that these neuromarkers would be associated with the development of HE in PALF. Methods PALF study participants enrolled between May 2012 and December 2014 by 12 participating centers were the subjects of this analysis. Daily HE assessments were determined by study investigators. Neurological and inflammatory markers were measured using enzyme-linked immunosorbent assay and MILLIPLEX techniques, respectively. To model encephalopathy, these markers were log2 transformed and individually examined for association with HE using a generalized linear mixed model with a logit link and random intercept. Results Eighty-two children had neurological and inflammatory marker levels and HE assessments recorded, with the majority having assessments for 3 days during their illness. An indeterminate diagnosis (29%) was most common and the median age was 2.9 years. Significant associations were observed for HE with S100β (odds ratio 1.16, 95% confidence interval [1.03-1.29], P = 0.04) and IL-6 (odds ratio 1.24 [1.11-1.38], P = 0.006). Conclusions Serum S100β and IL-6 are associated with HE in children with PALF. Measuring these markers may assist in assessing neurological injury in PALF, impacting clinical decisions.

Author(s): Tate, Deborah F; Lytle, Leslie; Polzien, Kristen; Diamond, Molly; Leonard, Kelsey R; Jakicic, John M; Johnson, Karen C; Olson, Christine M; Patrick, Kevin; Svetkey, Laura P; Wing, Rena R; Lin, Pao-Hwa; Coday, Mathilda; Laska, Melissa N; Merchant, Gina; Czaja, Sara J; Schulz, Richard; Belle, Steven H | Abstract: ObjectiveThe goal of the present study was to deconstruct the 17 treatment arms used in the Early Adult Reduction of weight through LifestYle (EARLY) weight management trials.MethodsIntervention materials were coded to reflect behavioral domains and behavior change techniques (BCTs) within those domains planned for each treatment arm. The analytical hierarchy process was employed to determine an emphasis profile of domains in each intervention.ResultsThe intervention arms used BCTs from all of the 16 domains, with an average of 29.3 BCTs per intervention arm. All 12 of the interventions included BCTs from the six domains of Goals and Planning, Feedback and Monitoring, Social Support, Shaping Knowledge, Natural Consequences, and Comparison of Outcomes; 11 of the 12 interventions shared 15 BCTs in common across those six domains.ConclusionsWeight management interventions are complex. The shared set of BCTs used in the EARLY trials may represent a core intervention that could be studied to determine the required emphases of BCTs and whether additional BCTs add to or detract from efficacy. Deconstructing interventions will aid in reproducibility and understanding of active ingredients.

INTRODUCTION Alterations in the immune system can result in alanine aminotransferase (ALT) flares either during pregnancy or after delivery in women with chronic hepatitis B virus (HBV) infection. The aim of this study was to prospectively assess changes in serum biochemical and virological markers of HBV infection during and after pregnancy in a large North American cohort of pregnant women with chronic HBV. METHODS Adult pregnant women enrolled in the Hepatitis B Research Network between 2011 and 2016 were included. Serum ALT values and HBV DNA viral levels were obtained at 28 weeks of gestation and

Background Patients with chronic hepatitis B virus (HBV) may experience spontaneous biochemical flares of liver disease activity. This study aimed to determine (i) the prevalence of prior and possible acute hepatitis E virus (HEV) infection among persons with chronic HBV and (ii) whether HEV infection is associated with liver disease flares among persons with chronic HBV. Methods Serum from a random sample of 600 adults in the Hepatitis B Research Network Cohort Study was tested for HEV RNA and anti-HEV IgM and IgG. Logistic regression models were used to estimate crude and adjusted odds ratios of anti-HEV prevalence for participant characteristics. Results Anti-HEV IgG and IgM seroprevalence was 28.5% and 1.7%, respectively. No participants had detectable HEV RNA. Of the 10 anti-HEV IgM+ participants, only 1 had elevated serum ALT at seroconversion. The odds of anti-HEV seropositivity (IgG+ or IgM+) were higher in older participants, males, Asians, less educated people, and those born outside the United States and Canada. Conclusions Acute HEV infection is a rare cause of serum ALT flares among persons with chronic HBV. The high seroprevalence of anti-HEV IgG among the chronic HBV patients is strongly associated with various demographic factors in this largely Asian American cohort.

OBJECTIVE: To identify patient behaviors and characteristics related to weight regain following Roux-en-Y gastric bypass surgery (RYGB). BACKGROUND: There is considerable variation in the magnitude of weight regain following RYGB, highlighting the importance of patient-level factors. METHODS: A prospective cohort study of adults who underwent bariatric surgery in six US cities between 2006-2009 included pre-surgery, six month and annual assessments for up to seven years. Of 1573 eligible participants, 1278 (81%) with adequate follow-up were included (80% female, median age 46 years, median body mass index 46 kg/m(2)). Percentage of maximum weight lost was calculated each year following weight nadir. RESULTS: Weight was measured a median of 8 (25(th)-75(th)percentile, 7-8) times over a median of 6.6 (25(th)-75(th)percentile, 5.9-7.0) years. β coefficients, i.e. the mean weight regain, compared to the reference, and 95% confidence interval are reported. Post-surgery behaviors independently associated with weight regain were: sedentary time (2.9%, [1.2-4.7], for highest versus lowest quartile), eating fast food (0.5%, [0.2-0.7], per meal/week), eating when feeling full (2.9%, [1.2-4.5]), eating continuously (1.6%, [0.1-3.1]), binge eating and loss of control eating (8.0%, [5.1-11.0] for binge eating; 1.6, [−0.1-3.3], for loss of control, versus neither), and weighing oneself < weekly (4.2%, [2.9-5.4]). Post-surgery characteristics independently associated with greater weight regain included: younger age, venous edema, poorer physical function, and more depressive symptoms. CONCLUSION: Several behaviors and characteristics associated with greater weight regain were identified, which inform integrated health care approaches to patient care and identify high-risk patients to improve long-term weight loss maintenance after RYGB.

The optimal management strategy for children with immune-tolerant chronic hepatitis B virus (HBV) infection remains unknown. The purpose of this clinical trial was to determine the safety and efficacy of therapy with entecavir and peginterferon in a group of children in the immune-tolerant phase of HBV infection. Children with immune-tolerant features of chronic hepatitis B (CHB) received entecavir once-daily in a dose of 0.015 mg/kg (0.5 mg maximum) for 48 weeks; peginterferon alfa-2a (180 µg/1.73m2 subcutaneously) once-weekly was added at the end of week 8 and continued until week 48. The primary endpoint was lack of detectable hepatitis B e antigen (HBeAg) with HBV DNA levels ≤1,000 IU/mL 48 weeks after stopping therapy. Sixty children (75% female), median age 10.9 (range, 3.4-17.9) years, were enrolled. All were positive for hepatitis B surface antigen (HBsAg) and HBeAg and had high levels of HBV DNA with normal or minimally elevated levels of alanine aminotransferase (ALT). Fifty-five children completed the entire 48-week course of therapy. At 48 weeks after treatment ended (week 96), 2 children (3%) achieved the primary endpoint and were also HBsAg negative and anti-hepatitis B surface antigen antibody (anti-HBs) positive. One child was HBeAg positive but HBsAg negative at week 60; another was HBeAg negative but HBsAg positive at week 72, which were their last clinic visits. In the remaining children, serum ALT and HBV DNA levels at week 96 were similar to baseline. Thirty-seven children experienced adverse events (AEs), and 1 had a serious AE (SAE). Conclusion: The combination of entecavir and peginterferon for up to 48 weeks rarely led to loss of HBeAg with sustained suppression of HBV DNA levels in children in the immune-tolerant phase of HBV infection, and treatment was associated with frequent AEs.

Background Some studies suggest that changes in weight or metabolic outcomes are affected by the lengths of the gastrointestinal limbs in the Roux-en-Y gastric bypass. Methods Participants (N = 1,770) underwent primary Roux-en-Y gastric bypass and were followed ≤7 years in the Longitudinal Assessment of Bariatric Surgery-2, a multicenter US cohort study. Alimentary limb and biliopancreatic limb lengths were measured according to research protocol; common channel was measured in a subsample (N = 547). Aimentary limb, biliopancreatic limb, and common channel ratio to total small bowel length were calculated. Results Median presurgery body mass index was 46 (25th–75th percentile: 43–51) kg/m2. Medians (25th–75th percentiles) for alimentary limb length were 125 cm (100–150), for biliopancreatic limb length were 50 cm (50–60), and common channel length were 410 cm (322–520). Statistics for ratios to the small bowel length were 0.23 (0.18–0.27) for alimentary limb, 0.09 (0.07–0.10) for biliopancreatic limb, and 0.69 (0.63–0.73) for common length. There were no significant associations between alimentary limb, biliopancreatic limb, common channel, alimentary limb ratio, biliopancreatic limb ratio or common channel ratio, and either weight loss or improvement in cardiometabolic outcomes. Conclusion The common channel length in Roux-en-Y gastric bypass is highly variable between individuals. None of the limb lengths in this study, nor alimentary limb, biliopancreatic limb, or common channel ratios, seem to be related to weight loss or metabolic improvements >7 years.

Hepatitis B e antigen (HBeAg) is an important serological marker of hepatitis B virus (HBV) infection and is associated with higher levels of viraemia, increased risk of infectivity to others and increased risk of hepatocellular carcinoma. We analysed HBeAg status in a large cohort of adults and children enrolled in Cohort Studies of the Hepatitis B Research Network, long-term natural history studies of chronic HBV infection. A cross-sectional analysis examined factors associated with HBeAg positivity, including demographic and virologic data, across the age spectrum. Among 2241 enrolled participants who met criteria for this analysis, 825 (37%) were seropositive for HBeAg. The prevalence of HBeAg was lower in those with older age, ranging from 85% among those up to 10 years of age to only 12% among those older than 50 years. In addition to age, both race and HBV genotype were independently associated with HBeAg positivity. There was a significant interaction between age and race; the prevalence of HBeAg was significantly higher among Asians > 10-30 years old vs Whites or Blacks who were >10 to 30 years old and those infected with HBV genotype C. Conversely, the presence of the basal core promoter and precore variants was associated with significantly lower prevalence of HBeAg, even when adjusted for age, race and genotype. These data will provide a better understanding of factors associated with seropositivity for HBeAg and may lead to better strategies for preventing HBV infection and broader indications for antiviral therapy.

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.

Combining and analyzing data from heterogeneous randomized controlled trials of complex multiple-component intervention studies, or discussing them in a systematic review, is not straightforward. The present article describes certain issues to be considered when combining data across studies, based on discussions in an NIH-sponsored workshop on pooling issues across studies in consortia (see Belle et al. in Psychol Aging, 18(3):396-405, 2003). Several statistical methodologies are described and their advantages and limitations are explored. Whether weighting the different studies data differently, or via employing random effects, one must recognize that different pooling methodologies may yield different results. Pooling can be used for comprehensive exploratory analyses of data from RCTs and should not be viewed as replacing the standard analysis plan for each study. Pooling may help to identify intervention components that may be more effective especially for subsets of participants with certain behavioral characteristics. Pooling, when supported by statistical tests, can allow exploratory investigation of potential hypotheses and for the design of future interventions.

Background Few studies have examined the effect of a behavioral weight loss intervention (BWLI) on young adults (age = 18 to 35 years).

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.

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

IMPORTANCE: More information is needed about the durability of weight loss and health improvements after bariatric surgical procedures. OBJECTIVE: To examine long-term weight change and health status following Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB). DESIGN, SETTING, AND PARTICIPANTS: The Longitudinal Assessment of Bariatric Surgery (LABS) study is a multicenter observational cohort study at 10 US hospitals in 6 geographically diverse clinical centers. Adults undergoing bariatric surgical procedures as part of clinical care between 2006 and 2009 were recruited and followed up until January 31, 2015. Participants completed presurgery, 6-month, and annual research assessments for up to 7 years. MAIN OUTCOME AND MEASURES: Percentage of weight change from baseline, diabetes, dyslipidemia, and hypertension, determined by physical measures, laboratory testing, and medication use. RESULTS: Of 2348 participants, 1738 underwent RYGB (74%) and 610 underwent LAGB (26%). For RYBG, the median age was 45 years (range, 19-75 years), the median body mass index (calculated as weight in kilograms divided by height in meters squared) was 47 (range, 34-81), 1389 participants (80%) were women, and 257 participants (15%) were nonwhite. For LAGB, the median age was 48 years (range, 18-78), the body mass index was 44 (range, 33-87), 465 participants (76%) were women, and 63 participants (10%) were nonwhite. Follow-up weights were obtained in 1300 of 1569 (83%) eligible for a year-7 visit. Seven years following RYGB, mean weight loss was 38.2 kg (95% CI, 36.9-39.5), or 28.4% (95% CI, 27.6-29.2) of baseline weight; between years 3 and 7 mean weight regain was 3.9% (95% CI, 3.4-4.4) of baseline weight. Seven years after LAGB, mean weight loss was 18.8 kg (95% CI, 16.3-21.3) or 14.9% (95% CI, 13.1-16.7), with 1.4% (95% CI, 0.4-2.4) regain. Six distinct weight change trajectory patterns for RYGB and 7 for LAGB were identified. Most participants followed trajectories in which weight regain from 3 to 7 years was small relative to year-3 weight loss, but patterns were variable. Compared with baseline, dyslipidemia prevalence was lower 7 years following both procedures; diabetes and hypertension prevalence were lower following RYGB only. Among those with diabetes at baseline (488 of 1723 with RYGB [28%]; 175 of 604 with LAGB [29%]), the proportion in remission at 1, 3, 5, and 7 years were 71.2% (95% CI, 67.0-75.4), 69.4% (95% CI, 65.0-73.8), 64.6% (95% CI, 60.0-69.2), and 60.2% (95% CI, 54.7-65.6), respectively, for RYGB and 30.7% (95% CI, 22.8-38.7), 29.3% (95% CI, 21.6-37.1), 29.2% (95% CI, 21.0-37.4), and 20.3% (95% CI, 9.7-30.9) for LAGB. The incidence of diabetes at all follow-up assessments was less than 1.5% for RYGB. Bariatric reoperations occurred in 14 RYGB and 160 LAGB participants. CONCLUSIONS AND RELEVANCE: Following bariatric surgery, different weight loss patterns were observed, but most participants maintained much of their weight loss with variable fluctuations over the long term. There was some decline in diabetes remission over time, but the incidence of new cases is low following RYGB. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00465829

Background & Aims Many pediatric patients with acute liver failure (PALF) do not receive a specific diagnosis (such as herpes simplex virus or Wilson disease or fatty acid oxidation defects)—they are left with an indeterminate diagnosis and are more likely to undergo liver transplantation, which is contraindicated for some disorders. Strategies to facilitate complete diagnostic testing should increase identification of specific liver diseases and might reduce liver transplantation. We investigated whether performing recommended age-specific diagnostic tests (AS-DTs) at the time of hospital admission reduces the percentage PALFs with an indeterminate diagnosis. Methods We performed a multinational observational cohort study of 658 PALF participants in the United States and Canada, enrolled at 10 medical centers, during 3 study phases from December 1999 through December 2014. A learning collaborative approach was used to implement AS-DT using an electronic medical record admission order set at hospital admission in phase 3 of the study. Data from 10 study sites participating in all 3 phases were compared before (phases 1 and 2) and after (phase 3) diagnostic test recommendations were inserted into electronic medical record order sets. Results The percentage of subjects with an indeterminate diagnosis decreased significantly between phases 1–2 (48.0%) and phase 3 (to 30.8%) (P = .0003). The 21-day cumulative incidence rates for liver transplantation were significantly different among phase 1 (34.6%), phase 2 (31.9%), and phase 3 (20.2%) (P = .030). The 21-day cumulative incidence rates for death did not differ significantly among phase 1 (17.9%), phase 2 (11.9%), and phase 3 (11.3%) (P = .20). Conclusions In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children.

Objective To evaluate change in sedentary behavior (SB) and physical activity (PA) over 3 years following bariatric surgery. Methods A subset of participants in an observational study (n = 473 of 2,458; 79% female, median body mass index 45 kg m−2) wore an activity monitor presurgery and at 1-3 annual postsurgery assessments. Results Over the first year, on average, sedentary time decreased from 573 (95% CI: 563-582) to 545 (95% CI: 534-555) min days−1 and moderate- to vigorous-intensity PA (MVPA) increased from 77 (95% CI: 71-84) to 106 (95% CI: 98-116) min week−1, or 7 (95% CI: 5-10) to 24 (95% CI: 18-29) min week−1 in MVPA bouts ≥10 min. There were no changes in these parameters from years 1 to 3 (P for all > 0.05). The percentage of participants achieving ≥150 min week−1 of bout-related MVPA was not different at year 3 [6.5% (95% CI: 3.1-12.7)] vs. presurgery [3.4% (95% CI: 1.8-5.0); P = 0.45]. Most participants followed SB and PA trajectories that paralleled mean change and were consistent with their presurgery position in relation to the group. Conclusions On average, bariatric surgical patients make small reductions in SB and increases in PA during the first postsurgery year, which are maintained through 3 years. Still, postsurgery PA levels fall short of PA guidelines for general health or weight control.

Objective:Viral infections are often suspected to cause pediatric acute liver failure (PALF), but large-scale studies have not been performed. We analyzed the results of viral testing among nonacetaminophen PALF study participants.Methods:Participants were enrolled in the PALF registry. Diag

Liver biopsy is not routine during bariatric surgery. Alanine aminotransferase (ALT) is widely used to screen for liver disease. We assessed the relationship between ALT and pathology in biopsies from Longitudinal Assessment of Bariatric Surgery (LABS) patients with normal preoperative ALTs. Biopsies from the LABS-1 and LABS-2 studies were scored using the NASH CRN and Ishak systems. Diagnosis and histology were examined in relation to alanine aminotransferase (ALT) values. Six-hundred ninety-three suitable biopsies were evaluated. Biopsied patients had a median age of 45 years; 78.6% were female and 35.1% diabetic; median body mass index was 46 kg/m 2 . Six-hundred thirty-five biopsied patients had preoperative ALTs. Median ALT was 25 IU/L (interquartile range [IQR] 19–36 IU/L); 26.6% had an ALT > 35 IU/L and 29.9% exceeded the more restrictive Prati criteria for normal. Using the Prati criteria, 7.9% of participants with normal ALT had steatohepatitis and 5.3% had ≥ stage 2 fibrosis. Logistic regression models were used to predict the probabilities of having bridging fibrosis/cirrhosis or a diagnosis of borderline/definite steatohepatitis in the unbiopsied LABS-2 sample. The proportion of biopsied participants with these findings was very similar to the modeled results from the unbiopsied cohorts. We estimated that 86.0% of participants with advanced fibrosis and 88.1% of participants with borderline/definite steatohepatitis were not biopsied and went undiagnosed. As ALT did not reliably exclude significant obesity-related liver disease in bariatric surgery patients, consideration should be given to routine liver biopsy during bariatric surgery and medical follow-up of significant hepatic pathology.

Young adulthood has been identified as a high-risk period for the development of obesity but few interventions have been tested in this population. One way to escalate our learning about effective interventions is to test a number of interventions simultaneously as a consortium of research trials. This paper describes the Early Adult Reduction of weight through LifestYle intervention (EARLY) trials. Seven research sites were funded to conduct intervention trials, agreeing to test similar primary outcomes and cooperating to use a set of common measurement tools. The EARLY consortium was able to work cooperatively using an executive committee, a steering committee, workgroups and subcommittees to help direct the common work and implement a set of common protocol and measurement tools for seven independent but coordinated weight-related intervention trials. Using a consortium of studies to help young adults reach or maintain a healthy weight will result in increased efficiency and speed in understanding the most effective intervention strategies.

Baseline characteristics of participants in the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) study Steven H. Belle, Ph.D., M.Sc.Hyg.*, Paul D. Berk, M.D., William H. Chapman, M.D., Nicholas J. Christian, Ph.D., Anita P. Courcoulas, M.D., M.P.H., F.A.C.S., Greg F. Dakin, M.D., David R. Flum, M.D., M.P.H., F.A.C.S., Mary Horlick, M.D., Wendy C. King, Ph.D., Carol A. McCloskey, M.D., James E. Mitchell, M.D., Emma J. Patterson, M.D., John R. Pender, M.D., Kristine J. Steffen, Pharm.D., Ph.D., Richard C. Thirlby, M.D., Bruce M. Wolfe, M.D., F.A.C.S., Susan Z. Yanovski, M.D., for The LABS Consortium University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania Columbia University Medical Center, New York, New York East Carolina University, Greenville, North Carolina University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Weill Cornell University Medical Center, New York, New York University of Washington, Seattle, Washington National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland Neuropsychiatric Research Institute, Fargo, North Dakota Legacy Good Samaritan Hospital, Portland, Oregon Virginia Mason Medical Center, Seattle, Washington Oregon Health and Science University, Portland, Oregon Received January 23, 2013; accepted January 29, 2013

Background Although it is recognized that a standardized approach to reporting weight change is essential to meaningful comparisons among cohorts and across studies, consensus is lacking. This study aimed to propose a method of reporting weight change that would allow meaningful comparisons among studies of patients who underwent bariatric surgery and to demonstrate its utility using an example from the Longitudinal Assessment of Bariatric Surgery (LABS). Methods Relationships among several measures of weight change are described. Results from an observational, longitudinal cohort study of adults undergoing bariatric surgery and from simulation studies are used to illustrate the proposed method. Results Baseline weight is a critical parameter when assessing weight change. Men undergoing a bariatric procedure other than gastric bypass or adjustable band tended to have greater weight loss 12 months after surgery than men undergoing gastric bypass when not accounting for baseline weight, but the opposite was found when results were adjusted for baseline weight. Simulation results show that with relatively modest sample sizes, the adjusted weight loss was significantly different between the 2 groups of men. Conclusion A consistent metric for reporting weight loss after bariatric surgery is essential to interpret outcomes across studies and among subgroups. The baseline weight adjusted percent of weight loss (A%WL) uses a standard population (e.g., the LABS cohort) to account for differences between cohorts with respect to baseline weight, and its use can change the interpretation of results compared with an unadjusted measure.

Empirical distribution function (EDF) is a commonly used estimator of population cumulative distribution function. Survival function is estimated as the complement of EDF. However, clinical diagnosis of an event is often subjected to misclassification, by which the outcome is given with some uncertainty. In the presence of such errors, the true distribution of the time to first event is unknown. We develop a method to estimate the true survival distribution by incorporating negative predictive values and positive predictive values of the prediction process into a product-limit style construction. This will allow us to quantify the bias of the EDF estimates due to the presence of misclassified events in the observed data. We present an unbiased estimator of the true survival rates and its variance. Asymptotic properties of the proposed estimators are provided and these properties are examined through simulations. We evaluate our methods using data from the VIRAHEP-C study.

Background Retaining participants in observational longitudinal studies after bariatric surgery is difficult yet critical because the retention rate affects interpretation and generalizability of results. Strategies for keeping participants involved in such studies are not commonly published. The objective of this study was to review LABS retention strategies and present the 24-month retention data. Methods The LABS Consortium monitors an observational cohort study of 2458 adults enrolled before bariatric surgery at 10 centers within the United States (LABS-2). To maximize data completeness, the investigators developed retention strategies, including flexible scheduling, a call protocol, reminder letters, abbreviated visit options, honoraria, travel reimbursement, providing research progress reports, laboratory results, newsletters, study website, and retention surveys. Strategies for locating participants included frequent updates of contact information, sending registered letters, and searching medical and public records. Results At 12 and 24 months, 2426 and 2405 participants remained active, with vital status known for 98.7% and 97.3% and weight obtained for 95.2% and 92.2%, respectively. There were 148 missed visits (6.2%) at 24 months primarily because of inability to contact the participant. Only 15 (0.6%) active participants at 24 months missed all follow-up visits. Although 42 participants could not be located or contacted at 6 months, data were obtained for 23 (54.7%) of them at 12 months, and of the 52 participants who could not be located or contacted at 12 months, data were obtained for 18 (34.6%) at 24 months. Conclusion Longitudinal studies provide the ability to evaluate long-term effects of bariatric surgical procedures. The retention achieved in LABS is superior to that of many published reports but requires extensive effort and resources. This report identifies useful retention strategies. Further research is needed to identify the efficacy and cost-effectiveness of specific retention strategies.

We sought to determine whether markers of T-cell immune activation, including soluble interleukin 2 receptor alpha (sIL2Rα) levels predict outcome in pediatric acute liver failure and may target potential candidates for immunomodulatory therapy.We analyzed markers of immune activation in 77 patients with pediatric acute liver failure enrolled in a multinational, multicenter study. The outcomes were survival with native liver, liver transplantation (LT), and death without transplantation within 21 days after enrollment.Adjusting for multiple comparisons, only normalized serum sIL2Rα level differed significantly among the 3 outcomes, and was significantly higher in patients who died (P=0.02) or underwent LT (P=0.01) compared with those who survived with their native liver. The 37 patients with normal sIL2Rα levels all lived, 30 with their native liver. Of the 15 subjects with markedly high sIL2Rα (≥5000 IU/mL), 5 survived with their native liver, 2 died, and 8 underwent LT.Evidence of immune activation is present in some patients who die or undergo LT. Patients with higher sIL2Rα levels were more likely to die or undergo LT within 21 days than those with lower levels. Identifying a subset of patients at risk for poor outcome may form the foundation for targeted clinical trials with immunomodulatory drugs.

BACKGROUND: Acetaminophen (N-acetyl-p-aminophenol [APAP]) is a widely used medication that can cause hepatotoxicity. We examined characteristics and outcomes of children with chronic exposure (CE) to APAP in the multinational Pediatric Acute Liver Failure (PALF) Study. METHODS: A total of 895 children enrolled from 2002 to 2009 were grouped by APAP exposure history as: CE (received multiple doses \x{2265}2 days; n = 83), single dose exposure (SE; n = 85), and no exposure (NE; n = 498). CE was the reference group for pairwise comparisons. Median values are shown. RESULTS: Patients with CE compared with those with SE were younger (3.5 vs 15.2 years, P < .0001), less likely to be female (46% vs 82%, P < .0001), and more likely to be Hispanic (25% vs 7%, P = .001), but they did not differ significantly from the NE group. At enrollment, total bilirubin was lower with CE than with NE (3.2 vs 13.1 mg/dL, P < .001). Alanine aminotransferase levels were higher with CE than with NE (2384 vs 855 IU/L, P < .0001), but lower than with SE (5140 IU/L, P < .0001). Survival without liver transplantation at 21 days was worse for CE than for SE (68% vs 92%, P = .0004) but better than for NE (49%, P = .008). CONCLUSIONS: Children in the PALF study with CE had lower bilirubin and higher alanine aminotransferase than those with NE. Outcomes with CE were worse than with SE but better than with NE. Potential reasons for this outcomes advantage over non–APAP-exposed subjects should be explored.

Pediatric acute liver failure (PALF) is a rare and devastating syndrome in which previously healthy children rapidly lose hepatic function due to a variety of causes and become critically ill within days.(1–2) Management is largely supportive unless conditions that are amenable to directed therapy, such as acute acetaminophen toxicity, herpes virus, and potentially treatable causes such as Wilson disease and autoimmune hepatitis are identified and treated.(3–4) Early referral to a liver transplantation (LTx) center, improvements in medical management and LTx are associated with improved survival in PALF.(5) Long term outcomes following LTx for PALF are poor compared to other indications for LTx(6-7), hence the need to identify treatments that improve survival. N-acetylcysteine (NAC), used for treating acute acetaminophen (APAP) toxicity, has been used to treat non-APAP PALF but has not been rigorously tested in a multi-center placebo-controlled clinical trial in children.(8–9) NAC replenishes mitochondrial and cytosolic glutathione stores and is the treatment of choice for acute APAP toxicity.(10–11) Intravenous NAC became incorporated into the general management of acute liver failure in a number of sites in Europe and North America following a small uncontrolled study suggesting improved cardiovascular hemodynamics and oxygen transport in both APAP and non-APAP liver failure in adults.(12) A retrospective single-site review in children affirmed the view that NAC may provide benefit in PALF.(8) In a randomized trial of intravenous NAC versus placebo in adults with non-APAP liver failure, NAC did not improve survival at 21 days.(13) However, an analysis of the secondary outcomes revealed improved LTx-free survival at 3 weeks for those with grade 1–2 hepatic encephalopathy (HE). The primary objective of this study was to determine if a continuous intravenous infusion of NAC for up to seven days would improve overall survival compared to placebo one year following treatment allocation in non-APAP PALF.

OBJECTIVES Hepatic encephalopathy (HE) is challenging to identify in children with acute liver failure and was not a requirement for enrollment into the Pediatric Acute Liver Failure Study Group (PALFSG). The outcomes of PALFSG participants presenting with and without HE are presented. METHODS PALFSG participants were classified based on daily assessment of HE during the first 7 days following study enrollment: group 1-never developed HE; group 2-no HE at enrollment with subsequent HE development; and group 3-HE at study enrollment. Clinical and biochemical parameters and outcomes of death, spontaneous recovery, or liver transplantation were compared between groups. RESULTS Data from 769 PALFSG (54% boys; median age 4.2 years; range 0-17.9 years) participants were analyzed, with 277 in group 1 (36%), 83 in group 2 (11%), and 409 in group 3 (53%). Mortality occurred in 11% of all participants and was highest among group 3 participants who demonstrated persistent grade III-IV HE (55%) or showed progression of HE (26%). Eleven (4%) group 1 participants died within 21 days of enrollment. Spontaneous recovery was highest in group 1 (79%) and lowest in group 2 (25%; P