Development of inhibitory antibodies to infused factor VIII (FVIII) concentrates continues to be the most serious complication of haemophilia A management. Induction of immune tolerance by ...administering high doses of FVIII concentrate (antigen) and prothrombin complex concentrates to control bleeding was originated in the 1970s in Bonn, Germany, by Dr Hans‐Hermann Brackmann, and became known as the Bonn protocol. ITI transformed the life of the index patient, who was 19 years of age when he began treatment, and dramatically improved the medical landscape for all patients with haemophilia and inhibitors. Over the past 40 years, variations to the Bonn protocol have been proposed. All protocols are effective although some are better suited than others for use in certain situations. The specific molecular defect in FVIII and the human leucocyte antigen (HLA) type of an individual with haemophilia are major codependent determinants to inhibitor development. Given the range of potential molecular defects and the staggering number of potential HLA types, it is likely that treatment arms of randomized studies in haemophilia represent highly diverse populations, which reduces the power of a study to demonstrate differences between treatments. Although available clinical guidelines and consensus recommendations for ITI therapy are not always in complete agreement, collectively the guidelines provide a reasonable level of guidance for administering ITI therapy under different clinical scenarios. Several studies of ITI therapy are ongoing with the aim of clarifying unresolved issues in haemophilia management including the role of von Willebrand factor in inhibitor eradication.
The use of accelerated beams of electrons, protons or ions has furthered the development of nearly every scientific discipline. However, high-energy muon beams of equivalent quality have not yet been ...delivered. Muon beams can be created through the decay of pions produced by the interaction of a proton beam with a target. Such 'tertiary' beams have much lower brightness than those created by accelerating electrons, protons or ions. High-brightness muon beams comparable to those produced by state-of-the-art electron, proton and ion accelerators could facilitate the study of lepton-antilepton collisions at extremely high energies and provide well characterized neutrino beams
. Such muon beams could be realized using ionization cooling, which has been proposed to increase muon-beam brightness
. Here we report the realization of ionization cooling, which was confirmed by the observation of an increased number of low-amplitude muons after passage of the muon beam through an absorber, as well as an increase in the corresponding phase-space density. The simulated performance of the ionization cooling system is consistent with the measured data, validating designs of the ionization cooling channel in which the cooling process is repeated to produce a substantial cooling effect
. The results presented here are an important step towards achieving the muon-beam quality required to search for phenomena at energy scales beyond the reach of the Large Hadron Collider at a facility of equivalent or reduced footprint
.
The classification of neuronal subpopulations has significantly advanced, yet its relevance for behavior remains unclear. The highly organized flocculus of the cerebellum, known to fine-tune ...multi-axial eye movements, is an ideal substrate for the study of potential functions of neuronal subpopulations. Here, we demonstrate that its recently identified subpopulations of 9+ and 9- Purkinje cells exhibit an intermediate Aldolase C expression and electrophysiological profile, providing evidence for a graded continuum of intrinsic properties among PC subpopulations. By identifying and utilizing two Cre-lines that genetically target these floccular domains, we show with high spatial specificity that these subpopulations of Purkinje cells participate in separate micromodules with topographically organized connections. Finally, optogenetic excitation of the respective subpopulations results in movements around the same axis in space, yet with distinct kinematic profiles. These results indicate that Purkinje cell subpopulations integrate in discrete circuits and mediate particular parameters of single movements.
We present a comprehensive analysis of electronic recoil vs nuclear recoil discrimination in liquid/gas xenon time projection chambers, using calibration data from the 2013 and 2014–2016 runs of the ...Large Underground Xenon experiment. We observe strong charge-to-light discrimination enhancement with increased event energy. For events with S1 = 120 detected photons, i.e., equivalent to a nuclear recoil energy of ∼100 keV, we observe an electronic recoil background acceptance of < 10−5 at a nuclear recoil signal acceptance of 50%. We also observe modest electric field dependence of the discrimination power, which peaks at a field of around 300 V/cm over the range of fields explored in this study (50 – 500 V/cm). In the weakly interacting massive particle search region of S1 = 1−80 phd , the minimum electronic recoil leakage we observe is (7.3 ± 0.6) × 10−4, which is obtained for a drift field of 240 – 290V/cm. Pulse shape discrimination is utilized to improve our results, and we find that, at low energies and low fields, there is an additional reduction in background leakage by a factor of up to 3. We develop an empirical model for recombination fluctuations which, when used alongside the Noble Element Scintillation Technique simulation package, correctly reproduces the skewness of the electronic recoil data. We use this updated simulation to study the width of the electronic recoil band, finding that its dominant contribution comes from electron-ion recombination fluctuations, followed in magnitude of contribution by fluctuations in the S1 signal, fluctuations in the S2 signal, and fluctuations in the total number of quanta produced for a given energy deposition.
1. Elevational gradients create environmental variation that is hypothesized to promote variation in life-history strategies. We tested whether differences in life-history strategies were associated ...with elevation in a songbird, the dark-eyed junco (Junco hyemalis; Aves; A.O.U. 1998 ). 2. We monitored birds in four replicated sites per elevation, at 2000 m a.s.l. (high elevation) and 1000 m a.s.l. (low elevation), in the Rocky Mountains of Canada. 3. Over 5 years, we measured the following traits and vital rates: egg-laying schedules, morphological indicators of reproductive stage, seasonal reproductive success, indicators of competitive class (age, size, arrival time), and survival rates. 4. We found two main patterns: with an increase in breeding elevation, dark-eyed juncos delayed the development of structures necessary for reproduction (e.g. cloacal protuberance in males) and reduced the duration of their reproductive period to less than half of the time used by low-elevation birds; and 5. Juncos at high-elevation sites had 55-61% lower annual reproductive success and 15 to 20% higher survival rates. While adult juncos at high elevations produced fewer offspring, those offspring were in better condition. Proportions of age and size classes in high- compared to low-elevation populations were similar, suggesting that a life-history trade-off is present, rather than competition forcing inferior competitors to breed in a peripheral habitat. The apparent trade-off between reproduction and survival corresponded to a shorter period of favourable weather and available food in high- compared to low-elevation habitats. 6. Thus, elevation had a strong influence on life-history characteristics of a single species over a short spatial distance, suggesting a shift in life history from a high reproductive strategy at lower elevations to a high survivor strategy at high elevations. 7. This is the first paper to show a shift in avian life-history strategies along an elevational gradient (in both genders, of multiple age classes) when region (latitude) and phylogenetic histories are controlled for.
Hydrothermal duodenal mucosal resurfacing (DMR) is a safe, outpatient endoscopic procedure. REVITA-2, a double-blind, superiority randomised controlled trial, investigates safety and efficacy of DMR ...using the single catheter Revita system (Revita DMR (catheter and system)), on glycaemic control and liver fat content in type 2 diabetes (T2D).
Eligible patients (haemoglobin A1c (HbA1c) 59-86 mmol/mol, body mass index≥24 and ≤40 kg/m
, fasting insulin >48.6 pmol/L, ≥1 oral antidiabetic medication) enrolled in Europe and Brazil. Primary endpoints were safety, change from baseline in HbA1c at 24 weeks, and liver MRI proton-density fat fraction (MRI-PDFF) at 12 weeks.
Overall mITT (DMR n=56; sham n=52), 24 weeks post DMR, median (IQR) HbA1c change was -10.4 (18.6) mmol/mol in DMR group versus -7.1 (16.4) mmol/mol in sham group (p=0.147). In patients with baseline liver MRI-PDFF >5% (DMR n=48; sham n=43), 12-week post-DMR liver-fat change was -5.4 (5.6)% in DMR group versus -2.9 (6.2)% in sham group (p=0.096). Results from prespecified interaction testing and clinical parameter assessment showed heterogeneity between European (DMR n=39; sham n=37) and Brazilian (DMR n=17; sham n=16) populations (p=0.063); therefore, results were stratified by region. In European mITT, 24 weeks post DMR, median (IQR) HbA1c change was -6.6 mmol/mol (17.5 mmol/mol) versus -3.3 mmol/mol (10.9 mmol/mol) post-sham (p=0.033); 12-week post-DMR liver-fat change was -5.4% (6.1%) versus -2.2% (4.3%) post-sham (p=0.035). Brazilian mITT results trended towards DMR benefit in HbA1c, but not liver fat, in context of a large sham effect. In overall PP, patients with high baseline fasting plasma glucose ((FPG)≥10 mmol/L) had significantly greater reductions in HbA1c post-DMR versus sham (p=0.002). Most adverse events were mild and transient.
DMR is safe and exerts beneficial disease-modifying metabolic effects in T2D with or without non-alcoholic liver disease, particularly in patients with high FPG.
NCT02879383.
A measurement of the energy dependence of antineutrino disappearance at the Daya Bay reactor neutrino experiment is reported. Electron antineutrinos (ν¯(e)) from six 2.9 GW(th) reactors were ...detected with six detectors deployed in two near (effective baselines 512 and 561 m) and one far (1579 m) underground experimental halls. Using 217 days of data, 41 589 (203 809 and 92 912) antineutrino candidates were detected in the far hall (near halls). An improved measurement of the oscillation amplitude sin(2)2θ(13)=0.090(-0.009)(+0.008) and the first direct measurement of the ν¯(e) mass-squared difference |Δm(ee)2|=(2.59(-0.20)(+0.19))×10(-3) eV2 is obtained using the observed ν¯(e) rates and energy spectra in a three-neutrino framework. This value of |Δm(ee)2| is consistent with |Δm(μμ)2| measured by muon neutrino disappearance, supporting the three-flavor oscillation model.
PDF
