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.

The cost of prescription drugs in the United States continues to be a source of concern for patients, caregivers, and policymakers. Drug prices typically decline rapidly once generic drugs receive US Food and Drug Administration (FDA) approval and enter the market, but the past decade has witnessed rising costs and shortages of generic drugs. We describe the strategies used by brand‐name manufacturers to undermine generic competition and the reasons underlying the price increases of off‐patent drugs, some of which continue to lack any competition from generic versions, and others that have increased in price despite having generic versions. We discuss the FDA's role in addressing drug prices and promoting competition, including recent agency policies to modify its process of reviewing generic drug applications and to prioritize applications for off‐patent drugs with few competitors. We also examine proposed policy solutions and research areas that could help address the price increases of off‐patent drugs.

SummaryThere is a need for efficacious, convenient treatments with long‐term tolerability for patients with relapsed/refractory multiple myeloma (RRMM). This phase 2 study evaluated the all‐oral combination of ixazomib, cyclophosphamide and dexamethasone (ICd). Patients with RRMM received ixazomib 4 mg and cyclophosphamide 300 mg/m2 on days 1, 8 and 15, and dexamethasone 40 mg on days 1, 8, 15 and 22 in 28‐day cycles. The primary endpoint was overall response rate (ORR). Seventy‐eight patients were enrolled (median age 63·5 years). At data cut‐off, patients had received a median of 12 treatment cycles; 31% remained on treatment. ORR was 48% [16% very good partial response or better (≥VGPR)]. ORR was 64% and 32% in patients aged ≥65 and <65 years (25% and 16% ≥VGPR), respectively. At a median follow‐up of 15·2 months, median progression‐free survival (PFS) was 14·2 months, with a trend towards better PFS in patients aged ≥65 years vs. <65 years (median 18·7 months vs. 12·0 months; hazard ratio 0·62, P = 0·14). ICd was well tolerated. The most common treatment‐emergent adverse events were diarrhoea (33%), nausea (24%), upper respiratory tract infection (24%), and thrombocytopenia (22%); 10 patients (13%) had peripheral neuropathy (one grade 3). This study is registered at ClinicalTrials.gov (NCT02046070).

AbstractRationale, aims, and objectivesWaist circumference (WC) and waist‐to‐height ratio (WHtR) are superior surrogate markers of central obesity than body mass index. However, WC is not measured routinely in paediatric clinics. The objective of this study was to implement measurement of WC during routine assessment of children in an ambulatory outpatient clinic setting and subsequent dissemination of cardiometabolic risk counselling in children with central obesity (defined as WHtR ≥0.5).MethodProspective cohort of patients aged 6 to 20 years. Study period was divided into three phases: baseline (3 months), process improvement (2 months), and implementation (6 months). Define‐Measure‐Analyse‐Improve‐Control (DMAIC) strategy was applied. Measurement of WC was implemented as a component of the physical examination in patients. Outcome measures were (1) improvement in frequency of WC measurement and (2) utilization of WHtR in cardiometabolic risk counselling.ResultsWaist circumference was not measured in any patient during baseline phase (n = 551). During process improvement phase, of the total 347 patients, WC was measured in 35% vs target of 30%. In the implementation phase, WC was measured in 37% patients (365 out of 964). Of these 365 patients, 175 (48%) had elevated WHtR, and 73% of them (n = 128) were counselled about their increased cardiometabolic risk.ConclusionsApplication of an evidence‐based DMAIC protocol led to significant improvement in assessment for central obesity in an ambulatory clinic practice and appropriate counselling regarding cardiometabolic risk reduction in children and adolescents with central obesity over an 8‐month period. Meticulous planning and execution, frequent reinforcement, and integrating feedback from the involved multi‐disciplinary team were important factors in successful implementation of this quality improvement project.

Abstract Background Lumbar spinal stenosis ( LSS ) can lead to compression of neural elements and manifest as low back and leg pain. LSS has traditionally been treated with a variety of conservative (pain medications, physical therapy, epidural spinal injections) and invasive (surgical decompression) options. Recently, several minimally invasive procedures have expanded the treatment options. Methods The Lumbar Spinal Stenosis Consensus Group convened to evaluate the peer‐reviewed literature as the basis for making minimally invasive spine treatment ( MIST ) recommendations. Eleven consensus points were clearly defined with evidence strength, recommendation grade, and consensus level using U.S. Preventive Services Task Force criteria. The Consensus Group also created a treatment algorithm. Literature searches yielded 9 studies (2 randomized controlled trials [ RCT s]; 7 observational studies, 4 prospective and 3 retrospective) of minimally invasive spine treatments, and 1 RCT for spacers. Results The LSS treatment choice is dependent on the degree of stenosis; spinal or anatomic level; architecture of the stenosis; severity of the symptoms; failed, past, less invasive treatments; previous fusions or other open surgical approaches; and patient comorbidities. There is Level I evidence for percutaneous image‐guided lumbar decompression as superior to lumbar epidural steroid injection, and 1 RCT supported spacer use in a noninferiority study comparing 2 spacer products currently available. Conclusions MISTs should be used in a judicious and algorithmic fashion to treat LSS , based on the evidence of efficacy and safety in the peer‐reviewed literature. The MIST Consensus Group recommend that these procedures be used in a multimodal fashion as part of an evidence‐based decision algorithm.

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long‐term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event‐free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver‐related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P= not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P= 0.002), but 5‐year event‐free survival was similar (74% versus 77%, P= NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5‐year event‐free survival was better (91% versus 67%, P< 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5‐year event‐free survival 88% versus 61%, P= 0.005). Conclusion:A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5‐year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.