Successful Delivery of RRT in Ebola Virus Disease

AKI has been observed in cases of Ebola virus disease. We describe the protocol for the first known successful delivery of RRT with subsequent renal recovery in a patient with Ebola virus disease treated at Emory University Hospital, in Atlanta, Georgia. Providing RRT in Ebola virus disease is complex and requires meticulous attention to safety for the patient, healthcare workers, and the community. We specifically describe measures to decrease the risk of transmission of Ebola virus disease and report pilot data demonstrating no detectable Ebola virus genetic material in the spent RRT effluent waste. This article also proposes clinical practice guidelines for acute RRT in Ebola virus disease.     

Epidemiology,pathophysiology and contemporary management of cardiogenic shock – a position statement from the Heart Failure Association of the European Society of Cardiology

Cardiogenic shock (CS) is a complex multifactorial clinical syndrome with extremely high mortality, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large spectrum of CS presentations resulting from the interaction between an acute cardiac insult and a patient's underlying cardiac and overall medical condition. Phenotyping patients with CS may have clinical impact on management because classification would support initiation of appropriate therapies. CS management should consider appropriate organization of the health care services, and therapies must be given to the appropriately selected patients, in a timely manner, whilst avoiding iatrogenic harm. Although several consensus‐driven algorithms have been proposed, CS management remains challenging and substantial investments in research and development have not yielded proof of efficacy and safety for most of the therapies tested, and outcome in this condition remains poor. Future studies should consider the identification of the new pathophysiological targets, and high‐quality translational research should facilitate incorporation of more targeted interventions in clinical research protocols, aimed to improve individual patient outcomes. Designing outcome clinical trials in CS remains particularly challenging in this critical and very costly scenario in cardiology, but information from these trials is imperiously needed to better inform the guidelines and clinical practice. The goal of this review is to summarize the current knowledge concerning the definition, epidemiology, underlying causes, pathophysiology and management of CS based on important lessons from clinical trials and registries, with a focus on improving in‐hospital management.     

Health Economic Modelling of Treatment Sequences for Rheumatoid Arthritis: A Systematic Review

The objective of the work reported in this paper was to critically assess how sequential disease-modifying anti-rheumatic drugs (DMARDs) have been modelled in the context of economic evaluation of the use of DMARDs for treatment of rheumatoid arthritis (RA). A secondary purpose was to identify the methodological challenges of modelling sequential therapies. Systematic searches of 10 databases were undertaken in February 2013. Studies were included if they were in the English language and a full comparative economic evaluation was reported. They were appraised by use of the Drummond checklist (Appendix to this paper). Data extracted included economic evaluation data, data relating to sequential treatment, and data on the modelling methods used. Fifty-seven studies were identified, with 25 (44 %) modelling a sequence of treatments. Forty-three (75 %) were cost–utility analyses. Eleven (19 %) were UK studies and 11 (19 %) were US. The remainder were mainly European (26 (46 %)). A distinction was made between studies of recent-onset RA (14 (25 %)) and those of established RA (42 (74 %)). One study (1 %) was unclear. Individual-level models were more likely to meet the Drummond criteria and evaluate sequences. No study identified an optimum sequence of multiple treatments given a set of treatment options. The level of reporting of the methods and evidence used to assess the effect of downstream treatments in the sequence was generally poor. When lifelong models and downstream treatment sequences were considered, evidence gaps were identified. The review discovered that methods have not been consistently applied, leading to varied estimates of cost-effectiveness. Treatment sequences have not been fully considered and modelled, potentially resulting in inaccurate estimates of cost-effectiveness.     

Methamphetamine Increases the Proportion of SIV-Infected Microglia/Macrophages,Alters Metabolic Pathways,and Elevates Cell Death Pathways: A Single-Cell Analysis

Both substance use disorder and HIV infection continue to affect many individuals. Both have untoward effects on the brain, and the two conditions often co-exist. In the brain, macrophages and microglia are infectable by HIV, and these cells are also targets for the effects of drugs of abuse, such as the psychostimulant methamphetamine. To determine the interaction of HIV and methamphetamine, we isolated microglia and brain macrophages from SIV-infected rhesus monkeys that were treated with or without methamphetamine. Cells were subjected to single-cell RNA sequencing and results were analyzed by statistical and bioinformatic analysis. In the animals treated with methamphetamine, a significantly increased proportion of the microglia and/or macrophages were infected by SIV. In addition, gene encoding functions in cell death pathways were increased, and the brain-derived neurotropic factor pathway was inhibited. The gene expression patterns in infected cells did not cluster separately from uninfected cells, but clusters comprised of microglia and/or macrophages from methamphetamine-treated animals differed in neuroinflammatory and metabolic pathways from those comprised of cells from untreated animals. Methamphetamine increases CNS infection by SIV and has adverse effects on both infected and uninfected microglia and brain macrophages, highlighting the dual and interacting harms of HIV infection and drug abuse on the brain.     

Long-Term Stability at ?20°C of Aspergillus Galactomannan in Serum and Bronchoalveolar Lavage Specimens

Research to develop and validate novel methods for diagnosis of aspergillosis based on detection of galactomannan requires the use of clinical specimens that have been stored frozen. Data indicating that galactomannan remains stable when frozen are scant. The objective of this study was to determine the stability of galactomannan in clinical specimens stored at −20°C that were positive in the Platelia Aspergillus enzyme immunoassay when initially tested. Prospective real-time testing of serum and bronchoalveolar lavage (BAL) fluid pools from positive and negative patient specimens showed no decline in galactomannan index (GMI) over 11 months at −20°C and no development of positive reactions in the negative-control pool. Retrospective testing of positive specimens that had been stored at −20°C for 5 years showed that 28 of 30 serum (n = 15) or BAL (n = 15) specimens remained positive. These findings support the use of frozen serum or BAL specimens stored for at least 5 years in evaluation of diagnostic tests based on detection of galactomannan.     

Morquio A Syndrome‐Associated Mutations: A Review of Alterations in the GALNS Gene and a New Locus‐Specific Database

Morquio A syndrome (mucopolysaccharidosis IVA) is an autosomal recessive disorder that results from deficient activity of the enzyme N‐acetylgalactosamine‐6‐sulfatase (GALNS) due to alterations in the GALNS gene, which causes major skeletal and connective tissue abnormalities and effects on multiple organ systems. The GALNS alterations associated with Morquio A are numerous and heterogeneous, and new alterations are continuously identified. To aid detection and interpretation of GALNS alterations, from previously published research, we provide a comprehensive and up‐to‐date listing of 277 unique GALNS alterations associated with Morquio A identified from 1,091 published GALNS alleles. In agreement with previous findings, most reported GALNS alterations are missense changes and even the most frequent alterations are relatively uncommon. We found that 48% of patients are assessed as homozygous for a GALNS alteration, 39% are assessed as heterozygous for two identified GALNS alterations, and in 13% of patients only one GALNS alteration is detected. We report here the creation of a locus‐specific database for the GALNS gene ( http://galns.mutdb.org/ ) that catalogs all reported alterations in GALNS to date. We highlight the challenges both in alteration detection and genotype–phenotype interpretation caused in part by the heterogeneity of GALNS alterations and provide recommendations for molecular testing of GALNS.     

A multi‐centre,single‐arm,open‐label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory,relapsed or chronic idiopathic thrombocytopenic purpura (R‐ITP1000 study)

The efficacy of a fixed‐dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 × 10⁹/l and ≤50 × 10⁹/l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed‐up on weeks 1–8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 × 10⁹/l) or partial response (PR; platelet count >50 × 10⁹/l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 × 10⁹/l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m² four‐dose schedule in relapsed/chronic ITP.