Challenges and successes in the treatment of hemophilia: the story of a patient with severe hemophilia A and high-titer inhibitors

In the past, patients with severe hemophilia have suffered a substantially reduced quality of life with frequent bleeding episodes, disabling arthropathy, and shorter life expectancy. In addition, methods of treatment and management have been costly and time-consuming, and have placed a considerable burden on patients’ physical and psychological well-being. With the advent of the on-demand therapy and prophylactic treatment paradigm, patients have been able to receive care with less interruption of daily activities. Treatments may be more challenging for hemophiliacs with inhibitors to replacement factor; however, recent advances in the use of bypassing agents and immune tolerance therapy have enabled them to aggressively manage their disease while maintaining their independence. This review focuses on the challenges of treating such a severe hemophiliac through examination of the lifetime experience of a young adult male with a severe form of congenital hemophilia A. At this stage of his life, the patient has minimal disabilities and is inhibitor-free through optimal care and strong family support. His aspiration to pursue a productive life has led him to a career in medicine. After receiving his medical degree, he pursued a specialty in the treatment of hemophilia. By assisting other hemophilia patients, he exemplifies both the rewards of persevering through episodes of bleeding and other complications and the fact that disabilities can be minimized when managed meticulously and in a timely fashion to enable a productive and dignified life

The Anticoagulant Activity of Lysosomal Cationic Proteins from Polymorphonuclear Leukocytes * HUSSAIN I. SABA,t

Summary. A cationic protein fraction from rabbit polymorphonuclear leukocyte lysosomes has been shown to exert a potent anticoagulant effect on human blood in vitro. The anticoagulant activity is detectable in the whole blood clotting time, the recalcification time of platelet-rich plasma, the prothrombin time, the partial thromboplastin time, and the thromboplastin generation test. The lysosomal cationic proteins do not inhibit any of the known specific procoagulants. They appear to inhibit clotting by blocking the formation of intrinsic thromboplastin possibly by interfering with the role of phospholipids in the reaction involving Factors V and X and calcium

Substantial and sustained reduction in under-5 mortality, diarrhea, and pneumonia in Oshikhandass, Pakistan : Evidence from two longitudinal cohort studies 15 years apart

Funding Information: Study 1 was funded through the Applied Diarrheal Disease Research Program at Harvard Institute for International Development with a grant from USAID (Project 936–5952, Cooperative Agreement # DPE-5952-A-00-5073-00), and the Aga Khan Health Service, Northern Areas and Chitral, Pakistan. Study 2 was funded by the Pakistan US S&T Cooperative Agreement between the Pakistan Higher Education Commission (HEC) (No.4–421/PAK-US/HEC/2010/955, grant to the Karakoram International University) and US National Academies of Science (Grant Number PGA-P211012 from NAS to the Fogarty International Center). The funding bodies had no role in the design of the study, data collection, analysis, interpretation, or writing of the manuscript. Publisher Copyright: © 2020 The Author(s).Peer reviewedPublisher PD

Determining neutrino oscillation parameters from atmospheric muon neutrino disappearance with three years of IceCube DeepCore data

We present a measurement of neutrino oscillations via atmospheric muon neutrino disappearance with three years of data of the completed IceCube neutrino detector. DeepCore, a region of denser instrumentation, enables the detection and reconstruction of atmospheric muon neutrinos between 10 GeV and 100 GeV, where a strong disappearance signal is expected. The detector volume surrounding DeepCore is used as a veto region to suppress the atmospheric muon background. Neutrino events are selected where the detected Cherenkov photons of the secondary particles minimally scatter, and the neutrino energy and arrival direction are reconstructed. Both variables are used to obtain the neutrino oscillation parameters from the data, with the best fit given by $\Delta m^2_{32}=2.72^{+0.19}_{-0.20}\times 10^{-3}\,\mathrm{eV}^2$ and $\sin^2\theta_{23} = 0.53^{+0.09}_{-0.12}$ (normal mass hierarchy assumed). The results are compatible and comparable in precision to those of dedicated oscillation experiments.Comment: 10 pages, 7 figure

Zilucoplan in immune-mediated necrotising myopathy: a phase 2, randomised, double-blind, placebo-controlled, multicentre trial

BACKGROUND: Immune-mediated necrotising myopathy is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase concentrations, and autoantibodies recognising 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or the signal recognition particle (SRP). No approved therapies exist for people with immune-mediated necrotising myopathy. Previous studies have suggested that complement activation might be pathogenic in immune-mediated necrotising myopathy; therefore, zilucoplan, a complement C5 (C5) inhibitor, could be a potential therapy. We aimed to evaluate the efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive immune-mediated necrotising myopathy. METHODS: IMNM-01 was a phase 2, multicentre, randomised, double-blind, placebo-controlled study done at 15 hospital sites across the USA, the UK, France, and the Netherlands. Participants aged 18–74 years were eligible for inclusion if they had a clinically confirmed diagnosis of immune-mediated necrotising myopathy, positive serology for anti-HMGCR or anti-SRP autoantibodies, clinical evidence of weakness, serum total creatine kinase concentration of more than 1000 U/L at screening, and no change in glucocorticoids or other immunosuppressive therapies for 30 days before baseline or expected during the first 8 weeks of the study. Participants were randomly assigned (1:1) to receive daily subcutaneous zilucoplan (0·3 mg/kg) or placebo for 8 weeks by use of a computerised randomisation algorithm; with optional enrolment in the study open-label extension. Randomisation was stratified by autoantibody status. Participants and study staff were masked to treatment group assignment. Primary efficacy endpoint (in the intent-to-treat population, defined as all participants who were randomly assigned to a treatment group) was percent change from baseline to week 8 in creatine kinase concentrations. Safety analyses were performed on the safety population (participants who received at least one dose of study drug during the main study, irrespective of whether they continued to the extension period—study participants were analysed on the basis of the treatment received). This study is registered with ClinicalTrials.gov, NCT04025632. FINDINGS: Between Nov 7, 2019, and Jan 7, 2021, we randomly assigned 27 participants (13 female and 14 male) to receive zilucoplan (n=12) or placebo (n=15). All 27 participants completed the 8-week main study. At week 8 there were no significant differences between treatment groups in median percent change of creatine kinase concentrations versus baseline (–15·1% [IQR –31·1 to 3·2] in the zilucoplan group vs –16·3% [–43·8 to 5·9] in the placebo group; p=0·46) and no clinically relevant improvement over time within the treatment group despite target engagement based on mode of action. There were no unexpected adverse safety or tolerability findings. Treatment-emergent adverse events were reported in nine (75%) of 12 participants in the zilucoplan group, and in 13 (87%) of 15 participants in the placebo group, and serious treatment-emergent adverse events were reported in zero participants in the zilucoplan group and three (20%) participants in the placebo group. The most frequent treatment-emergent adverse events were headache (four [33%] participants in the zilucoplan group and four [27%] participants in the placebo group) and nausea (three [25%] participants in the zilucoplan group and three [20%] participants in the placebo group). INTERPRETATION: C5 inhibition does not appear to be an efficacious treatment modality for people with immune-mediated necrotising myopathy. Rather than being the primary driver for disease activity, complement activation might be secondary to muscle injury. FUNDING: Ra Pharmaceuticals (now part of UCB Pharma)

An improved method for measuring muon energy using the truncated mean of dE/dx

The measurement of muon energy is critical for many analyses in large Cherenkov detectors, particularly those that involve separating extraterrestrial neutrinos from the atmospheric neutrino background. Muon energy has traditionally been determined by measuring the specific energy loss (dE/dx) along the muon's path and relating the dE/dx to the muon energy. Because high-energy muons (E_mu > 1 TeV) lose energy randomly, the spread in dE/dx values is quite large, leading to a typical energy resolution of 0.29 in log10(E_mu) for a muon observed over a 1 km path length in the IceCube detector. In this paper, we present an improved method that uses a truncated mean and other techniques to determine the muon energy. The muon track is divided into separate segments with individual dE/dx values. The elimination of segments with the highest dE/dx results in an overall dE/dx that is more closely correlated to the muon energy. This method results in an energy resolution of 0.22 in log10(E_mu), which gives a 26% improvement. This technique is applicable to any large water or ice detector and potentially to large scintillator or liquid argon detectors.Comment: 12 pages, 16 figure

Determining neutrino oscillation parameters from atmospheric muon neutrino disappearance with three years of IceCube DeepCore data

We present a measurement of neutrino oscillations via atmospheric muon neutrino disappearance with three years of data of the completed IceCube neutrino detector. DeepCore, a region of denser instrumentation, enables the detection and reconstruction of atmospheric muon neutrinos between 10 GeV and 100 GeV, where a strong disappearance signal is expected. The detector volume surrounding DeepCore is used as a veto region to suppress the atmospheric muon background. Neutrino events are selected where the detected Cherenkov photons of the secondary particles minimally scatter, and the neutrino energy and arrival direction are reconstructed. Both variables are used to obtain the neutrino oscillation parameters from the data, with the best fit given by $\Delta m^2_{32}=2.72^{+0.19}_{-0.20}\times 10^{-3}\,\mathrm{eV}^2$ and $\sin^2\theta_{23} = 0.53^{+0.09}_{-0.12}$ (normal mass hierarchy assumed). The results are compatible and comparable in precision to those of dedicated oscillation experiments.Comment: 10 pages, 7 figure

Searches for Extended and Point-like Neutrino Sources with Four Years of IceCube Data

We present results on searches for point-like sources of neutrinos using four years of IceCube data, including the first year of data from the completed 86-string detector. The total livetime of the combined dataset is 1,373 days. For an E$^{-2}$ spectrum the median sensitivity at 90\% C.L. is $\sim 10^{-12}$ TeV$^{-1}$cm$^{-2}$s$^{-1}$ for energies between 1 TeV$-$1 PeV in the northern sky and $\sim 10^{-11}$ TeV$^{-1}$cm$^{-2}$s$^{-1}$ for energies between 100 TeV $-$ 100 PeV in the southern sky. The sensitivity has improved from both the additional year of data and the introduction of improved reconstructions compared to previous publications. In addition, we present the first results from an all-sky search for extended sources of neutrinos. We update results of searches for neutrino emission from stacked catalogs of sources, and test five new catalogs; two of Galactic supernova remnants and three of active galactic nuclei. In all cases, the data are compatible with the background-only hypothesis, and upper limits on the flux of muon neutrinos are reported for the sources considered.Comment: 36 pages, 15 figures. Submitted to the Astrophysical Journa