Redox active or thiol reactive? Optimization of rapid screens to identify less evident nuisance compounds

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity are routinely encountered in assays at various stages of drug discovery. We observed that assays for the investigation of thiol-reactive and redox-active compounds have not been collected in a comprehensive review. Here, we review these assays and subject them to experimental optimization to improve their reliability. We demonstrate the usefulness of our assay cascade by assaying a library of bioactive compounds, chemical probes, and a set of approved drugs. These high-throughput assays should complement the array of wet-lab and in silico assays during the initial stages of hit discovery campaigns to pursue only hit compounds with tractable mechanisms of action.     

Successful Treatment for BK Virus Nephropathy by Leflunomide in a Kidney Transplant Patient: A Case Report

IntroductionThe immunosuppressant agents in kidney transplantation (KT) may lead to various complications such as opportunistic infections and malignancies. BK virus associated nephropathy is a significant complication following KT, and it can result in graft failure. BK virus causes tubulointerstitial nephritis, ureter stenosis, and even graft failure in KT recipients with impaired immune system. We described a 63-year-old woman, who was a hepatitis C carrier and on dialysis for 22 years before KT, who received cadaveric-donor KT 2 years previously. She reported decreasing urine output and general weakness. The serum creatinine level was slightly increased from 2.94 to 4.38 mg/dL.MethodsImmunosuppressant medications including prednisolone, everolimus, cyclosporin, and mycophenolate sodium were continued as maintenance therapy post KT. Kidney biopsy was performed due to deterioration of graft function.ResultsThe kidney biopsy showed consistent results with early-stage polyomavirus nephropathy, characterized by focal viral cytopathic changes with positive immunohistochemical signals and mesangial proliferative glomerulonephritis, immune-complex-mediated (Fig 1 and Fig 2). Negative C4d staining at peritubular capillary was reported. The dosage of mycophenolate sodium was tapered from 720 to 360 mg daily and that of everolimus increased from 0.5 to 1.0 mg daily due to BK viral infection with BK nephropathy. The serum creatinine level was 2.75 mg/dL after treatment.ConclusionEarly detection of BK nephropathy and decreasing immunosuppressant agents are the mainstay of treatment. Substituting leflunomide for mycophenolate sodium and increasing dosage of everolimus has been proposed to solve BK nephropathy. We presented that the use of leflunomide in such situation is in a timely manner.     

红皮病患者低钾血症预后的影响因素分析

<正>机体的血钾参与并维持细胞代谢,保持细胞内液渗透压及酸碱平衡,并可维持神经肌肉组织兴奋及心肌功能~([1-2])。中重度低血钾主要表现为肌无力,可延及机体的躯干和呼吸肌,造成呼吸困难,还可引发腱反射减弱或消失、肠麻痹及心脏传导阻滞、节律异     

Optimizing access and configuration of trauma centre care in New South Wales

IntroductionGetting the right patient, to the right place, at the right time is dependent on a multitude of modifiable and non-modifiable factors. One potentially modifiable factor is the number and location of trauma centres (TC). Overabundance of TC dilutes volumes and could be associated with worse outcomes. We describe a methodology that evaluates trauma system reconfiguration without reductions in potential access to care. We used the mature trauma system of New South Wales (NSW) as a model given the perceived overabundance of urban major trauma centres (MTC).MethodsWe first evaluated potential access to TC care via ground and air transport through the use of geographic information systems (GIS) network analysis. Potential access was defined as the proportion of the population living within 60-min transport time from a potential scene of injury to a TC by ground or rotary-wing aircraft. Sensitivity analyses were carried out in order to account for potential pre-hospital interventions and/or transport delays; travel times of 15-, 30-, 45-, 60-, and 90-min were also analyzed. We then evaluated if the current configuration of the system (number of urban MTS in the Sydney basin) could be optimized without reductions in potential access to care using two GIS methodologies: location-allocation and individual removal of MTC.Results86% of the NSW population has potential access to a TC within 60 min ground travel time; potential access improves to 99% with rotary-wing transport. The 1% of the population without potential TC access lives in 48% of the land area (>384,000km2). Utilizing two different methodologies we identified that there was no change in potential access by ground transport after removing 1 or 2 MTC in the Sydney basin at the 30-, 45-, and 60-min transport times. However, 0.02% and 0.5% of the population would not have potential access to MTC care at 15 min after removing one and two MTC respectively.DiscussionRedistribution of the number of MTC in the Sydney basin could be achieved without a significant impact on potential access to care. Our approach can be utilized as an initial tool to evaluate a trauma system where overabundance of coverage is present.     

Survival and Outcomes of Newly Diagnosed Multiple Myeloma Patients Stratified by Transplant Status 2007-2018: Retrospective Analysis from the Canadian Myeloma Research Group Database

BackgroundConsiderable progress has been made in therapeutic options for multiple myeloma (MM). Understanding the current landscape of MM treatment options and associated outcomes in the real world is important in providing key insights into clinical and knowledge gaps which could be targeted for further optimization.MethodsThe Canadian Myeloma Research Group Database (CMRG-DB) is a prospectively maintained disease-specific database with >7000 patients. The objective of this study was to describe the trends in the treatment landscape and outcomes including early mortality, time to next treatment, and overall survival (OS) in each line of treatment stratified by autologous stem cell transplant (ASCT) receipt among newly-diagnosed MM patients in Canada between 2007 and 2018.ResultsA total of 5154 patients were identified among which 3030 patients (58.8%) received an upfront ASCT and 2124 (41.2%) did not. At diagnosis, the median age was 64 years and 58.6% were males. Bortezomib and lenalidomide were most frequently used (>50%) in first and second-line treatment respectively among both the ASCT and non-ASCT cohort. The median OS was 122.0 months (95% Cl 115.0-135.0 months) and 54.3 months (95% CI 50.8-58.8 months) for the ASCT and non-ASCT cohort respectively with an incremental decrease in OS in each subsequent line of treatment.ConclusionWe present the largest study to date in the Canadian landscape showing the characteristics, therapy usage, and outcomes among MM patients. This information will be critical in benchmarking current outcomes and provide key insight into areas of unmet needs and gaps for improvement of MM patients nationally.     

Pump Speed Optimization in Patients Implanted With the HeartMate 3 Device

Background

Pump speed optimization in patients implanted with a ventricular assist device represents a major challenge during the follow-up period. We present our findings on whether combined invasive hemodynamic ramp tests and cardiopulmonary exercise testing (CPX) can help optimize patient management.