Stochastic scanning events on the GCN4 mRNA 5' untranslated region generate cell-to-cell heterogeneity in the yeast nutritional stress response.

Gene expression stochasticity is inherent in the functional properties and evolution of biological systems, creating non-genetic cellular individuality and influencing multiple processes, including differentiation and stress responses. In a distinct form of non-transcriptional noise, we find that interactions of the yeast translation machinery with the GCN4 mRNA 5'UTR, which underpins starvation-induced regulation of this transcriptional activator gene, manifest stochastic variation across cellular populations. We use flow cytometry, fluorescence-activated cell sorting and microfluidics coupled to fluorescence microscopy to characterize the cell-to-cell heterogeneity of GCN4-5'UTR-mediated translation initiation. GCN4-5'UTR-mediated translation is generally not de-repressed under non-starvation conditions; however, a sub-population of cells consistently manifests a stochastically enhanced GCN4 translation (SETGCN4) state that depends on the integrity of the GCN4 uORFs. This sub-population is eliminated upon deletion of the Gcn2 kinase that phosphorylates eIF2α under nutrient-limitation conditions, or upon mutation to Ala of the Gcn2 kinase target site, eIF2α-Ser51. SETGCN4 cells isolated using cell sorting spontaneously regenerate the full bimodal population distribution upon further growth. Analysis of ADE8::ymRuby3/ GCN4::yEGFP cells reveals enhanced Gcn4-activated biosynthetic pathway activity in SETGCN4 cells under non-starvation conditions. Computational modeling interprets our experimental observations in terms of a novel translational noise mechanism underpinned by natural variations in Gcn2 kinase activity.

A simple risk-based reimbursement system for kidney transplant.

Transplant centers were challenged by the Executive Order on Advancing Kidney health to increase access to kidney transplant (KTx) by accepting higher risk patients and organs. However, Medicare reimbursement for KTx does not include adjustment for major complicating comorbidities (MCCs) like other transplants. The prevalence of MCCs was assessed for KTx performed from 10/15 to 10/19 at a single academic center, using Medicare ICD10 MCC criteria exclusive of end-stage kidney disease. KTx hospital resource utilization and estimated margin, assuming Medicare reimbursement, were determined for cases with and without MCC. Among 260 KTx recipients, 49 (19%) had an MCC. Patients with MCCs had longer wait times (1121 days vs 703 days, P < .001); however, there were no differences in age, gender, race, or diagnosis. Donor characteristics associated with an MCC included greater cold ischemic time (1042 vs 670 minutes, P < .001) and fewer living donor KTx (9% vs 32%, P < .001). KTx cost, exclusive of organ acquisition, was 31% higher (MCC: $38 293 vs No MCC: $29 132) and estimated margin was markedly lower (-$7750 vs -$1001, P = .001). In conclusion, KTx with qualifying MCCs resulted in significant financial losses and modification of KTx payment methodology to align with other organ transplants is needed.

Implications of the Advancing American Kidney Health Initiative for kidney transplant centers.

The announcement of the Advancing American Kidney Health (AAKH) Initiative on July 10, 2019 was met with a mix of excitement and trepidation, befitting a proposed radical reconfiguration of the delivery of kidney disease care. Aspiring to reduce the incidence of end-stage renal disease, increase the prevalence of home dialysis, and double the number of organs available for transplant, the AAKH payment models primarily focus on incenting behaviors of general nephrologists, though actualizing positive incentives will require the active cooperation of dialysis providers and transplant centers. Here, we review the AAKH initiatives' potential impact on all stakeholders and opine on financial and regulatory pressures on kidney transplant programs, outlining areas of uncertainty and concern, and suggest key points of reflection for clinical and administrative leaders of kidney transplant centers weighing participation in any of the voluntary payment models.

Implementing an innovated preservation technology: The American Society of Transplant Surgeons' (ASTS) Standards Committee White Paper on Ex Situ Liver Machine Perfusion.

The pervasive shortage of deceased donor liver allografts contributes to significant waitlist mortality despite efforts to increase organ donation. Ex vivo liver perfusion appears to enhance preservation of donor organs, extending viability and potentially evaluating function in organs previously considered too high risk for transplant. These devices pose novel challenges for organ allocation, safety, training, and finances. This white paper describes the American Society of Transplant Surgeons' belief that organ preservation technology is a vital advance, but its use should not change fundamental aspects of organ allocation. Additional data elements need to be collected, made available for organ assessment by transplant professionals to allow determination of organ suitability in the case of reallocation and incorporated into risk adjustment methodology. Finally, further work is needed to determine the optimal strategy for management and oversight of perfused organs prior to transplantation.

Patient-reported immunosuppression nonadherence 6 to 24 months after liver transplant: association with pretransplant psychosocial factors and perceptions of health status change.

CONTEXT: Knowing the prevalence and risk factors of immunosuppression nonadherence after liver transplant may help guide intervention development. OBJECTIVE: To examine whether sociodemographic and psychosocial variables before liver transplant are predictive of nonadherence after liver transplant. DESIGN: Structured telephone interviews were used to collect self-report immunosuppression adherence and health status information. Medical record reviews were then completed to retrospectively examine the relationship between immunosuppression adherence and pretransplant variables, including sociodemographic and medical characteristics and the presence or absence of 6 hypothesized psychosocial risk factors. SETTING AND PARTICIPANTS: A nonprobability sample of 236 adults 6 to 24 months after liver transplant at 2 centers completed structured telephone interviews. MAIN OUTCOME MEASURE: Immunosuppressant medication nonadherence, categorized as missed-dose and altered-dose "adherent" or "nonadherent" during the past 6 months; immunosuppression medication holidays. RESULTS: Eighty-two patients (35%) were missed-dose nonadherent and 34 patients (14%) were altered-dose nonadherent. Seventy-one patients (30%) reported 1 or more 24-hour immunosuppression holidays in the past 6 months. Missed-dose nonadherence was predicted by male sex (odds ratio, 2.46; P= .01), longer time since liver transplant (odds ratio, 1.08; P= .01), pretransplant mood disorder (odds ratio, 2.52; P=.004), and pretransplant social support instability (odds ratio, 2.25; P=.03). Altered-dose nonadherence was predicted by pretransplant mood disorder (odds ratio, 2.15; P= .04) and pretransplant social support instability (odds ratio, 1.89; P= .03). CONCLUSION: Rates of immunosuppressant nonadherence and drug holidays in the first 2 years after liver transplant are unacceptably high. Pretransplant mood disorder and social support instability increase the risk of nonadherence, and interventions should target these modifiable risk factors.

Incentives for organ donation: proposed standards for an internationally acceptable system.

Incentives for organ donation, currently prohibited in most countries, may increase donation and save lives. Discussion of incentives has focused on two areas: (1) whether or not there are ethical principles that justify the current prohibition and (2) whether incentives would do more good than harm. We herein address the second concern and propose for discussion standards and guidelines for an acceptable system of incentives for donation. We believe that if systems based on these guidelines were developed, harms would be no greater than those to today's conventional donors. Ultimately, until there are trials of incentives, the question of benefits and harms cannot be satisfactorily answered.

The prevalence of self-reported lactose intolerance and the consumption of dairy foods among African American adults are less than expected.

OBJECTIVE: To determine the self-reported incidence of lactose intolerance and its influence on dairy choices among African American adults. DESIGN, SETTING, AND PARTICIPANTS: An online survey closely matched to the 2000 US Census was administered to a nationally representative sample of African Americans (2016 adults) and a comparison sample of the general population (1084 adults). Statistical analyses performed included pairwise t tests for proportion conducted on percent responses at the 95% confidence level. RESULTS: African Americans were more likely to eat fewer dairy foods, experience physical discomfort after consumption, and believe they were lactose intolerant. While 49% of African Americans had ever experienced "some type of physical discomfort" after eating dairy foods, 24% believed they were lactose intolerant. Within this group, 85% of African Americans would be willing to consume more dairy products if they could avoid lactose intolerance symptoms. CONCLUSIONS AND IMPLICATIONS: Dairy food, calcium, and vitamin D intake in African Americans and the general population are below US recommendations. Deficiencies of these nutrients are associated with chronic diseases that disproportionately affect African Americans. In the United States, dairy foods are the primary source of calcium and vitamin D, and lactose intolerance can be a significant barrier to dairy food intake. However, self-described lactose intolerance is less than commonly reported in African American populations. Low dairy intake may reflect concerns about lactose intolerance, other factors such as learned food habits and cultural preferences. Nutrition recommendations for African Americans and the general population should focus on the health benefits of dairy foods, provide culturally sensitive dietary options, and strategies to increase tolerance.

Is Model for End-Stage Liver Disease score associated with quality of life after liver transplantation?

CONTEXT: The Model for End-Stage Liver Disease (MELD) is used to predict short-term mortality of patients on the liver transplant waiting list and to allocate deceased donor livers for transplantation. OBJECTIVE: To examine the relationship between MELD score before transplant and quality of life and other functional status indicators after transplant. DESIGN, SETTING, AND PATIENTS: Two-hundred sixty-five adults from 2 transplant programs completed quality-of-life measures 1 year after transplantation. A subcohort (n = 115) also completed quality-of-life assessments before transplant. Clinical parameters at the time of transplantation were collected from their medical records. MAIN OUTCOME MEASURES: Short Form-36 Health Survey, version 2; Transplant Symptom Frequency Questionnaire. RESULTS: Patients with MELD scores greater than 25 at transplantation had significantly higher scores on the Short Form-36 general health (P = .004) and physical component summary (P = .02) than did patients with MELD scores of 25 or less. However, scores on the Transplant Symptom Frequency Questionnaire did not vary significantly by MELD score. Child-Turcotte-Pugh (CTP) score, a measure of disease severity, was significantly associated with total symptom frequency after transplant (P = .03) but was not correlated with any domains on the Short Form-36. In the subcohort of 115 patients, a MELD score greater than 25 at the time of transplantation was associated with greater improvement in physical functioning (11.3 vs 4.8, P = .02), role functioning-physical (10.7 vs 4.7, P = .04), general health (11.9 vs 5.5, P = .03), vitality (10.4 vs 5.2, P = .02), and physical component summary (12.3 vs 5.4, P = .01) relative to patients with MELD scores of 15 to 25. CONCLUSIONS: The relationship between disease severity before transplant and quality of life after transplant is different depending on the index of disease severity used (MELD vs CTP) and whether the assessment of quality of life is general or specific to transplant-related symptoms.

Viewpoints on Healthcare Delivery Science Education Among Practicing Physicians in a Rural State.

INTRODUCTION: Healthcare Delivery Science Education (HDSE) covers important aspects of the business of medicine, including, operations management, managerial accounting, entrepreneurship, finance, marketing, negotiations, e-health and policy/advocacy. We need to investigate and understand practicing physicians' viewpoints on HDSE in order to inform interventions capable of preventing the double loss phenomena and improving medical and continuing medical education opportunities in HDSE. This qualitative study aims to provide a rich, contextualized understanding of the HDSE experiences and interests of physicians practicing in a rural state through the intensive study of particular cases. MATERIALS AND METHODS: We interviewed 18 practicing physicians from a rural, Midwestern state over the telephone about their viewpoints on past experiences obtaining HDSE, interest in HDSE, barriers to pursuing HDSE, and interest in an example HDSE certificate program. RESULTS: Salient themes in our study were that physicians were interested in HDSE and believed HDSE could lead to improved patient care and practice efficiency. However, many of the respondents had not received longitudinal, diversified, didactic or practical HDSE. Time limited many physicians from pursuing HDSE opportunities. Many physicians in the study were interested in the example HDSE certificate program. DISCUSSION AND CONCLUSIONS: Physicians in our qualitative study were interested in obtaining HDSE and had not received diversified, didactic HDSE in the past. Our research suggests innovative HDSE programs will likely be utilized and pursued if they are developed.

Fatigue and sleep quality before and after liver transplantation.

CONTEXT: Recent publications suggest that fatigue and sleep disturbance are problems in patients with chronic liver disease and in liver transplant recipients. OBJECTIVES: To characterize the severity and nature of fatigue and sleep quality before and after liver transplantation, to examine the relationship between fatigue/ sleep quality and quality of life, and to identify their multivariate correlates. DESIGN, SETTINGS, AND PARTICIPANTS: Cross-sectional survey administered to 110 patients before and 95 patients after liver transplantation at 2 transplant centers. MAIN OUTCOME MEASURES: Fatigue and sleep quality. RESULTS: Most pretransplant (86%) and posttransplant (76%) patients experienced high fatigue severity. Correlates of pretransplant fatigue severity were being female (odds ratio [OR] = 0.22, P = .04), higher body mass index (OR = 1.07, P = .04), higher mood disturbance (OR = 1.05, P = .02), and poor sleep quality (OR = 0.26, P = .02). Correlates of posttransplant fatigue severity were use of sleep medications in the past month (OR = 0.51, P = .02) and higher mood disturbance (OR = 1.06, P = .004). Seventy-three percent of pretransplant and 77% of posttransplant patients were classified as having poor sleep quality. Higher body mass index (OR = 1.06, P = .05), sleep medications (OR = 0.43, P = .03), and more mood disturbance (OR = 1.04, P = .007) were predictive of poor sleep quality in pretransplant patients, whereas higher body mass index (OR = 1.07, P = .04) and more anxious mood (OR = 1.28, P = .03) were predictive of poor sleep quality in posttransplant patients. CONCLUSION: A very high proportion of both pretransplant and posttransplant patients experience clinically severe fatigue levels. Prospective research is necessary to identify causal mechanisms of these disorders and to evaluate strategies to reduce fatigue severity and improve sleep quality.

An Unmet Need in Healthcare Leadership: A Survey of Practicing Physicians' Perspectives on Healthcare Delivery Science Education.

BACKGROUND: Healthcare delivery science education (HDSE) is increasingly needed by physicians balancing clinical care, practice management, and leadership responsibilities in their daily lives. However, most practicing physicians have received little HDSE in undergraduate through residency training. The purpose of this study is to 1) quantify the perception of the need for HDSE and interest in HDSE among a diverse sample of physicians, and 2) determine if perspectives on HDSE vary by specialty, rurality, and years in practice. METHODS: Using a cross-sectional, single state, mailed questionnaire, we surveyed 170 physicians about their perspectives on HDSE and interest in an HDSE program. Descriptive statistics and a multivariable logistic regression are presented. RESULTS: Among the 70.5% of responding eligible physicians, 75% of physicians had less HDSE than they would like and 90% were interested in obtaining more HDSE. Thirty-five percent of physicians were interested in joining the described HDSE program. The most prevalent barriers to obtaining HDSE were a lack of time and existing programs. Physician perspectives were similar across specialties, years in practice, and rurality. CONCLUSION: There is a high unmet need for HDSE among physicians. Diverse and innovative HDSE programming needs to be developed to meet this need. Programming should be developed not only for physicians but also for undergraduate through residency training programs.

A case of dual thoracoabdominal impalement in vehicular trauma.

Impalement injuries are relatively uncommon during vehicular trauma. We present a dual case report of patients sustaining simultaneous impalement injuries during a high-speed motor vehicle collision in a rural (austere) environment. After Institutional Review Board approval, we performed a review of the patients' medical records. Two young men were traveling in an automobile at high speed when the driver lost control of the vehicle, causing it to strike a wooden fence. Portions of the fence were dislodged, penetrated the windshield, and impaled both the driver and passenger. Both patients were extricated rapidly and transported to our trauma center. Multidisciplinary teams consisting of trauma, thoracic, plastic, and hepatobiliary surgeons addressed the injuries of both patients. Both survived their injuries and have since returned to their homes. This case of dual impalements highlights three key points: first, the principles of management of thoracoabdominal impalement injuries; second, the importance of rapid action of first responders in complex traumas; and finally, the value of using a multidisciplinary surgical team in complicated trauma cases.

Deceased donor kidney and liver transplantation to nonresident aliens in the United States.

BACKGROUND: Policies governing the allocation of deceased donor organs to nonresident aliens (NRAs) have existed from the early days of transplantation. However, there is a paucity of research describing this population. The aim of the present study is to examine characteristics and allocation patterns for NRAs compared to U.S. citizens in the context of the two most common forms of solid organ transplantation. METHODS: The study included kidney and liver transplant candidates and deceased donor transplant recipients from 1988-2005 in the United States. We describe demographic characteristics, insurance coverage, geographic variability, and donor relationship based on citizenship and residency status. We additionally examined the association of citizenship with time to transplantation utilizing survival models. RESULTS: From 1988-2005, there were 2724 solitary kidney and 2072 liver NRA candidate listings with United Network for Organ Sharing. NRA recipients had more self-pay (liver 36% and kidney 22%) and foreign sources (liver 26% and kidney 13%) of insurance coverage. Transplants to NRAs were more frequent than deceased donations deriving from NRAs for both organs. Adjusted models indicated that NRA kidney candidates received transplants at the same rate as U.S. citizens while liver NRA candidates received transplants more rapidly during the pre-Model for End-Stage Liver Disease (MELD; adjusted hazard ratio [AHR] 1.2, confidence interval [CI] 1.2-1.3) and post-MELD (AHR 1.5, CI 1.3-1.7) eras. CONCLUSIONS: NRAs are demographically and socioeconomically diverse and have historically had a more rapid progression on the waiting list to receive a liver transplant. Further discussion and investigation concerning the ethical, economic, and public health ramifications of transplantation to NRA patients are warranted.

Liver transplantation from donation after cardiac death: a single center experience.

BACKGROUND: Liver transplantation (LT) from controlled donation after cardiac death (DCD) donors has increased steadily during the past decade because of the donor shortage in the United States. Although early reports of LT from DCD donors provided evidence for acceptable outcomes, long-term graft and patient survival rates from these procedures have been reviewed only recently. METHODS: From February 1990 to June 2006, 1209 LTs were performed from donation after brain death (DBD) donors, and 24 were performed from DCD donors at our institution. Detailed review of donor and recipient characteristics, and survival rates were evaluated in the two groups. RESULTS: One- and 3-year patient survival was similar in both groups, (DCD 86.8%, 81.7% vs. DBD 84.0%, 76.0%, respectively; P=0.713). Graft survival appeared inferior in the DCD group compared with the DBD group at 1 year (69.1% vs. 78.7%) and 3 years (58.6% vs. 70.2%), but there was no statistical difference (P=0.082). There were no significant differences in hepatic artery thrombosis, portal vein thrombosis, primary nonfunction, and biliary stricture between the two groups. All cases with biliary stricture in DCD group finally led to graft loss, and all survived with retransplantation. CONCLUSION: The outcome of LT from DCD donors remains acceptable in our institution. Although biliary complication rate was similar in two groups, the consequence of this complication in DCD was more severe and often led to graft loss. Close observation of biliary complications after LT from DCD donors would be beneficial.

The financial burden of transplantation: a single-center survey of liver and kidney transplant recipients.

Little is known about the financial impact of transplantation on patients and families. We interviewed 333 liver transplant (LT) and 318 kidney transplant (KT) recipients who were at least 1 year posttransplant. Patients were asked whether transplantation caused financial problems, whether income had changed since transplantation, what resources they used to pay for transplant-related expenses, and what their out-of-pocket monthly expenses were. Descriptive and comparative statistics, measures of association, and logistic regression analyses were calculated. Many patients reported financial problems secondary to transplantation (40.6%) and less monthly income now than in the year preceding transplantation (46.5%). Average monthly out-of-pocket expense was $476.60. LT recipients had higher out-of-pocket expenses than KT recipients (t=2.46, P=0.015). Patients used personal savings (53.9%) and credit cards (25.0%) to help offset these expenses, among other strategies. For both LT and KT recipients, older age, nonworking status before transplantation, and current nonworking status predicted greater financial impact, whereas younger age and current nonworking status predicted higher monthly out-of-pocket expenses. These findings highlight the potential financial impact of transplantation on patients and families, and they have implications for assisting patients in managing out-of-pocket expenses after transplantation.

Is early recurrence of hepatitis C associated with biliary anastomotic stricture after liver transplantation?

BACKGROUND: While the main effect of hepatitis C virus (HCV) is hepatitis, HCV is also known to cause a variety of systemic immunologic inflammatory abnormalities. The effect of HCV infection on the biliary tract after liver transplantation (LT) is not well understood. The aim of the current study is to determine if recurrence of hepatitis C affects biliary complications after LT, with special reference to late biliary anastomotic strictures (LBAS). METHODS: A total of 688 consecutive adult LT recipients with a choledochocholedochostomy without T-tube placement between 1990 and 2005 were reviewed. Biliary anastomotic stricture was confirmed by endoscopic retrograde cholangiopancreatography. LBAS was defined as stricture that occurred 30 days or more after LT. Early HCV recurrence was defined as recurrence within 6 months after LT. RESULTS: LBAS occurred in 55 patients (8% of total). Patients with HCV infection had a higher occurrence of LBAS than non-HCV patients (11% vs. 5%, P=0.0093). Among HCV patients, those with early HCV recurrence had an exceedingly high rate of LBAS (16%). In multivariate analyses, early recurrence of hepatitis C (P<0.0001), as well as occurrence of hepatic artery thrombosis (P=0.0018) and prolonged cold ischemic time (P=0.034), were independent risk factors affecting LBAS. Among HCV patients, those with LBAS had a significantly higher hepatitis activity index score (3.1 vs. 1.4, P<0.0001) and fibrosis stage (0.9 vs. 0.4, P<0.0001) as compared to patients without LBAS. CONCLUSION: Patients with early recurrence of HCV have increased occurrence of late biliary anastomotic stricture after liver transplantation.