Citations

ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell‐released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV‐associated functional activities. Finally, a checklist is provided with summaries of key points.

SummaryObjectiveStudies of dehydroepiandrosterone (DHEA) therapy in older adults suggest sex‐specific effects on bone mineral density (BMD) and body composition, but the ability of a single study to reach this conclusion was limited. We evaluated the effects of DHEA on sex hormones, BMD, fat mass and fat‐free mass in older women and men enrolled in four similar clinical trials.DesignPooled analyses of data from four double‐blinded, randomized controlled trials.ParticipantsWomen (n = 295) and men (n = 290) aged 55 years or older who took DHEA or placebo tablet daily for 12 months.MeasurementsTwelve‐month changes in BMD, fat mass, fat‐free mass and serum DHEA sulphate (DHEAS), (17)estradiol, testosterone and insulin‐like growth factor‐1 (IGF‐1).ResultsWomen on DHEA had increases (mean ± SD; all P < 0.001 vs placebo) in DHEAS (231 ± 164 µg/dL), testosterone (18.6 ± 20.9 µg/dL), (17)estradiol (8.7 ± 11.0 pg/mL) and IGF‐1 (25.1 ± 52.3 ng/mL), and men had increases in DHEAS (269.0 ± 177 µg/dL; P < 0.01), (17)estradiol (4.8 ± 12.2 pg/m; P < 0.01) and IGF‐1 (6.3 ± 41.4 ng/mL; P < 0.05). Women on DHEA had increases in lumbar spine (1.0% ± 3.4%) and trochanter (0.5% ± 3.8%) BMD and maintained total hip BMD (0.0% ± 2.8%); men had no BMD benefit and a decrease in fat mass (−0.4 ± 2.6 kg; all P < 0.01 vs placebo).ConclusionsDehydroepiandrosterone therapy may be an effective approach for preserving bone and muscle mass in women. Key questions are (a) the extent to which longer duration DHEA can attenuate the loss of bone and muscle in women, and (b) whether DHEA has a more favourable benefit‐to‐risk profile for women than oestrogen therapy.

An infant with complex congenital heart disease suffers a prolonged cardiac arrest with minutes of anoxia. He is left with severe brain damage and profound neurologic impairment. He no longer responds to caregivers. Much of the time, he cries and grimaces as if in pain. He has required increasing sedation to control these symptoms. His parents live hours from the hospital and seldom visit. When their infant’s situation is explained to them over the telephone, they request that doctors “do everything to keep him alive.” His bedside caregivers report high levels of moral and psychological distress and frequently discuss J.S.’s “suffering.” An ethics consultation is requested, asking whether it is permissible to withdraw life support despite the parents’ request that therapy continue.

Background Aortic syndromes (ASs), including aortic dissection, intramural hematoma, and penetrating aortic ulcer, carry significant acute and long-term morbidity and mortality. However, the contemporary incidence and outcomes of AS are unknown. Methods and Results We used the Rochester Epidemiology Project record linkage system to identify all Olmsted County, MN, residents with AS (1995–2015). Diagnostic imaging, medical records, and death certificates were reviewed to confirm the diagnosis and AS subtype. Age- and sex-adjusted incidence rates were estimated using annual county-level census data. Survival for patients with AS was compared with age- and sex-matched controls using Cox regression to adjust for comorbid conditions. We identified 133 patients with AS (77, aortic dissection; 21, intramural hematoma; and 35, penetrating aortic ulcer). Average age was 71.8 years (SD=14.1), and 57% were men. The age- and sex-adjusted incidence was 7.7 per 100 000 person-years, was higher for men than women (10.2 versus 5.7 per 100 000 person-years), and increased with age. Among subtypes, the incidence of aortic dissection was highest (4.4 per 100 000 person-years), whereas the incidence of penetrating aortic ulcer and intramural hematoma was lower (2.1 and 1.2 per 100 000 person-years). Overall, the incidence of AS was stable over time ( P trend=0.33), although the incidence of penetrating aortic ulcer seemed to increase from 0.6 to 2.6 per 100 000 person-years ( P =0.008) with variability over the study interval. Patients with AS had more than twice the mortality rate at 5, 10, and 20 years when compared with population-based controls (5-, 10-, and 20-year mortality 39%, 57%, and 91% versus 18%, 41%, and 66%; overall adjusted mortality hazards ratio=2.1; P <0.001). Survival was lower than expected up to 90 days after AS diagnosis and did not differ significantly by subtype or by 5-year strata of diagnosis. Conclusions Overall, the incidence of aortic dissection and intramural hematoma has remained stable since 1995, despite the decline noted for other cardiovascular disease. AS confers increased early and long-term mortality that has not changed. These data highlight the need to improve long-term care to impact the prognosis of this patient group.

BACKGROUNDA prior practice survey revealed variations in the management of patients with sickle cell disease (SCD) and stressed the need for comprehensive guidelines. Here we discuss: 1) common indications for red blood cell exchange (RCE), 2) options for access, 3) how to prepare the red blood cells (RBCs) to be used for RCE, 4) target hemoglobin (Hb) and/or hematocrit (Hct) and HbS level, 5) RBC depletion/RCE, and 6) some complications that may ensue.STUDY DESIGN AND METHODSFifteen physicians actively practicing apheresis from 14 institutions representing different areas within the United States discussed how they manage RCE for patients with SCD.RESULTSSimple transfusion is recommended to treat symptomatic anemia with Hb level of less than 9 g/dL. RCE is indicated to prevent or treat complications arising from the presence of HbS. The most important goals are reduction of HbS while also preventing hyperviscosity. The usual goals are a target HbS level of not more than 30% and Hct level of less than 30%.CONCLUSIONAlthough a consensus as to protocol details may not be possible, there are areas of agreement in the management of these patients, for example, that it is optimal to avoid hyperviscosity and iron overload, that a target Hb S level in the range of 30% is generally desirable, and that RCE as an acute treatment for pain crisis in the absence of other acute or chronic conditions is ordinarily discouraged.

Abstract Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. Patients and Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. Conclusions: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

ABSTRACT Introduction: The Amyotrophic Lateral Sclerosis (ALS)‐Specific Quality of Life instrument and its revised version (ALSSQOL and ALSSQOL‐R) have strong psychometric properties, and have demonstrated research and clinical utility. In this study we aimed to develop a short form (ALSSQOL‐SF) suitable for limited clinic time and patient stamina. Methods: The ALSSQOL‐SF was created using Item Response Theory and confirmatory factor analysis on 389 patients. A cross‐validation sample of 162 patients assessed convergent, divergent, and construct validity of the ALSSQOL‐SF compared with psychosocial and physical functioning measures. Results: The ALSSQOL‐SF consisted of 20 items. Compared with the ALSSQOL‐R, optimal precision was retained, and completion time was reduced from 15–25 minutes to 2–4 minutes. Psychometric properties for the ALSSQOL‐SF and its subscales were strong. Discussion: The ALSSQOL‐SF is a disease‐specific global QOL instrument that has a short administration time suitable for clinical use, and can provide clinically useful, valid information about persons with ALS. Muscle Nerve 58: 646–654, 2018