A Call for Systematic Research on Solute Carriers

Solute carrier (SLC) membrane transport proteins control essential physiological functions, including nutrient uptake, ion transport, and waste removal. SLCs interact with several important drugs, and a quarter of the more than 400 SLC genes are associated with human diseases. Yet, compared to other gene families of similar stature, SLCs are relatively understudied. The time is right for a systematic attack on SLC structure, specificity, and function, taking into account kinship and expression, as well as the dependencies that arise from the common metabolic space.

Efficient list-generation techniques for scheduling assessment centers

Human resources managers often conduct assessment centers to evaluate candidates for a job position. During an assessment center, the candidates perform a series of tasks. The tasks require one or two assessors (e.g., managers or psychologists) that observe and evaluate the candidates. If an exercise is designed as a role-play, an actor is required who plays, e.g., an unhappy customer with whom the candidate has to deal with. Besides performing the tasks, each candidate has a lunch break within a prescribed time window. Each candidate should be observed by approximately half the number of the assessors; however, an assessor may not observe a candidate if they personally know each other. The planning problem consists of determining (1) resource-feasible start times of all tasks and lunch breaks and (2) a feasible assignment of assessors to candidates, such that the assessment center duration is minimized. We present a list-scheduling heuristic that generates feasible schedules for such assessment centers. We propose several novel techniques to generate the respective task lists. Our computational results indicate that our approach is capable of devising optimal or near-optimal schedules for real-world instances within short CPU time.

A heuristic approach for scheduling assessment centers

Human resources managers often use assessment centers to evaluate candidates for a job position. During an assessment center, the candidates perform a series of exercises. The exercises require one or two assessors (e.g., managers or psychologists) that observe and evaluate the candidate. If an exercise is designed as a role-play, an actor is required as well which plays, e.g., an unhappy customer with whom the candidate has to deal with. Besides performing the exercises, the candidates have a lunch break within a prescribed time window. Each candidate should be observed by approximately half the number of the assessors. Moreover, an assessor cannot be assigned to a candidate if they personally know each other. The planning problem consists of determining (1) resource-feasible start times of all exercises and lunch breaks and (2) a feasible assignment of assessors to candidates, such that the assessment center duration is minimized. We propose a list-scheduling heuristic that generates feasible schedules for such assessment centers. We develop novel procedures for devising an appropriate scheduling list and for incorporating the problem-specific constraints. Our computational results indicate that our approach is capable of devising optimal or near-optimal solutions to real-world instances within short CPU time.

Risk of severe hypoglycemia in sulfonylurea-treated patients from diabetes centers in Germany/Austria: how big is the problem? which patients are at risk?

BACKGROUND We investigated the rate of severe hypoglycemic events and confounding factors in patients with type-2-diabetes treated with sulfonylurea (SU) at specialized diabetes centers, documented in the German/Austrian DPV-Wiss-database. METHODS Data from 29,485 SU-treated patients were analyzed (median[IQR] age 70.8[62.2-77.8]yrs, diabetes-duration 8.2[4.3-12.8]yrs). The primary objective was to estimate the event-rate of severe hypoglycemia (requiring external help, causing unconsciousness/coma/convulsion and/or emergency.hospitalization). Secondary objectives included exploration of confounding risk-factors through group-comparison and Poisson-regression. RESULTS Severe hypoglycemic events were reported in 826(2.8%) of all patients during their most recent year of SU-treatment. Of these, n = 531(1.8%) had coma, n = 501(1.7%) were hospitalized at least once. The adjusted event-rate of severe hypoglycemia [95%CI] was 3.9[3.7-4.2] events/100 patient-years (coma: 1.9[1.8-2.1]; hospitalization: 1.6[1.5-1.8]). Adjusted event-rates by diabetes-treatment were 6.7 (SU + insulin), 4.9 (SU + insulin + other OAD), 3.1 (SU + other OAD), and 3.8 (SU only). Patients with ≥1 severe event were older (p < 0.001) and had longer diabetes-duration (p = 0.020) than patients without severe events. Participation in educational diabetes-programs and indirect measures of insulin-resistance (increased BMI, plasma-triglycerides) were associated with fewer events (all p < 0.001). Impaired renal function was common (N = 3,113 eGFR ≤30 mL/min) and associated with an increased rate of severe events (≤30 mL/min: 7.7; 30-60 mL/min: 4.8; >60 mL/min: 3.9). CONCLUSIONS These real-life data showed a rate of severe hypoglycemia of 3.9/100 patient-years in SU-treated patients from specialized diabetes centers. Higher risk was associated with known risk-factors including lack of diabetes-education, older age, and decreased eGFR, but also with lower BMI and lower triglyceride-levels, suggesting that SU-treatment in those patients should be considered with caution. This article is protected by copyright. All rights reserved.

Non-metastatic castrate-resistant prostate cancer: a call for improved guidance on clinical management.

BACKGROUND Guidelines on the clinical management of non-metastatic castrate-resistant prostate cancer (nmCRPC) generally focus on the need to continue androgen deprivation therapy and enrol patients into clinical trials of investigational agents. This guidance reflects the lack of clinical trial data with established agents in the nmCRPC patient population and the need for trials of new agents. AIM To review the evidence base and consider ways of improving the management of nmCRPC. CONCLUSION Upon the development of castrate resistance, it is essential to rule out the presence of metastases or micrometastases by optimising the use of bone scans and possibly newer procedures and techniques. When nmCRPC is established, management decisions should be individualised according to risk, but risk stratification in this diverse population is poorly defined. Currently, prostate-specific antigen (PSA) levels and PSA doubling time remain the best method of assessing the risk of progression and response to treatment in nmCRPC. However, optimising imaging protocols can also help assess the changing metastatic burden in patients with CRPC. Clinical trials of novel agents in nmCRPC are limited and have problems with enrolment, and therefore, improved risk stratification and imaging may be crucial to the improved management. The statements presented in this paper, reflecting the views of the authors, provide a discussion of the most recent evidence in nmCRPC and provide some advice on how to ensure these patients receive the best management available. However, there is an urgent need for more data on the management of nmCRPC.

Post-H1N1 Flu Vaccination Narcolepsy in Switzerland: A Retrospective Survey in the 30 Sleep-Certified Swiss Centers

Narcolepsy-cataplexy is a sleep-wake disorder and suggested to be immune-mediated, involving genetic and environmental factors. The autoimmune process eventually leads to a loss of hypocretin neurons in the lateral hypothalamus. Epidemiological studies in several countries proved an increased incidence of narcolepsy after H1N1 flu vaccination and infection. This survey in 30 sleep centers in Switzerland led to the identification of 9 H1N1-vaccinated children and adults as newly diagnosed narcolepsy. Clinical features included the abrupt and severe onset of sleepiness, cataplexy and sleep fragmentation.