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In an aging population with cardiovascular comorbidities, anticoagulant (AC), antiplatelet (AP), and nonsteroidal anti-inflammatory drug (NSAID) use are increasing. It remains unclear whether these agents pose increased bleeding risk in cirrhosis. This study aimed to assess the association between these medications and bleeding and portal hypertension complications in cirrhosis.The IMS PharMetrics database was used to identify privately insured adults diagnosed with cirrhosis from 2007 to 2015, stratified as compensated or decompensated based on the presence of portal hypertensive complications 1 year before cirrhosis diagnosis. Bleeding or decompensation outcomes were assessed 6 to 18 months after cirrhosis diagnosis using a landmark analysis design. Multivariable Cox proportional hazards regression modeling assessed associations between AC, AP, and NSAID drug exposures and outcomes adjusting for covariates.A total of 18,070 cirrhosis patients were analyzed; 57% male; 74% ages 50 to 64 years; 34% with a prior decompensation. Overall, 377 (2%) had claims for ACs; 385 (2%) APs; and 1231 (7%) NSAIDs. APs were associated with increased bleeding [adjusted hazard ratio (aHR)=1.31; 95% confidence interval (CI): 1.00, 1.72] and decompensation events (aHR=1.44; 95% CI: 1.06, 1.95) in a 9-month landmark analysis. NSAIDs were significantly associated with bleeding events (aHR=1.29; 95% CI: 1.06, 1.57) on 3-month landmark analysis. No statistically significant associations were seen between ACs and bleeding or decompensation outcomes in adjusted analyses.AP use was associated with increased bleeding and decompensation events among privately insured patients with cirrhosis. NSAID use was associated with significant early bleeding, but not decompensations. Lastly ACs were not associated with bleeding or decompensation outcomes.

BACKGROUND: The presence of esophageal varices is considered a relative contraindication to transesophageal echocardiography (TEE) by cardiology professional societies, so gastroenterologists are often consulted to perform upper endoscopy prior to TEE in patients with cirrhosis. AIM: Perform a systematic review to quantify the risk of bleeding complications in patients with cirrhosis following TEE METHODS: Two reviewers searched MEDLINE and EMBASE databases from January 1992 to May 2021 for studies reporting bleeding complications from TEE in patients with cirrhosis. We calculated the pooled incidence rate of bleeding events using the metaprop command with a random-effects model. RESULTS: We identified 21 studies comprising 4050 unique patients with cirrhosis; nine studies (n=3015) assessed risk of intraoperative TEE during liver transplant (LT) and twelve studies (n=1035) assessed bleeding risk in patients undergoing TEE for other indications. The pooled incidence of bleeding post-TEE was 0.37% (95%CI 0.04 – 0.94%) across all studies. Bleeding complications were low among patients undergoing TEE during LT as well as those undergoing TEE for other diagnostic reasons (0.97% vs 0.004%) and among studies with mean MELD >18 compared to those with mean MELD

Background & aims Survivorship is a well-established concept in the cancer care continuum with a focus on disease recurrence, quality of life, and minimizing competing risks for mortality; however, this has not been well studied in liver transplantation (LT). We aimed to investigate what survivorship means to LT patients and identify motivations and coping strategies for overcoming challenges after LT. Approach & results Twenty in-depth home interviews were conducted among adults 3 to 6 months after LT. Interviews were conducted by trained qualitative research experts, coded and analyzed using an inductive approach. A majority of LT recipients (75%) identified themselves as survivors. Integral to the definition of survivorship was overcoming hardship (including experiences on the waitlist) and the unique experience of being given a "second chance" at life. Motivations to survive included: 1) honoring a new chance at life (55%), 2) family (40%), 3) spirituality/faith (30%), and 4) fear of rejection (15%). LT recipients and caregivers identified multiple strategies to cope with post-LT challenges including relying on a large network of community, spiritual, and virtual support. These findings informed a conceptual model of LT survivorship based on socioecological theory, which identified the following variables influencing survivorship: 1) pre-transplant experiences, 2) individual attributes and challenges, 3) interpersonal relationships with caregivers and other social support, 4) community relationships, and, 5) largescale factors including neighborhood and financial issues. Conclusions LT recipients identify themselves as survivors, and post-LT identities were greatly influenced by pre-LT experiences. These perspectives informed an in depth conceptual model of survivorship after transplantation. We identified sources of motivation and coping strategies used in LT recovery that could be targets of survivorship interventions aimed at improving post-LT outcomes.

Background In an aging population with cardiovascular comorbidities, anticoagulant (AC), antiplatelet (AP), and nonsteroidal anti-inflammatory drug (NSAID) use are increasing. It remains unclear whether these agents pose increased bleeding risk in cirrhosis. This study aimed to assess the association between these medications and bleeding and portal hypertension complications in cirrhosis. Methods The IMS PharMetrics database was used to identify privately insured adults diagnosed with cirrhosis from 2007 to 2015, stratified as compensated or decompensated based on the presence of portal hypertensive complications 1 year before cirrhosis diagnosis. Bleeding or decompensation outcomes were assessed 6 to 18 months after cirrhosis diagnosis using a landmark analysis design. Multivariable Cox proportional hazards regression modeling assessed associations between AC, AP, and NSAID drug exposures and outcomes adjusting for covariates. Results A total of 18,070 cirrhosis patients were analyzed; 57% male; 74% ages 50 to 64 years; 34% with a prior decompensation. Overall, 377 (2%) had claims for ACs; 385 (2%) APs; and 1231 (7%) NSAIDs. APs were associated with increased bleeding [adjusted hazard ratio (aHR)=1.31; 95% confidence interval (CI): 1.00, 1.72] and decompensation events (aHR=1.44; 95% CI: 1.06, 1.95) in a 9-month landmark analysis. NSAIDs were significantly associated with bleeding events (aHR=1.29; 95% CI: 1.06, 1.57) on 3-month landmark analysis. No statistically significant associations were seen between ACs and bleeding or decompensation outcomes in adjusted analyses. Conclusions AP use was associated with increased bleeding and decompensation events among privately insured patients with cirrhosis. NSAID use was associated with significant early bleeding, but not decompensations. Lastly ACs were not associated with bleeding or decompensation outcomes.

Background Survivorship after liver transplantation (LT) is a novel concept providing a holistic view of the arduous recovery experienced after transplantation. We explored components of early survivorship including physical, emotional, and psychocological challenges to identify intervention targets for improving the recovery process of LT recipients and caregivers. Methods Twenty in-person interviews were conducted among adults 3-6 months post-LT. Trained qualitative research experts conducted interviews, coded, and analyzed transcripts to identify relevant themes and representative quotes. Results Early survivorship comprises overcoming: 1) physical challenges-the most-challenging experiences involving mobility, driving, dietary modifications, and medication adherence and 2) emotional and psychological challenges-including new health concerns, financial worries, body image/identity struggles, social isolation, dependency issues, and concerns about never returning to normal. Etiology of liver disease informed survivorship experiences including some patients with hepatocellular carcinoma expressing decisional regret or uncertainty in light of their post-LT experiences. Important topics were identified that framed LT recovery including setting expectations about waitlist experiences, hospital recovery, and ongoing medication requirements. Conclusion Early survivorship after LT within the first six months involves a wide array of physical, emotional and psychological challenges. Patients and caregivers identified what they wish they had known prior to transplant and strategies for recovery, which can inform targeted LT survivorship interventions.

The recent surge in telemedicine during the COVID-19 pandemic has highlighted how imperative it is to understand: 1) how liver transplant (LT) recipients use smartphone technology, and 2) what they need in terms of remote support to assist with post-transplant recovery. Smartphone applications (i.e. apps) have been used in other chronic medical conditions to improve coordination of care, patient education, and medication adherence (1).

We wish to thank Dr. Edelson and Dr. Rockey for their interest in and comments on our original manuscript investigating anesthesia complications related to endoscopic procedures among patients with cirrhosis.(1) We appreciate their remarks on incorporating objective measures (e.g., model for end-stage liver disease [MELD] score) when evaluating patients for procedural or sedation risk, as well as providing an algorithm for sedation in cirrhosis patients.(2).

BACKGROUND AND AIMS Anesthesia services for endoscopic procedures have proliferated with the promise of increased comfort and safety. Cirrhosis patients are higher risk for sedation, yet limited data are available describing anesthesia complications in this population. APPROACH AND RESULTS This cross-sectional study utilized the National Anesthesia Clinical Outcomes Registry, a multicenter quality-improvement database from 2010 to 2015. Patients with cirrhosis undergoing an endoscopy were identified by International Classification of Diseases, Ninth Revision (ICD-9)/Current Procedures Terminology (CPT) codes. The outcome of interest was serious anesthesia-related complication defined as cardiovascular, respiratory, neurological, drug related, patient injury, death, or unexpected admission. A mixed-effects multivariate logistic regression model determined odds ratios (ORs) between variables and serious complications, adjusting for potential confounders. In total, 9,007 endoscopic procedures were performed among patients with cirrhosis; 92% were esophagogastroduodenoscopies. The majority (81%) were American Society of Anesthesiologists (ASA) class ≥3, and 72% had a history of hepatic encephalopathy, ascites, varices, hepatorenal syndrome, or spontaneous bacterial peritonitis identified by ICD-9/CPT codes. In total, 87 complications were reported, 33 of which were serious. Frequency of serious complications was 0.4% or 378.6 per 100,000 procedures (95% confidence interval [CI], 260.8, 531.3). The majority of serious complications were cardiovascular (21 of 33), including 15 cardiac arrests. Serious complications were significantly associated with ASA 4/5 (OR, 3.84; 95% CI, 1.09, 13.57) and general anesthesia (OR, 4.71; 95% CI, 1.20, 18.50), adjusting for age, sex, ASA class, anesthesia type, inpatient status, portal hypertension history, and variable complication reporting practices. CONCLUSIONS Anesthesia complications among endoscopic procedures in cirrhosis are rare overall. Serious complications were predominantly cardiac and associated with sicker patients undergoing general anesthesia. The complexity of end-stage liver disease may warrant more intensive care during endoscopic procedures, including anesthesia monitoring.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with decreased health‐related quality of life and debilitating symptoms. These experiences can be defined as patient‐reported outcome (PRO) concepts and measured using PRO instruments. We identified all PRO concepts and instruments used in the PBC and PSC literature. This systematic review identified PBC and/or PSC studies from January 1, 1990, to May 6, 2019, that measured at least one PRO concept. Study population, design, PRO concept, PRO instrument, and validation data for PRO instruments were investigated. We provided descriptive statistics of PRO concepts and instruments used, stratified by population type. Use of PRO concepts and instruments were assessed over time. The search yielded 318 articles (69% in PBC, 18% in PSC, 13% in both, and 24% in drug trials). Forty‐nine unique PRO concepts were identified. The five most common PRO concepts included pruritus (25%), fatigue (19%), broad health‐related quality of life (16%), gastrointestinal adverse events (6%), and physical adverse events (6%). Only 60% of PRO concepts were measured with a PRO instrument, most of which were nonvalidated visual analogue or numeric rating scales. Only three of 83 PRO instruments were developed with feedback from the target populations (one for PBC, one for PSC, and one for both), and only six documented any psychometric testing in the target populations. Use of PRO instruments increased over time from 30% in the 1990s to 67% by 2019. Conclusion: The overwhelming majority of PRO instruments used in PBC/PSC were nonspecific and lacked patient validation or empirical justification. Significant opportunities exist to use qualitative methods to better understand patient experiences, and translate this knowledge into meaningful, patient‐driven study outcomes.

BACKGROUND: Opioids are often prescribed for pain in cirrhosis and may increase risk of hepatic encephalopathy (HE). AIMS: To assess the association between opioids and hepatic encephalopathy in patients with well-compensated cirrhosis. METHODS: We used the IQVIA PharMetrics (Durham, NC) database to identify patients aged 18–64 years with cirrhosis. We excluded patients with any decompensation event from 1 year before cirrhosis diagnosis to 6 months after cirrhosis diagnosis. Over the 6 months after cirrhosis diagnosis, we determined the duration of continuous opioid use and classified use into short term (1–89 days) and chronic (90–180 days). We assessed whether patients developed hepatic encephalopathy over the subsequent year (i.e. 6–18 months after cirrhosis diagnosis). We used a landmark analysis and performed multivariable Cox proportional hazards regression to assess associations between opioid use and hepatic encephalopathy, adjusting for relevant confounders. RESULTS: The cohort included 6,451 patients with compensated cirrhosis, of whom 23.3% and 4.7% had short term and chronic opioid prescriptions, respectively. Over the subsequent year, hepatic encephalopathy occurred in 6.3% patients with chronic opioid prescriptions, 5.0% with short term opioid prescriptions, and 3.3% with no opioid prescriptions. In the multivariable model, an increased risk of hepatic encephalopathy was observed with short term (adjusted HR 1.44, 95% CI 1.07–1.94) and chronic opioid prescriptions (adjusted HR 1.83, 95% CI 1.07–3.12) compared to no opioid prescriptions. CONCLUSION: In this national cohort of privately-insured patients with cirrhosis, opioid prescriptions were associated with risk of incident hepatic encephalopathy. Opioid use should be minimized in those with cirrhosis and, when required, limited to short duration.

Given the numerous questions related to patient selection, surgical technique, and posttransplant care requiring evidence-based answers, transplantation programs should be conducting research with patients waiting to receive an organ and those who have undergone organ transplantation. Yet, there continues to be a dearth of human subjects research in the field of transplantation medicine. Here, we discuss challenges that may deter transplantation programs from engaging in transplant-related research. Taking liver transplantation as our illustrative example, we explain the vulnerabilities of patients with end-stage organ failure and the complex ethical issues of decisional capacity, coercion, and the timing of study enrollment. Ultimately, we argue that all transplant candidates should be invited and encouraged to participate in research. We maintain that clinical care should be provided in the context of active research so that clinicians can further their understanding of transplantation medicine while also providing high-quality patient care. We suggest that early discussion with patients about participating in research and about a research advance directive may help to overcome reluctance about and the ethical challenges of transplantation research with human subjects.

AIM To investigate the relationship between post-liver transplantation (LT) glycemic control and LT outcomes. METHODS A qualitative systematic review on relevant prospective interventions designed to control glucose levels including insulin protocols. Studies investigating an association between glycemic control and post-LT outcomes such as mortality, graft rejection, and infection rate were reviewed. PubMed, EMBASE, and other databases were searched through October 2016. RESULTS Three thousands, six hundreds and ninety-two patients from 14 studies were included. Higher mortality rate was seen when blood glucose (BG) ≥ 150 mg/dL (P = 0.05). BG ≥ 150 mg/dL also led to higher rates of infection. Higher rates of graft rejection were seen at BG > 200 mg/dL (P < 0.001). Mean BG ≥ 200 mg/dL was associated with more infections (P = 0.002). Nurse-initiated protocols and early screening strategies have shown a reduction in negative post-LT outcomes. CONCLUSION Hyperglycemia in the perioperative period is associated with poor post-LT outcomes. Only a few prospective studies have designed interventions aimed at managing post-LT hyperglycemia, post-transplant diabetes mellitus (PTDM) and their impact on post-LT outcomes.

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease, contributing to significant morbidity and mortality. Yet, the only available therapies that improve survival are corticosteroids and liver transplantation with no new drugs successfully developed for decades. This article describes briefly the current state of affairs in AH therapy and examines the practical and ethical challenges to conducting controlled trials in patients with severe AH. While prednisolone is considered to be standard of care in severe AH, this recommendation remains controversial given the marginal benefits and questionable longterm safety of steroids. Placebo controlled trials without steroids may be necessary and ethically justified in certain populations of AH who have not been adequately investigated. Ultimately, we suggest the field will advance with the development of a plausible animal model of true AH, a consensus on a composite clinical end-point that does not rely solely on mortality for use in future RCTs, and the adoption of the recommendations of the NIAAA Alcoholic Hepatitis Consortia regarding standard definitions and when to require a liver biopsy prior to study entry.

Background. The 2013 HIV Organ Policy Equity Act has increased liver transplantation (LT) in HIV+ patients; however, transplant centers may remain reluctant to perform LT in HIV/hepatitis C virus (HCV)-coinfected patients due to inferior outcomes. We aimed to assess how direct-acting antivirals (DAAs) have impacted HIV+/HCV+-coinfected LT recipient outcomes. Methods. national data including 70 125 adult LT recipients between 2008 and 2019 were analyzed. Kaplan-Meier survival analysis and Cox proportional hazards model were used to analyze outcomes. Results. LT for HIV+ individuals increased in the DAA era from 28 in 2014 to 64 in 2019 (23 had HIV+/HCV+ coinfection). In the pre-DAA era, HIV+/HCV+-coinfected LT recipients had an increased risk of graft failure compared with HIV−/HCV−-uninfected LT recipients (hazard ratio [HR], 1.85; P

Background Post-transplant diabetes mellitus (PTDM) is common after liver transplantation (LT). Yet, how PTDM relates to graft outcomes and survival needs elucidation as more individuals are transplanted for nonalcoholic fatty liver disease (NAFLD). Methods This single-center, retrospective study of adult LT recipients (2003-2016) identified PTDM incidence and associations with graft steatosis, rejection, and post-LT patient survival. Multivariable analysis investigated predictors of PTDM. Kaplan-Meier curves depicted patient survival 5 years post-LT. Results Among 415 adult LT recipients, 23% had pre-LT DM and 13% were transplanted for NAFLD. PTDM incidence was 34.7%, 46.9%, and 56.2% and overall survival was 90%, 80.9%, and 71.7% at 1, 3, and 5 years, respectively. Over a third of non-NAFLD patients developed PTDM. Half of PTDM cases developed by 6 months and 75% by 12 months. The PTDM group had more rejection episodes compared to no PTDM (31.9% vs 21.8%, P = 0.055), with trends toward worse patient survival 5 years post-LT (log-rank test P = 0.254). Age was the only significant predictor of PTDM. Conclusions Post-transplant diabetes mellitus occurs rapidly in the post-LT period and is a significant problem for both NAFLD and non-NAFLD LT recipients. Age is a significant risk factor for PTDM. Outcomes trended toward increased rejection and worse survival among PTDM individuals, suggesting the benefit of early strategies targeting glucose control.

Given the numerous questions related to patient selection, surgical technique, and posttransplant care requiring evidence-based answers, transplantation programs should be conducting research with patients waiting to receive an organ and those who have undergone organ transplantation. Yet, there continues to be a dearth of human subjects research in the field of transplantation medicine. Here, we discuss challenges that may deter transplantation programs from engaging in transplant-related research. Taking liver transplantation as our illustrative example, we explain the vulnerabilities of patients with end-stage organ failure and the complex ethical issues of decisional capacity, coercion, and the timing of study enrollment. Ultimately, we argue that all transplant candidates should be invited and encouraged to participate in research. We maintain that clinical care should be provided in the context of active research so that clinicians can further their understanding of transplantation medicine while also providing high-quality patient care. We suggest that early discussion with patients about participating in research and about a research advance directive may help to overcome reluctance about and the ethical challenges of transplantation research with human subjects.

Despite the increased use of anesthesia services for endoscopic procedures in the United States, the risks of anesthesia-directed sedation (ADS) are unclear. We analyzed national data from multiple centers to determine patterns of use of anesthesia services and risk factors for serious complications.We performed a cross-sectional study using the National Anesthesia Clinical Outcomes Registry, a national quality improvement database. Univariable and bivariate analyses investigated frequencies and relationships between predefined variables and serious complications of anesthesia (cardiovascular, respiratory, neurologic, drug-related, patient injury, death, or unexpected admission). A multivariable mixed-effects model determined the odds ratios between these variables and serious complications, adjusting for confounders and varying reporting practices.In total, 428,947 endoscopic procedures of adults were performed using ADS from 2010 to 2015. The population was 54.9% female with a mean age of 59.1 years, and predominantly American Society of Anesthesiologists classes 2 and 3 (74.4%). More than half of the procedures were colonoscopies (51.4%); 37.4% were esophagogastroduodenoscopies and 6.5% were endoscopic retrograde cholangiopancreatographies. A total of 4441 complications (1.09%) were reported; 1349 were serious complications (0.34%). In multivariable analysis, older age, American Society of Anesthesiologists classes 4 and 5, esophagogastroduodenoscopy, general anesthesia, cases performed on an overnight shift, and longer cases were associated independently and significantly with serious complications.In an analysis of data from the National Anesthesia Clinical Outcomes Registry, we found ADS during endoscopy to be safe, with few serious complications (1% of procedures). Risk of ADS complications increased with older age, more severe disease, procedure type, and case complexity.

BACKGROUND & AIMS: Estimates of disease burden can inform national health priorities for research, clinical care, and policy. We aimed to estimate health care use and spending among gastrointestinal (GI) (including luminal, liver, and pancreatic) diseases in the United States. METHODS: We estimated health care use and spending based on the most currently available administrative claims from commercial and Medicare Supplemental plans, data from the GI Quality Improvement Consortium Registry, and national databases. RESULTS: In 2015, annual health care expenditures for gastrointestinal diseases totaled $135.9 billion. Hepatitis ($23.3 billion), esophageal disorders ($18.1 billion), biliary tract disease ($10.3 billion), abdominal pain ($10.2 billion), and inflammatory bowel disease ($7.2 billion) were the most expensive. Yearly, there were more than 54.4 million ambulatory visits with a primary diagnosis for a GI disease, 3.0 million hospital admissions, and 540,500 all-cause 30-day readmissions. There were 266,600 new cases of GI cancers diagnosed and 144,300 cancer deaths. Each year, there were 97,700 deaths from non-malignant GI diseases. An estimated 11.0 million colonoscopies, 6.1 million upper endoscopies, 313,000 flexible sigmoidoscopies, 178,400 upper endoscopic ultrasound examinations, and 169,500 endoscopic retrograde cholangiopancreatography procedures were performed annually. Among average-risk persons ages 50–75 years who underwent colonoscopy, 34.6% had 1 or more adenomatous polyps, 4.7% had 1 or more advanced adenomatous polyps, and 5.7% had 1 or more serrated polyps removed. CONCLUSIONS: GI diseases contribute substantially to health care use in the United States. Total expenditures for GI diseases are $135.9 billion dollars annually—greater than for other common diseases. Expenditures are likely to continue increasing.

When a liver transplantation candidate is declined for listing to receive a deceased organ, sometimes a loved one comes forward and offers to be a living donor. This raises the ethical question of whether a patient who is not eligible for deceased donor liver transplantation should be eligible for living donor liver transplantation. We compare living organ donation in kidney and liver transplantation and explore key ethical concepts of justice, fairness, and societal trust. Ultimately, because there is no alternative life-preserving therapy in end-stage liver disease, and because transplantation with a living donor organ does not involve removing a resource from the common pool of transplant organs, we argue that a “slightly less benefit” than what is required for deceased transplantation listing standard should be used to determine the acceptability of living donor liver transplantation.

Medication nonadherence is prevalent in transplant recipients and is a major reason for graft loss. The present review discusses the measurement of adherence in transplant recipients and strategies to improve adherence. SOURCES REVIEWED: Since adherence research is not confined to transplant recipients, our literature review included studies relevant to transplant recipients as well as adherence to medical recommendations more generally. We reviewed manuscripts in the English language indexed in PubMed Central, as well as ancillary sources of information such as textbook chapters that are not indexed.There is no consensus in the literature about an optimal way to monitor adherence, nor is there agreement about a preferred management strategy. Until definitive studies demonstrate the effectiveness of intervention strategies, knowledge of the monitoring as well as intervention methods that are described in this review is expected to give practitioners the initial tools to deal with nonadherence as an important aspect of patient care.

A psychosocial evaluation before liver transplant aims to identify risk factors for nonadherence and poor outcomes posttransplant. Despite broad support for such evaluations, evidence justifying its components is thus far limited. We investigated whether variables assessed during the psychosocial evaluation before liver transplant predict immunosuppressant nonadherence and graft rejection.Our study included 248 adult liver recipients at least 1 year after transplant with at least 3 measured tacrolimus levels. Predictor variables from the pretransplant evaluation were defined a priori and included sociodemographic factors (age, race, time since transplant), psychiatric history, substance abuse history, education level, and social support. Nonadherence was determined using the medication level variability index, which is an objective measure of adherence reflective of high medication level fluctuation from nonadherence. Outcomes (medication level variability index and biopsy-confirmed rejection) were obtained 1-year posttransplant to the present.We found that 50% of patients were nonadherent to tacrolimus (medication level variability index2.5). The 41 patients with rejection (t = 2.71, P.01) and black patients (F = 3.10, P = .02) had significantly higher index scores. Time since transplant was correlated with medical level variability index (r = 0.15, P = .02). However, in logistic regression, none of the predefined psychosocial variables predicted nonadherence (P = .40) or rejection (P = .19).Our results confirmed a significant association between medication level variability index and rejection, validating it as an objective measure of clinically significant nonadherence. In a large sample with high rates of nonadherence, none of the pretransplant psychosocial variables commonly used in standard liver transplant evaluations predicted nonadherence or rejection. These findings call into question current selection criteria. Future prospective studies are needed to investigate more com-prehensive psychosocial variables and their ability to determine posttransplant outcomes.

A growing number of older adults are undergoing liver transplantation (LT) in the United States. In some settings, it is thought that adherence declines with age. This retrospective study examined adherence and clinical outcomes in older vs younger adult LT recipients. Medical records of adult LT recipients from 2009 to 2012 from a single urban center were reviewed. The medication level variability index (MLVI) was the predefined primary outcome, with nonadherence defined as MLVI >2.5. The secondary outcome was incidence of rejection. Outcomes were evaluated starting 1 year post-LT until 2015. A total of 42 of 248 patients were ≥65 at transplant. Older adults had significantly better adherence than younger ones (65%≥65 were adherent vs 42% younger adults; chi-square two-tailed P=.02). Survival analyses of rejection between age groups censored by time since transplant showed no difference among the four age groups (χ2 =0.84, P=.84). Older age was not found to be a risk factor for reduced adherence or graft rejection in patients surviving at least 1 year post-LT.

The alarming rates of smoking, obesity, and substance abuse pose an enormous challenge for parents and public health officials: how do we prevent children and adolescents from adopting unhealthy behaviors? One new option that may soon be available is the use of nicotine vaccines. Immunological therapies to help smokers stop smoking have shown promise in phase I and II trials; similar therapies could combat smoking addiction before it starts. Nicotine vaccines are distinctive because they confer protection not against infection—the normal target for vaccines—but against enticing pleasures that lead to unhealthy behaviors. As a result, using them preventively in children would be likely to arouse some novel ethical concerns that should be addressed before the vaccines become commonly available and their off-label use as a preventive measure becomes a real option. In this paper, we consider whether it would be ethical for parents to vaccinate their children against smoking if a nicotine vaccine were to be proven effective as a preventive intervention for children or adolescents. We begin by explaining the current state of nicotine vaccine science and suggesting some likely ethical concerns about allowing parents to have their children receive a vaccine. We then present a preliminary argument for making vaccination permissible, at least if nicotine vaccination substantially reduces the probability that someone subsequently becomes a smoker. We consider a series of possible ethical objections, which are useful for identifying the conditions under which it would be ethical for parents to vaccinate their children against smoking. We conclude that it would be permissible for parents to give their child a nicotine vaccine if the following conditions were met: the vaccine is expected to result in a net benefit to each individual vaccinated, the expected harms from the side effects of the vaccine are lower than the nonvoluntary harms caused by smoking, and there are no other, less manipulative methods available that are as effective at preventing smoking initiation.

Non-adherence to medical therapy after liver transplantation is confounded by different methods of measurement. (1) To compare the performance of three different methods of measuring non-adherence: (a) biochemical (standard deviation [SD] tacrolimus levels), (b) clinician report, (c) self-report. (2) To identify pre-transplant predictors of post-transplant non-adherence. (3) To evaluate whether SD tacrolimus is an accurate predictor of graft outcomes. In this retrospective cohort study, charts of adult recipients of a liver transplant 2003–2009 (sample A, n = 444) were reviewed to determine pre-transplant predictors of non-adherence and clinician report of non-adherence. SD tacrolimus levels were measured between 6 and 18 months post-transplant. A subset of sample A (n = 122) completed a survey on non-adherence. The three methods were compared using linear and logistic regression. Multivariable analysis was used to investigate pre-transplant predictors of non-adherence. In sample B (transplant recipients 1995–2003, n = 544) Cox regression was used to determine the relationship between SD immunosuppressant level and graft failure. Non-adherence was found in 22–62 % of subjects, with the highest rates indicated by self-report. Clinician report of non-adherence was associated with both self-report and SD tacrolimus. On multivariable analysis, unemployment at time of listing and chart evidence of pre-transplant non-adherence were significant predictors of higher SD of tacrolimus. History of substance abuse and pre-transplant chart evidence of non-adherence were also significant independent predictors of post-transplant chart evidence of non-adherence. Drug variability in the immediate post-transplant setting was independently associated with graft failure over time (hazard ratio 1.005 per unit increase in standard deviation, p = 0.04). Non-adherence among liver transplant recipients is a common problem associated with increased risk of graft failure. SD tacrolimus can be used to measure non-adherent behavior and perhaps target patients for behavioral interventions.

Contracts with patients have become increasingly common in clinical practice and the medical literature. These include behavioral contracts for managing “difficult patients” 1, opioid contracts2–5, suicide prevention contracts6,7, and healthy living contracts8. Some physician practices have even asked patients to sign contracts promising not to litigate or post defamatory comments on the Internet9. Despite widespread adoption, few have stopped to consider the potential risks and ethical concerns with using these documents. This perspective will describe how patient contracts are ultimately about power and control, and if not used carefully could damage the patient-physician relationship.

Dysphagia and cough in an older male smoker raise concern for malignancy. However, a history of environmental exposures led to a much more interesting diagnosis in this case of pneumoconiosis due to silicosis. Silicosis is an uncommon pulmonary disease with rare associated gastrointestinal symptoms. We report a bronchoesophageal fistula resulting from silicosis causing dysphagia and cough. This is the first report of using endoscopic stenting to manage an esophageal fistula from silicosis. This case highlights how common symptoms of cough and dysphagia can masquerade as a pulmonary or oropharyngeal problem, when they are actually gastrointestinal manifestations of a rare disease.

As health care costs continue to rise, an increasing number of self-insured employers are using financial rewards or penalties to promote healthy behavior and control costs. These incentive programs have triggered a backlash from those concerned that holding employees responsible for their health, particularly through the use of penalties, violates individual liberties and discriminates against the unhealthy. This paper offers an ethical analysis of employee health incentive programs and presents an argument for a set of conditions under which penalties can be used in an ethical and responsible way to contain health care costs and encourage healthy behavior among employees.

In this issue, Loiselle et al. (1) address an important construct that surprisingly has not been adequately investigated in the transplant literature—namely, the degree to which adherence to immunosuppression is a stable or a “shifting” phenomenon. The answer to this question holds some important implications for the field of transplantation. Those important implications include, as the authors highlight, that adherence is important in terms of disease and financial burden; we would like to add another important implication of this construct: whether adherence is a stable phenomenon or not might also have implications with regards to the decision to allow or not allow retransplantation in a nonadherent patient. If nonadherence is stable, then hoping that these behaviors improve might be futile, and therefore re-transplantation should not be offered; if unstable, then nonadherence should be presumed to be modifiable and not be used to determine transplant eligibility. The authors found that the average rate of adherence in their sample did not change over time. However, individual patient adherence varied substantially—there were many patients whose adherence category shifted during the study period. The interpretation of this finding, if proven to be robust, is that patient-level decisions regarding adherence should assume that it is a shifting (unstable) phenomenon: past adherence is not a good indicator of future adherence. On the other hand, since on average the rate of nonadherence remains the same in an entire clinic population (different patients become more or less adherent, but the average remains the same), resource allocation decisions in entire clinics or programs should assume a stable need for resources to address this risk over time. While the results are interesting and might prove to be correct, this study also illustrates the enormous challenges that are encountered when one tries to study the phenomenon of adherence in transplantation medicine. Those challenges can be summarized as issues of inadequate sample size, selection bias, failure to pre-define a single primary hypothesis, measurement difficulties, and over-statement of clinical implications. A small sample size with selection bias is the rule, rather than the exception, in studies that purport to investigate adherence in pediatric transplantation (2). First, it is extremely difficult to achieve an adequate sample size in this population unless a large number of centers are involved. Second, in any population, it is difficult to recruit nonadherent patients for a study, let alone follow them up (3), because the same patients who are unable to take their medications consistently are also less likely to come to clinic, less likely to participate in a study, and less likely to have adequate data follow-up. The resulting bias favors adherent patients as participants. The combination of a small (inadequately powered) sample size and a substantial selection bias leads to a high likelihood of spurious results. The transplant field, fortunately, has recognized the issue of sample size limitations and created mechanisms to study phenomena related to behavioral constructs, such as nonadherence, within established consortia such as CTOT-C (4), SPLIT (5), and one smaller consortium (6) that is entirely dedicated to the study of adherence (MALT). Within those consortia, the promise of an adequate sample size can be realized. Manuscripts such as the one in this issue can be viewed as indicators of potentially important topics that can be taken up for further study in a multi-site trial. The problem of selection bias can be addressed in several ways, and again the transplant field is well positioned to minimize, or at least monitor, this issue. First, steps need to be taken to minimize patient burden and ensure adequate sampling methods. Second, a CONSORT-type diagram with CONSORT-type statements (7) of the discrepancy between patients who did and did not participate in this study must be provided in adequately powered studies, and any substantial differences should be discussed. Third, a comparison between the general outcomes in the study sample (e.g., rejection rates per patient year) with outcomes reported to data repositories such as the United Network for Organ Sharing (UNOS) or SPLIT can provide additional insight regarding whether the sample was representative, at least as far as rejection rates or other reported outcomes are concerned. This study provided none of those assurances; however, such rigor should not be expected and would be difficult to achieve in pilot studies or underpowered investigations. Rather, readers should assume that substantial selection bias is inevitable, and results in under-representation of severely nonadherent patients, in pilot and underpowered prospective investigations. Selection bias can be mitigated by a retrospective design in some circumstances, which means that sometimes results from retrospective studies are more powerful and generalizable than results from prospective studies in adherence research (2). A failure to pre-define a single primary hypothesis is a common feature of pilot studies. Failure to register trials on sites such as clinicaltrials.gov or failure to specify a primary hypothesis, even if registered, result in a situation in which data are mined for results rather than used to establish (or refute) a fact. In this situation, the meaning of statistical tests is questionable, as our conventional reliance on a “p” value of 0.05 for significance is predicated on the existence of a pre-specified primary hypothesis. For unregistered studies that do not pre-specify a single primary hypothesis, study results should be considered exploratory rather than conclusive. The issue of a lack of “gold standard” for measuring adherence has been previously reviewed (8) and is presented in the current manuscript as well. We caution against the tendency to assume (without supporting evidence) that multiple measures should be used to gain a more complete picture of adherence. For example, subjective measures (e.g. self-report) are considered to be low-quality measures of adherence in the broad literature of adherence research, while objective measures such as medication blood levels are considered to be higher quality (9). It is unlikely that coupling a high-quality measure with a low-quality measure will result in an aggregate measure that is superior to the high-quality measure when used alone. This is especially true if self-report vs. objective measures do not correlate with each other (as reported in the present study and others). Unless combined measures are decisively shown to be superior, the interpretation of the broad literature seems to be quite the opposite of the authors’ opinion (that combined measures are preferred). Combining multiple measures of varying levels of quality is time consuming and is not preferred – in our view, the “default” assumption should be that a single robust measurement technique (preferably, objective rather than subjective) is preferred (10). Finally, the fact unfortunately remains that not even one randomized controlled trial has ever shown that it is possible to improve post-transplant outcomes by addressing nonadherence, and one robust trial in adults showed no improvement in medical outcomes (11). In that trial, adherence was improved, but the investigators recruited primarily patients who were highly adherent at baseline. Therefore, presumably, a marginal improvement in their already excellent adherence did not translate into improved medical outcomes. It is extremely difficult to engage seriously nonadherent patients in research for obvious reasons, and thus if they are not targeted specifically, studies tend to exclude them (2,3). Because no study has ever shown that it is possible to improve transplant outcomes by addressing adherence, it is premature to recommend that adherence be measured routinely, let alone targeted, in clinical practice: why measure it if it has never been proven that it can inform any successful intervention strategy? In sum, the manuscript by Loiselle et al. is addressing an important topic. It should be read as a call to conduct rigorous trials that shed light on the longitudinal trajectory of adherence behavior in transplanted children. The transplant field, with its robust outcome measures that are reported to national repositories, highly successful and collaborative consortia, and invested interest in the topic, is well poised to answer some of the most intriguing questions raised in the current manuscript. It is time to take the study of adherence into the rigorous and exciting realm of well-powered multi-site clinical trials that would be able to decisively refute or prove rigorous, single, pre-specified hypotheses about the trajectory of nonadherence behavior and ways to address it. We hope that the authors of the manuscript, as well as the readers, see the manuscript in this issue as a first, and not the last, step in this direction.

Written documents called “contracts” are appearing with increasing frequency in clinical practice and the medical literature. There are behavioral contracts for managing “difficult patients,”1 opioid contracts,2 suicide prevention contracts,3 and healthy living contracts.4 Some practices have even asked patients to sign contracts promising not to litigate or post defamatory comments on the Internet.5 Despite this widespread adoption, the use of contracts in medicine has been subject to relatively little critical appraisal. As shown in Table 1, patient contracts do different things in different clinical situations. Some serve “administrative” goals, like deterring patients from mistreating clinical personnel or diverting narcotics. Others are educational; they draw the patient’s attention solemnly to information. Others clarify expectations and foster transparency, as when a prospective organ recipient agrees to substance-abuse rules. Others – like suicide-prevention contracts – help doctors express their concern for their patients. Finally, some “Ulysses contracts” help patients hold themselves to better health practices by bolstering their willpower through a written commitment. (Ulysses in Homer’s Odyssey had his men to tie him to the ship’s mast so he could not respond to the Sirens’ song.) Table 1 Common Types of Patient Contracts Not only do “patient contracts” have myriad purposes, they have uncertain success. A Cochrane review analyzed thirty randomized trials in addiction, weight-control or medication-adherence settings.4 The endpoints included processes (e.g., adherence to treatment) and targets (e.g., blood pressure). Results were mixed, with fifteen endpoints showing a benefit of contracts compared to usual care, six favoring standard care, and twenty-six endpoints showing no difference. Even less is known about other kinds of contracts. A review of eleven observational studies found weak evidence that opioid contracts reduced narcotic diversion or misuse.6 Contracts with other aims (like suicide prevention) have not been empirically studied.7 To some extent, any patient encounter can be viewed as contractual, whereby the patient and physician agree on mutually accepted responsibilities.8 But here the term “contract” becomes problematic. In the legal context, what makes a contract different from an agreement is that contracts are intended to be enforced. So turning informal agreements into formal documents emphasizes the consequences of breach, whether explicit or implied. In some clinical settings, these consequences are clear: the doctor will no longer prescribe narcotics, or the patient will not get a liver transplant. However, does adherence to terms of the contract also become a pre-condition for continued medical care? If so, many would argue this violates physicians’ ethical obligations to not abandon patients.9 Even if not, the consequences of breach may not always be clear to patients, who may assume from the word “contract” that the relationship would be terminated. Because of these implied consequences, contracts risk fundamentally altering the patient-physician relationship – a relationship traditionally founded on unconditional loyalty.10 If patients feel their medical care could be terminated at any time for perception of non-adherence, how can they openly communicate with their physicians? This risk is heightened when, as is common, patients are asked to sign a standard form drafted by the physician, without opportunity for negotiation of the terms. And a unilateral or authoritarian style of implementing contracts may cause patients to feel threatened or coerced, and perhaps even view the contract as a “prelude to abandonment.”11 Given the inconclusive evidence of the success of these contracts and the disadvantages they can present, we have some recommendations. First, clarify terminology. Written patient-physician agreements often do not fit the usual definition of a contract, and they serve varied purposes. Second, clarify aims. For example, where the primary aim is stating non-negotiable terms (like substance-abuse criteria for transplant candidacy), it is franker to label the document an “Acknowledgement of Clinic Policies.” Third, treat the “contract” as part of a therapeutic process. A boilerplate contract is one thing, helping patients set and meet goals is another. This is the principle behind “motivational interviewing,” a technique with strong empirical support12. Finally, patients should be given resources and assistance in meeting these goals. For example, structured weight loss programs work better than just telling patients to “go diet and exercise.” In sum, “contract” is a misleading term for documents which are increasingly used in a wide variety of clinical situations, with myriad purposes and uncertain effectiveness. Although the aims of contracting may be sound, physicians need to understand the limits of contracts and the ways they can be misunderstood, to the detriment of the patient-physician relationship. Whenever possible, written agreements should be bilateral, tailored to the patient, and presented in a way that signals ongoing commitment. Otherwise we risk alienating patients and damaging the therapeutic alliance.

We assessed hand hygiene adherence in 2 infectious disease units. In one unit, adherence declined slightly from year 1 (84.2%) to year 4 (71.0%) after a multimodal intervention but remained much higher than before intervention. Adherence dropped in the second unit after a loss of leadership (from 50.7% to 5.7%). Strong leadership presence may improve hand hygiene adherence.

Background Prolactin is a polypeptide hormone responsible for proliferation and differentiation of the mammary gland. More recently, prolactin's role in mammary carcinogenesis has been studied with greater interest. Studies from our laboratory and from others have demonstrated that three specific isoforms of the prolactin receptor (PRLR) are expressed in both normal and cancerous breast cells and tissues. Until now, reliable isoform specific antibodies have been lacking. We have prepared and characterized polyclonal antibodies against each of the human PRLR isoforms that can effectively be used to characterize human breast cancers. Methods Rabbits were immunized with synthetic peptides of isoform unique regions and immune sera affinity purified prior to validation by Western blot and immunohistochemical analyses. Sections of ductal and lobular carcinomas were stained with each affinity purified isoform specific antibody to determine expression patterns in breast cancer subclasses. Results We show that the rabbit antibodies have high titer and could specifically recognize each isoform of PRLR. Differences in PRLR isoform expression levels were observed and quantified using histosections from xenografts of established human breast cancer cells lines, and ductal and lobular carcinoma human biopsy specimens. In addition, these results were verified by real-time PCR with isoform specific primers. While nearly all tumors contained LF and SF1b, the majority (76%) of ductal carcinoma biopsies expressed SF1a while the majority of lobular carcinomas lacked SF1a staining (72%) and 27% had only low levels of expression. Conclusions Differences in the receptor isoform expression profiles may be critical to understanding the role of PRL in mammary tumorigenesis. Since these antibodies are specifically directed against each PRLR isoform, they are valuable tools for the evaluation of breast cancer PRLR content and have potential clinical importance in treatment of this disease by providing new reagents to study the protein expression of the human PRLR.