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.

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.

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.

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.

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.

MED SCHOOL STUDENTS GETTING THE BUSINESS.

Positive response to a major university's project designed to gauge interest in business and management among medical students leads to implementation of a new curriculum for the next wave of physician leaders.

Correction: Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy.

[This corrects the article DOI: 10.1371/journal.pone.0156456.].

Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy.

TASK-2, a member of the Two-Pore Domain (K2P) subfamily of K+ channels, is encoded by the KCNK5 gene. The channel is expressed primarily in renal epithelial tissues and a potentially deleterious missense variant in KCNK5 has recently been shown to be prevalent amongst patients predisposed to the development of Balkan Endemic Nephropathy (BEN), a chronic tubulointerstitial renal disease of unknown etiology. In this study we show that this variant (T108P) results in a complete loss of channel function and is associated with a major reduction in TASK-2 channel subunits at the cell surface. Furthermore, these mutant subunits have a suppressive or 'dominant-negative' effect on channel function when coexpressed with wild-type subunits. This missense variant is located at the extracellular surface of the M2 transmembrane helix and by using a combination of structural modelling and further functional analysis we also show that this highly-conserved threonine residue is critical for the correct function of other K2P channels. These results therefore provide further structural and functional insights into the possible pathophysiological effects of this missense variant in TASK-2.

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.

Cytochrome P450 3A4FNx011B as pharmacogenomic predictor of tacrolimus pharmacokinetics and clinical outcome in the liver transplant recipients.

BACKGROUND AND AIMS: Tacrolimus is a macrolide immunosuppressant used for prevention of allograft rejection in organ transplantation and metabolized in the liver and intestine by cytochrome P450 3A4 (CYP3A4) enzyme. A single nucleotide polymorphism (SNP) in the CYP3A4 promoter region has been identified. It has been shown that the presence of CYP3A4FNx011B allele (variant GG) is associated with a reduced catalytic activity of CYP3A4 in vivo. The aim of this study was to determine the role of CYP3A4FNx011B on tacrolimus dosing and clinical outcome in liver transplant recipients. SUBJECTS AND METHODS: Forty-eight liver transplant recipients were stratified according to the genotype. There were 32 wild-type (AA) patients and 5 homozygous variant (GG) and 11 (AG) heterozygous. Tacrolimus doses and trough concentrations as well as phenotypic data were collected in the first 10 days of the transplant. RESULTS: The tacrolimus concentration was significantly higher in the wild (AA) group as compared to homozygous variant (GG) and heterozygous (AG) patients. Homozygous variant (GG) group had significantly lower dose requirements. However, no significant difference was observed in the concentration/dose ratio between all groups. CONCLUSIONS: Based on our results, it may be concluded that CYP3A4FNx011B of recipient is an important factor influencing pharmacokinetic of tacrolimus, as patients with CYP3A4FNx011B polymorphism may require lower tacrolimus doses to maintain therapeutic levels. The dose reduction may not affect clinical outcomes after liver transplant.

Resection of the liver and inferior vena cava for hepatic malignancy.

BACKGROUND: Involvement of the IVC has traditionally been considered a relative contraindication to resection for advanced tumors of the liver. Combined resection of the liver and IVC for malignancy can be performed safely and results in long-term survival in select patients. STUDY DESIGN: Sixty patients undergoing hepatic and IVC resection by the primary author from 1996 to 2012 were reviewed. Median age was 52 years. Resections were carried out for cholangiocarcinoma (n = 26), hepatocellular carcinoma (n = 16), colorectal metastases (n = 13), gastrointestinal stromal tumor (n = 2), hepatoblastoma (n = 2), and squamous cell carcinoma (n = 1). Resections performed included 27 right and 5 left trisegmentectomies and 25 right and 3 left lobectomies, including the caudate lobe. Ex vivo procedures were performed in 6 patients using veno-venous bypass and the other 54 procedures were performed using varying degrees of vascular isolation. In situ cold perfusion of the liver was used in 8 patients. The IVC was reconstructed using a tube graft (n = 38) primarily (n = 8) or with patches (n = 14). RESULTS: There were 5 perioperative deaths (8%). Three patients died of liver failure, 1 patient died of pulmonary hemorrhage, and 1 patient died of massive pulmonary embolism. Nine patients had evidence of postoperative liver failure that resolved with supportive management. Three patients required temporary dialysis. With a median follow-up of 31 months, 14 patients have died of recurrent malignancy between 22 and 44 months, and an additional 4 patients are alive with disease at 16 to 33 months. Actuarial 1- and 5-year survival rates were 89% and 35%, respectively. CONCLUSIONS: Inferior vena cava involvement by malignancy does not obviate liver resection. The procedure's increased risk is balanced by the possible benefits, given the lack of alternative curative approaches.

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.