Citations

Some melanomas develop a striking avidity for lymphatic spread. In spite of multiple recurrences, patients can remain years without visceral metastasis. There is clearly a biologic reason for this lymphotrophic pattern of growth and dissemination, which we have yet to uncover. In‐transit metastases have widely diverse clinical presentations and can be a stubborn disease to cure. As a result, a host of treatments exist that should be tailored to the individual patient.

Purpose: To provide practice recommendations for the diagnosis and management of hypoparathyroidism in adults. Methods: Key questions pertaining to the diagnosis and management of hypoparathyroidism were addressed following a literature review. We searched PubMed, MEDLINE, EMBASE and Cochrane databases from January 2000 to March 2018 using keywords ‘hypoparathyroidism, diagnosis, treatment, calcium, PTH, calcidiol, calcitriol, hydrochlorothiazide and pregnancy’. Only English language papers involving humans were included. We excluded letters, reviews and editorials. The quality of evidence was evaluated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. These standards of care for hypoparathyroidism have been endorsed by the Canadian Society of Endocrinology and Metabolism. Results: Hypoparathyroidism is a rare disease characterized by hypocalcemia, hyperphosphatemia and a low or inappropriately normal serum parathyroid hormone level (PTH). The majority of cases are post-surgical (75%) with nonsurgical causes accounting for the remaining 25% of cases. A careful review is required to determine the etiology of the hypoparathyroidism in individuals with nonsurgical disease. Hypoparathyroidism is associated with significant morbidity and poor quality of life. Treatment requires close monitoring as well as patient education. Conventional therapy with calcium supplements and active vitamin D analogs is effective in improving serum calcium as well as in controlling the symptoms of hypocalcemia. PTH replacement is of value in lowering the doses of calcium and active vitamin D analogs required and may be of value in lowering long-term complications of hypoparathyroidism. This manuscript addresses acute and chronic management of hypoparathyroidism in adults. Main conclusions: Hypoparathyroidism requires careful evaluation and pharmacologic intervention in order to improve serum calcium and control the symptoms of hypocalcemia. Frequent laboratory monitoring of the biochemical profile and patient education is essential to achieving optimal control of serum calcium.

Given the relationship between explosive-type training and power adaptation, tracking movement velocity has become popular. However, unlike previous variables, tracking velocity necessitates the use of a valid and reliable tool to monitor adaptation over time. Therefore, the primary purpose of this research was to assess the validity and reliability of a commercially-available linear position transducer (LPT). Nine resistance-trained men completed four sessions consisting of a single set of barbell back squat to volitional failure at 75% or 90% one-repetition maximum. Kinetic and kinematic data were captured for each repetition by the LPT and a 3-dimensional motion capture system and bipedal force platforms. In total, 357 instances of data from both systems were analyzed using intraclass correlations (ICC), effect size estimates, and standard error of measurement. Overall, the LPT yielded excellent ICCs (all ≥0.94) and small/trivial differences (d < 0.60). When categorized by median values, ICCs remained high (all ≥0.89) and differences remained small or trivial with the exception of high peak velocities (d = −1.46). Together, these data indicate that the commercially-available LPT is a valid and reliable measure for kinetic and kinematic variables of interest with the exception of high peak velocities.

Abstract The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival [EFS]) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval [CI], 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.

Objective To summarise the available information on physician workforce modelling, to develop a rheumatology workforce prediction risk of bias tool and to apply it to existing studies in rheumatology. Methods A systematic literature review (SLR) was performed in key electronic databases (1946–2017) comprising an update of an SLR in rheumatology and a hierarchical SLR in other medical fields. Data on the type of workforce prediction models and the factors considered in the models were extracted. Key general as well as specific need/demand and supply factors for workforce calculation in rheumatology were identified. The workforce prediction risk of bias tool was developed and applied to existing workforce studies in rheumatology. Results In total, 14 studies in rheumatology and 10 studies in other medical fields were included. Studies used a variety of prediction models based on a heterogeneous set of need/demand and/or supply factors. Only two studies attempted empirical validation of the prediction quality of the model. Based on evidence and consensus, the newly developed risk of bias tool includes 21 factors (general, need/demand and supply). The majority of studies revealed high or moderate risk of bias for most of the factors. Conclusions The existing evidence on workforce prediction in rheumatology is scarce, heterogeneous and at moderate or high risk of bias. The new risk of bias tool should enable future evaluation of workforce prediction studies. This review informs the European League Against Rheumatism points to consider for the conduction of workforce requirement studies in rheumatology.

Objective Current methods used for forecasting workforce requirements in rheumatology are disparate, as are the parameters incorporated into workforce projection studies. The objective of these European League Against Rheumatism (EULAR points to consider (PTC) is to guide future workforce studies in adult rheumatology in order to produce valid and reliable manpower estimates. Methods The EULAR Standardised Operating Procedures were followed. A multidisciplinary task force with experts including patients with rheumatic diseases from 11 EULAR countries and the USA was assembled. A systematic literature review (SLR) was conducted to retrieve workforce models in rheumatology and other medical fields. PTC were based on expert opinion informed by the SLR, followed by group discussions with consensus obtained through informal voting. The level of agreement with the PTC was voted anonymously. Results A total of 10 PTC were formulated. The task force recommends models integrating supply (=workforce available in rheumatology), demand (=health services requested by the population) and need (=health services that are considered appropriate to serve the population). In general, projections of workforce requirements should consider all factors relevant for current and future workload in rheumatology inside and outside of direct patient care. Forecasts of workforce supply should consider demography and attrition of rheumatologists, as well as the effects of new developments in healthcare. Predictions of future need/demand should take demographic, sociocultural and epidemiological development of the population into account. Conclusion These EULAR-endorsed PTC will provide guidance on the methodology and the parameters to be applied in future national and international workforce requirement studies in rheumatology.

Abstract Current standards for husbandry and maintenance of zebrafish and other aquatic species in the laboratory are diverse, and are subject to laboratory performance, engineering, and practice standards (the Guide ), institutional interpretation, national animal welfare laws, and cultural differences. Consequently, it is difficult, and probably not advantageous, to establish a single standard in view of the hardy nature of zebrafish and the diversity of research requirements it is used to address. Based on their natural habitat, zebrafish can thrive in a variety of environmental conditions, which is a specific advantage for working with this laboratory organism. However, it also makes reporting and reproducibility difficult, because variations in the husbandry and environmental conditions, including the environmental conditions before and during experiments, are often underreported in the scientific literature. This lack of consistency presents a potential problem for research reproducibility. To begin addressing this emerging scientific gap, the National Institutes of Health's (NIH) Office of Research Infrastructure Programs (ORIP), Division of Construction and Instruments (DCI), hosted a workshop in late 2017, entitled “Zebrafish and Other Aquatic Models: Reporting of Environmental Husbandry Conditions for Rigorous Experiments and Reproducible Results,” that was attended by ∼60 participants. The objectives of the workshop were to bring together a diverse group of stakeholders—researchers, facility managers, veterinarians, journal editors, commercial vendors, and others to (1) review current husbandry and environmental management practices for the care of zebrafish and other aquatic organisms in the laboratory and to (2) propose a process for the development of a minimal set of environmental parameters that should be reported in publications to ensure rigor and robustness of experiments and reproducible outcomes. The participants also discussed how these recommendations, as an initial step, might be collected, disseminated, implemented, and improved upon after future iteration.

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.

Matrix metalloproteinases (MMPs) are secreted as proenzymes, containing propeptides that interact with the catalytic zinc, thereby controlling MMP activation. The MMP‐9 propeptide is unique in the MMP family because of its post‐translational modification with an N‐linked oligosaccharide. ProMMP‐9 activation by MMP‐3 occurs stepwise by cleavage of the propeptide in an aminoterminal (pro‐AT) and carboxyterminal (pro‐CT) peptide. We chemically synthesized aglycosyl pro‐AT and pro‐CT and purified recombinant glycosylated pro‐ATSf−9. First, we report new cleavage sites in the MMP‐9 propeptide by MMP‐3 and neutrophil elastase. Additionally, we demonstrated with the use of western blot analysis a higher resistance of glycosylated versus aglycosyl pro‐AT against proteolysis by MMP‐3, MMP‐9, meprin α, neutrophil elastase and by protease‐rich synovial fluids from rheumatoid arthritis patients. Moreover, we investigated the effect of glycosylation on proteolytic activation of human proMMP‐9 with the use of zymography and dye‐quenched gelatin cleavage analysis. Compared to recombinant Sf‐9 proMMP‐9 glycoforms, larger oligosaccharides of human neutrophil proMMP‐9 increased resistance against proteolytic activation. Additionally, proMMP‐9 from Congenital Disorder of Glycosylation patients, compared to healthy controls, showed a higher activation rate by MMP‐3. Finally, we demonstrated that glycan‐galectin‐3 interactions reduced proMMP‐9 activation. In conclusion, modification of MMP‐9 propeptide glycosylation is a fine‐tuning mechanism and co‐determines the specific activity of MMP‐9 in physiology and pathology.EnzymesMMP‐9 EC 3.4.24.35, MMP‐3 EC 3.4.24.17, meprin α EC 3.4.24.18, neutrophil elastase EC 3.4.21.37, trypsin EC 3.4.21.4 and PNGase F EC 3.5.1.52.