Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies

Hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder of ectopic calcification due to deficiency of or resistance to intact fibroblast growth factor 23 (iFGF23). Inactivating mutations in FGF23, N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO (KL) have been reported as causing HFTC/HHS. We present what we believe is the first identified case of autoimmune hyperphosphatemic tumoral calcinosis in an 8-year-old boy. In addition to the classical clinical and biochemical features of hyperphosphatemic tumoral calcinosis, the patient exhibited markedly elevated intact and C-terminal FGF23 levels, suggestive of FGF23 resistance. However, no mutations in FGF23, KL, or FGF receptor 1 (FGFR1) were identified. He subsequently developed type 1 diabetes mellitus, which raised the possibility of an autoimmune cause for hyperphosphatemic tumoral calcinosis. Luciferase immunoprecipitation systems revealed markedly elevated FGF23 autoantibodies without detectable FGFR1 or Klotho autoantibodies. Using an in vitro FGF23 functional assay, we found that the FGF23 autoantibodies in the patient's plasma blocked downstream signaling via the MAPK/ERK signaling pathway in a dose-dependent manner. Thus, this report describes the first case, to our knowledge, of autoimmune hyperphosphatemic tumoral calcinosis with pathogenic autoantibodies targeting FGF23. Identification of this pathophysiology extends the etiologic spectrum of hyperphosphatemic tumoral calcinosis and suggests that immunomodulatory therapy may be an effective treatment

Impact of an addiction medicine consult service on patients admitted to the hospital with injection drug use-associated infective endocarditis

Background: The addition of an addiction medicine consult service has been shown to improve mortality and decrease hospital costs but its impact on the proportion of patients discharged against medical advice (DAMA) and in-hospital initiation of medication for opioid use disorder (MOUD) has not been examined. Methods: A retrospective before-after cohort study was performed at an urban, academic medical center between January 1, 2015 and November 1, 2019. We included adult patients with infective endocarditis and injection drug use determined by admitting diagnosis ICD-9 or ICD-10 codes or documentation within the history section of electronic health recordEHR. Our institution implemented a formal addiction medicine consult service on July 1, 2018. We determined the proportion of patients DAMA and the proportion of patients started on MOUD among patients in the pre-intervention (i.e. hospitalized before July 1, 2018) and intervention (i.e. hospitalized July 1, 2018 or after) groups. Results: A total of 171 patients among hospitalized patients with injection drug use-associated infective endocarditis were included with 119 patients in the pre-intervention group and 52 patients in the intervention group. There was no statistically significant difference in patients DAMA [19% vs 15%, absolute risk difference 4.6% (95% confidence interval -8.6% to 17.7%)] between the intervention and pre-intervention groups. However, there was an increase in the proportion of inpatient MOUD initiation in the intervention group compared to the pre-intervention group [56% vs 21%, absolute risk difference 35% (95% confidence interval 19% to 50%)]. Conclusions: The initiation of an addiction medicine consult service was associated with a higher proportion of MOUD initiation but there was no statistically significant association with the proportion of patients DAMA

Multi-isotope reconstruction of Late Pleistocene large-herbivore biogeography and mobility patterns in Central Europe

We thank H. Dietl, K. G\u00E4rtner, S. Kimmig-V\u00F6lkner, R. Mischker and E. Pawlak, State Museum of Prehistory, Halle, for providing access to the material. We thank C. Pasda, Friedrich Schiller University, Jena, for providing research support.Peer reviewe

Transatlantic collection of health informatics competencies

The electronic collection, processing and management of information is becoming increasingly important in healthcare. Because of the nature of the healthcare provision and delivery process, where the health, safety and quality of human lives are impacted on a daily basis, it is critical that those who work in the field are competent and able to perform all clinical, administrative, research and technology-impacted facets of their roles.The United States and the European Union have been working to encourage broader and more effective use of Information and Communications Technology (ICT) within healthcare. The development, use and governance of ICT within healthcare, often called health informatics, requires a number of competences which need to be identified and integrated into relevant skills assessment, education and training. Ultimately, this will help produce a more proficient and a more confident mobile health informatics-empowered workforce.A structured set of health information technology and eHealth implementation competences was collected in a co-operation project by voluntary experts in USA and European Union. The project took a deliberately broad starting point, seeking and reviewing an extensive range of related competencies. The skills cover the following domains of professions working with health information technology: direct patient care; administrative; engineering/information, communication, and technology (ICT); informatics; and research and biomedicine. The aggregation of over one thousand competencies was classified to a baseline set of skills and four levels of expertise in 33 focus areas according to Bloom’s taxonomy. The data set also contains definitions of 268 ‘typical’ professional roles. The use of the collection of competencies is supported by an open access web tool through which all the competencies can be searched through a query mechanism.The limitation of this work is that only the Acute Care segment of roles and competencies impacted by ICT was evaluated within the scope of this project, however, this subset of other care settings such as ambulatory, rehabilitative care, surgery, and others serves as a representative set of roles and competencies within the health care field as well as a being an important proof of concept for future usefulness of the work if extended beyond its current span. This project has made a contribution to the potential improvement of workforce mobility internationally

Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia

PURPOSE: In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH. METHODS: After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and week 16. From week 66 to week 160, all patients received Q2W burosumab. RESULTS: Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9 ± 0.1 (least squares mean ± SE; P < 0.0001) from baseline to week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2-6.1 mg/dL) at week 160 (mean change from baseline P < 0.0001). Most adverse events were mild to moderate in severity. MAIN CONCLUSIONS: In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was well-tolerated. Long-term safety was consistent with the reported safety profile of burosumab. CLINICALTRIALS.GOV: NCT0216357

Best Practices for Cataloging DVD-Video and Blu-ray Discs Using RDA and MARC21

Best Practices for Cataloging DVD-video and Blu-ray Discs Using RDA and MARC21 builds upon the work of the 2008 Guide to Cataloging DVD and Blu-ray Discs Using AACR2r and MARC21, which in turn updated the 2002 Guide to Cataloging DVDs Using AACR2r Chapters 7 and 9 created by the DVD Cataloging Task Force of OLAC. The focus of this new document is to provide a set of “best practice” recommendations rather than a step-by-step instruction manual for cataloging DVD-video and Blu-ray Discs. One reason for this shift is that RDA cataloging practice is far from settled, particularly in regard to special format materials. Best practice recommendations will likely be easier to manage as RDA instructions evolve. This document is intended for use with Resource Description and Access (RDA) and the MARC21 Format for Bibliographic Data. It should not be considered a substitute for the RDA Toolkit. The best practice recommendations and cataloging examples presented in the document are intended only to clarify RDA principles and instructions used in cataloging DVD-video and Blu- ray Disc formats

Treatment of autosomal dominant hypocalcemia Type 1 with the calcilytic NPSP795 (SHP635)

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by heterozygous, gain‐of‐function mutations of the calcium‐sensing receptor gene (CAR). Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria. Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to 4 distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635) on 3 consecutive days. Pharmacokinetics, pharmacodynamics, efficacy, and safety were assessed. Parallel in vitro testing with subject CaR mutations assessed the effects of NPSP795 on cytoplasmic calcium concentrations (Ca2+i), and ERK and p38MAPK phosphorylation. These effects were correlated with clinical responses to administration of NPSP795. NPSP795 increased plasma PTH levels in a concentration‐dependent manner up to 129% above baseline (p=0.013) at the highest exposure levels. Fractional excretion of calcium (FECa) trended down but not significantly so. Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol and little calcium supplementation. NPSP795 was generally safe and well‐tolerated. There was significant variability in response clinically across genotypes. In vitro, all mutant CaRs were half‐maximally activated (EC50) at lower concentrations of extracellular calcium (Ca2+o) compared to wild type (WT) CaR; NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any clinical parameters. NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose‐dependent manner, and thus, serves as proof‐of‐concept that calcilytics could be an effective treatment for ADH1. Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype, or the response to calcilytics, suggesting that other parameters impact the response to the drug

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON) : a randomised controlled phase III trial

Acknowledgments This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant 12/206/52). Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care. We thank our Collaborative Group (listed in the Supplementary Material) for their contribution to recruitment, randomisation and collection of data, and to our Trial Steering and Data Monitoring Committees (members listed in Supplementary Material).Peer reviewedPublisher PD

Fish Farms at Sea: The Ground Truth from Google Earth

In the face of global overfishing of wild-caught seafood, ocean fish farming has augmented the supply of fresh fish to western markets and become one of the fastest growing global industries. Accurate reporting of quantities of wild-caught fish has been problematic and we questioned whether similar discrepancies in data exist in statistics for farmed fish production. In the Mediterranean Sea, ocean fish farming is prevalent and stationary cages can be seen off the coasts of 16 countries using satellite imagery available through Google Earth. Using this tool, we demonstrate here that a few trained scientists now have the capacity to ground truth farmed fish production data reported by the Mediterranean countries. With Google Earth, we could examine 91% of the Mediterranean coast and count 248 tuna cages (circular cages >40 m diameter) and 20,976 other fish cages within 10 km offshore, the majority of which were off Greece (49%) and Turkey (31%). Combining satellite imagery with assumptions about cage volume, fish density, harvest rates, and seasonal capacity, we make a conservative approximation of ocean-farmed finfish production for 16 Mediterranean countries. Our overall estimate of 225,736 t of farmed finfish (not including tuna) in the Mediterranean Sea in 2006 is only slightly more than the United Nations Food and Agriculture Organization reports. The results demonstrate the reliability of recent FAO farmed fish production statistics for the Mediterranean as well as the promise of Google Earth to collect and ground truth data