Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension

Objectives To report the impact of burosumab on patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia (XLH) through 96 weeks. Methods Adults diagnosed with XLH were randomised 1:1 in a double-blinded trial to receive subcutaneous burosumab 1 mg/kg or placebo every 4 weeks for 24 weeks (NCT02526160). Thereafter, all subjects received burosumab every 4 weeks until week 96. PROs were measured using the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC), Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory (BFI), and ambulatory function was measured with the 6 min walk test (6MWT). Results Subjects (N=134) were randomised to burosumab (n=68) or placebo (n=66) for 24 weeks. At baseline, subjects experienced pain, stiffness, and impaired physical and ambulatory function. At week 24, subjects receiving burosumab achieved statistically significant improvement in some BPI-SF scores, BFI worst fatigue (average and greatest) and WOMAC stiffness. At week 48, all WOMAC and BPI-SF scores achieved statistically significant improvement, with some WOMAC and BFI scores achieving meaningful and significant change from baseline. At week 96, all WOMAC, BPI-SF and BFI achieved statistically significant improvement, with selected scores in all measures also achieving meaningful change. Improvement in 6MWT distance and percent predicted were statistically significant at all time points from 24 weeks. Conclusions Adults with XLH have substantial burden of disease as assessed by PROs and 6MWT. Burosumab treatment improved phosphate homoeostasis and was associated with a steady and consistent improvement in PROs and ambulatory function. Trial registration number NCT02526160

True substrates: The exceptional resolution and unexceptional preservation of deep time snapshots on bedding surfaces

Abstract: Rock outcrops of the sedimentary–stratigraphic record often reveal bedding planes that can be considered to be true substrates: preserved surfaces that demonstrably existed at the sediment–water or sediment–air interface at the time of deposition. These surfaces have high value as repositories of palaeoenvironmental information, revealing fossilized snapshots of microscale topography from deep time. Some true substrates are notable for their sedimentary, palaeontological and ichnological signatures that provide windows into key intervals of Earth history, but countless others occur routinely throughout the sedimentary–stratigraphic record. They frequently reveal patterns that are strikingly familiar from modern sedimentary environments, such as ripple marks, animal trackways, raindrop impressions or mudcracks: all phenomena that are apparently ephemeral in modern settings, and which form on recognizably human timescales. This paper sets out to explain why these short‐term, transient, small‐scale features are counter‐intuitively abundant within a 3.8 billion year‐long sedimentary–stratigraphic record that is known to be inherently time‐incomplete. True substrates are fundamentally related to a state of stasis in ancient sedimentation systems, and distinguishable from other types of bedding surfaces that formed from a dominance of states of deposition or erosion. Stasis is shown to play a key role in both their formation and preservation, rendering them faithful and valuable archives of palaeoenvironmental and temporal information. Further, the intersection between the time–length scale of their formative processes and outcrop expressions can be used to explain why they are so frequently encountered in outcrop investigations. Explaining true substrates as inevitable and unexceptional by‐products of the accrual of the sedimentary–stratigraphic record should shift perspectives on what can be understood about Earth history from field studies of the sedimentary–stratigraphic record. They should be recognized as providing high‐definition information about the mundane day to day operation of ancient environments, and critically assuage the argument that the incomplete sedimentary–stratigraphic record is unrepresentative of the geological past

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Effect of bundle size on cladding deformation in LOCA simulation tests. [PWR; BWR]

Two LOCA simulation tests were conducted to investigate the effects of temperature uniformity and radial restraint boundary conditions on Zircaloy cladding deformation. In one of the tests (B-5), boundary conditions typical of a large array were imposed on an inner 4 x 4 square array by two concentric rings of interacting guard fuel pin simulators. In the other test (B-3), the boundary conditions were imposed on a 4 x 4 square array by a non-interacting heated shroud. Test parameters conducive to large deformation were selected in order to favor rod-to-rod interactions. The tests showed that rod-to-rod interactions play an important role in the deformation process

Boundary effects on Zircaloy-4 cladding deformation in LOCA simulation tests. [PWR; BWR]

Deformation behavior of Zircaloy-4 cladding under simulated loss-of-coolant accident (LOCA) conditions is being investigated in the Multirod Burst Test (MRBT) program in single rod and multirod tests. In these tests, internally-pressurized unirradiated Zircaloy-4 tubes containing internal electrical heaters are heated to failure in a low-pressure, superheated-steam environment (200 < Re < 800). The results provide a data base for evaluating deformation and blockage models employed with design-basis accident sequences to assess LWR core coolability for licensing purposes. Results of a recent 8 X 8 test indicate that models derived from smaller test arrays may not be representative of the behavior in large arrays, particularly for those temperature ranges in which large deformation can be expected. Two MRBT LOCA simulation tests conducted under the same nominal conditions (approx. 10 K/s heating rate from approx. 340/sup 0/C to failure at approx. 770/sup 0/C) were examined to determine the effects of array size and boundary conditions on deformation

Zircaloy cladding deformation in a steam environment with transient heating

The results of zircaloy cladding deformation tests in which the test parameters simulated LWR fuel rods and LOCA conditions are presented