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In high-temperature superconductivity, the process that leads to the formation of Cooper pairs, the fundamental charge carriers in any superconductor, remains mysterious. We used a femtosecond laser pump pulse to perturb superconducting Bi₂Sr₂CaCu₂08+δ and studied subsequent dynamics using time and angle-resolved photoemission and infrared reflectivity probes. Gap and quasiparticle population dynamics revealed marked dependencies on both excitation density and crystal momentum. Close to the d-wave nodes, the superconducting gap was sensitive to the pump intensity, and Cooper pairs recombined slowly. Far from the nodes, pumping affected the gap only weakly, and recombination processes were faster. These results demonstrate a new window into the dynamical processes that govern quasiparticle recombination and gap formation in cuprates.

Invasive melanoma is the deadliest type of skin cancer, with 101,110 expected cases to be diagnosed in 2021. Recurrent BRAF and NRAS mutations are well documented in melanoma. Biologic implications of gene fusions and the efficacy of therapeutically targeting them remains unknown. Retrospective review of patient samples that underwent next-generation sequencing of the exons of 592 cancer-relevant genes and whole transcriptome sequencing for the detection of gene fusion events and gene expression profiling. Expression of PDL1 and ERK1/2 was assessed by immunohistochemistry (IHC). There were 33 (2.6%) cases with oncogenic fusions (14 novel), involving BRAF, RAF1, PRKCA, TERT, AXL, and FGFR3. MAPK pathway-associated genes were over-expressed in BRAF and RAF1 fusion-positive tumors in absence of other driver alterations. Increased expression in tumors with PRKCA and TERT fusions was concurrent with MAPK pathway alterations. For a subset of samples with available tissue, increased phosphorylation of ERK1/2 was observed in BRAF, RAF1, and PRKCA fusion-positive tumors. Oncogenic gene fusions are associated with transcriptional activation of the MAPK pathway, suggesting they could be therapeutic targets with available inhibitors. Additional analyses to fully characterize the oncogenic effects of these fusions may support biomarker driven clinical trials.

We present the strain and temperature dependence of an anomalous nematic phase in optimally doped BaFe\\(_2\\)(As,P)\\(_2\\). Polarized ultrafast optical measurements reveal broken 4-fold rotational symmetry in a temperature range above \\(T_c\\) in which bulk probes do not detect a phase transition. Using ultrafast microscopy, we find that the magnitude and sign of this nematicity vary on a \\({50{-}100}~\\mu\\)m length scale, and the temperature at which it onsets ranges from 40 K near a domain boundary to 60 K deep within a domain. Scanning Laue microdiffraction maps of local strain at room temperature indicate that the nematic order appears most strongly in regions of weak, isotropic strain. These results indicate that nematic order arises in a genuine phase transition rather than by enhancement of local anisotropy by a strong nematic susceptibility. We interpret our results in the context of a proposed surface nematic phase.

In high-temperature superconductivity, the process that leads to the formation of Cooper pairs, the fundamental charge carriers in any superconductor, remains mysterious. We use a femtosecond laser pump pulse to perturb superconducting Bi2Sr2CaCu2O8+{\\delta}, and study subsequent dynamics using time- and angle-resolved photoemission and infrared reflectivity probes. Gap and quasiparticle population dynamics reveal marked dependencies on both excitation density and crystal momentum. Close to the d-wave nodes, the superconducting gap is sensitive to the pump intensity and Cooper pairs recombine slowly. Far from the nodes pumping affects the gap only weakly and recombination processes are faster. These results demonstrate a new window into the dynamical processes that govern quasiparticle recombination and gap formation in cuprates.

Acute exercise suppresses appetite and alters food‐cue reactivity, but the extent exercise‐induced changes in cerebral blood flow (CBF) influences the blood‐oxygen‐level‐dependent (BOLD) signal during appetite‐related paradigms is not known. This study examined the impact of acute running on visual food‐cue reactivity and explored whether such responses are influenced by CBF variability. In a randomised crossover design, 23 men (mean ± SD: 24 ± 4 years, 22.9 ± 2.1 kg/m2) completed fMRI scans before and after 60 min of running (68% ± 3% peak oxygen uptake) or rest (control). Five‐minute pseudo‐continuous arterial spin labelling fMRI scans were conducted for CBF assessment before and at four consecutive repeat acquisitions after exercise/rest. BOLD‐fMRI was acquired during a food‐cue reactivity task before and 28 min after exercise/rest. Food‐cue reactivity analysis was performed with and without CBF adjustment. Subjective appetite ratings were assessed before, during and after exercise/rest. Exercise CBF was higher in grey matter, the posterior insula and in the region of the amygdala/hippocampus, and lower in the medial orbitofrontal cortex and dorsal striatum than control (main effect trial p ≤ .018). No time‐by‐trial interactions for CBF were identified (p ≥ .087). Exercise induced moderate‐to‐large reductions in subjective appetite ratings (Cohen's d = 0.53–0.84; p ≤ .024) and increased food‐cue reactivity in the paracingulate gyrus, hippocampus, precuneous cortex, frontal pole and posterior cingulate gyrus. Accounting for CBF variability did not markedly alter detection of exercise‐induced BOLD signal changes. Acute running evoked overall changes in CBF that were not time dependent and increased food‐cue reactivity in regions implicated in attention, anticipation of reward, and episodic memory independent of CBF. We investigated the impact of a single running bout on cerebral blood flow (CBF) and food cue reactivity using functional magnetic resonance imaging (fMRI) in healthy men. Running did not alter the time‐course of grey matter or regional CBF up to 30 min after exercise cessation but increased food cue reactivity in brain regions implicated in attention, reward and episodic memory retrieval. Exercise‐related BOLD signal changes were detected in the presence of underlying CBF.

BackgroundLarge-scale improvement programmes are a frequent response to quality and safety problems in health systems globally, but have mixed impact. The extent to which they meet criteria for programme quality, particularly in relation to transparency of reporting and evaluation, is unclear.AimTo identify large-scale improvement programmes focused on intrapartum care implemented in English National Health Service maternity services in the period 2010–2023, and to conduct a structured quality assessment.MethodsWe drew on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidance to inform the design and reporting of our study. We identified relevant programmes using multiple search strategies of grey literature, research databases and other sources. Programmes that met a prespecified definition of improvement programme, that focused on intrapartum care and that had a retrievable evaluation report were subject to structured assessment using selected features of programme quality.ResultsWe identified 1434 records via databases and other sources. 14 major initiatives in English maternity services could not be quality assessed due to lack of a retrievable evaluation report. Quality assessment of the 15 improvement programmes meeting our criteria for assessment found highly variable quality and reporting. Programme specification was variable and mostly low quality. Only eight reported the evidence base for their interventions. Description of implementation support was poor and none reported customisation for challenged services. None reported reduction of inequalities as an explicit goal. Only seven made use of explicit patient and public involvement practices, and only six explicitly used published theories/models/frameworks to guide implementation. Programmes varied in their reporting of the planning, scope and design of evaluation, with weak designs evident.ConclusionsPoor transparency of reporting and weak or absent evaluation undermine large-scale improvement programmes by limiting learning and accountability. This review indicates important targets for improving quality in large-scale programmes.

Generalised myasthenia gravis is a chronic, unpredictable, and debilitating rare disease, often accompanied by high treatment burden and with an unmet need for more efficacious and well tolerated treatments. Zilucoplan is a subcutaneous, self-administered macrocyclic peptide complement C5 inhibitor. We aimed to assess safety, efficacy, and tolerability of zilucoplan in patients with acetylcholine receptor autoantibody (AChR)-positive generalised myasthenia gravis. RAISE was a randomised, double-blind, placebo-controlled, phase 3 trial that was done at 75 sites in Europe, Japan, and North America. We enrolled patients (aged 18–74 years) with AChR-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America disease class II–IV), a myasthenia gravis activities of daily living (MG-ADL) score of least 6, and a quantitative myasthenia gravis score of at least 12. Participants were randomly assigned (1:1) to receive subcutaneous zilucoplan 0·3 mg/kg once daily by self-injection, or matched placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in MG-ADL score in the modified intention-to-treat population (all randomly assigned patients who received at least one dose of study drug and had at least one post-dosing MG-ADL score). Safety was mainly assessed by the incidence of treatment-emergent adverse events (TEAEs) in all patients who had received at least one dose of zilucoplan or placebo. This trial is registered at ClinicalTrials.gov, NCT04115293. An open-label extension study is ongoing (NCT04225871). Between Sept 17, 2019, and Sept 10, 2021, 239 patients were screened for the study, of whom 174 (73%) were eligible. 86 (49%) patients were randomly assigned to zilucoplan 0·3 mg/kg and 88 (51%) were assigned to placebo. Patients assigned to zilucoplan showed a greater reduction in MG-ADL score from baseline to week 12, compared with those assigned to placebo (least squares mean change −4·39 [95% CI –5·28 to –3·50] vs −2·30 [–3·17 to –1·43]; least squares mean difference −2·09 [−3·24 to −0·95]; p=0·0004). TEAEs occurred in 66 (77%) patients in the zilucoplan group and in 62 (70%) patients in the placebo group. The most common TEAE was injection-site bruising (n=14 [16%] in the zilucoplan group and n=8 [9%] in the placebo group). Incidences of serious TEAEs and serious infections were similar in both groups. One patient died in each group; neither death (COVID-19 [zilucoplan] and cerebral haemorrhage [placebo]) was considered related to the study drug. Zilucoplan treatment showed rapid and clinically meaningful improvements in myasthenia gravis-specific efficacy outcomes, had a favourable safety profile, and was well tolerated, with no major safety findings. Zilucoplan is a new potential treatment option for a broad population of patients with AChR-positive generalised myasthenia gravis. The long-term safety and efficacy of zilucoplan is being assessed in an ongoing open-label extension study. UCB Pharma.

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments. Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population. Design: Ongoing, multicenter, phase III open-label extension (OLE) study. Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11–4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline −6.06 [−7.09, −5.03]) and were sustained through to Week 60 (−6.04 [−7.21, −4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (−6.46 [−8.19, −4.72]), and were sustained through to Week 60 (−6.51 [−8.37, −4.65]). Consistent results were observed in other efficacy endpoints. Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses. Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871)

The performance of the atmospheric component of the new Hadley Centre Global Environmental Model (HadGEM1) is assessed in terms of its ability to represent a selection of key aspects of variability in the Tropics and extratropics. These include midlatitude storm tracks and blocking activity, synoptic variability over Europe, and the North Atlantic Oscillation together with tropical convection, the Madden–Julian oscillation, and the Asian summer monsoon. Comparisons with the previous model, the Third Hadley Centre Coupled Ocean–Atmosphere GCM (HadCM3), demonstrate that there has been a considerable increase in the transient eddy kinetic energy (EKE), bringing HadGEM1 into closer agreement with current reanalyses. This increase in EKE results from the increased horizontal resolution and, in combination with the improved physical parameterizations, leads to improvements in the representation of Northern Hemisphere storm tracks and blocking. The simulation of synoptic weather regimes over Europe is also greatly improved compared to HadCM3, again due to both increased resolution and other model developments. The variability of convection in the equatorial region is generally stronger and closer to observations than in HadCM3. There is, however, still limited convective variance coincident with several of the observed equatorial wave modes. Simulation of the Madden–Julian oscillation is improved in HadGEM1: both the activity and interannual variability are increased and the eastward propagation, although slower than observed, is much better simulated. While some aspects of the climatology of the Asian summer monsoon are improved in HadGEM1, the upper-level winds are too weak and the simulation of precipitation deteriorates. The dominant modes of monsoon interannual variability are similar in the two models, although in HadCM3 this is linked to SST forcing, while in HadGEM1 internal variability dominates. Overall, analysis of the phenomena considered here indicates that HadGEM1 performs well and, in many important respects, improves upon HadCM3. Together with the improved representation of the mean climate, this improvement in the simulation of atmospheric variability suggests that HadGEM1 provides a sound basis for future studies of climate and climate change.

We describe the HadGEM2 family of climate configurations of the Met Office Unified Model, MetUM. The concept of a model \"family\" comprises a range of specific model configurations incorporating different levels of complexity but with a common physical framework. The HadGEM2 family of configurations includes atmosphere and ocean components, with and without a vertical extension to include a well-resolved stratosphere, and an Earth-System (ES) component which includes dynamic vegetation, ocean biology and atmospheric chemistry. The HadGEM2 physical model includes improvements designed to address specific systematic errors encountered in the previous climate configuration, HadGEM1, namely Northern Hemisphere continental temperature biases and tropical sea surface temperature biases and poor variability. Targeting these biases was crucial in order that the ES configuration could represent important biogeochemical climate feedbacks. Detailed descriptions and evaluations of particular HadGEM2 family members are included in a number of other publications, and the discussion here is limited to a summary of the overall performance using a set of model metrics which compare the way in which the various configurations simulate present-day climate and its variability.