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We consider measurements of exclusive rare semi-tauonic b -hadron decays, mediated by the b → s τ + τ - transition, at a future high-energy circular electron–positron collider (FCC- ee ). We argue that the high boosts of b -hadrons originating from on-shell Z boson decays allow for a full reconstruction of the decay kinematics in hadronic τ decay modes (up to discrete ambiguities). This, together with the potentially large statistics of Z → b b ¯ , opens the door for the experimental determination of τ polarizations in these rare b -hadron decays. In the light of the current experimental situation on lepton flavor universality in rare semileptonic B decays, we discuss the complementary short-distance physics information carried by the τ polarizations and suggest suitable theoretically clean observables in the form of single- and double- τ polarization asymmetries.

Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.

Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis. For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel). We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68–0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5–14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58–0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12–19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69–1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61–0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5–10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79–0·98]; p=0·025), which translates to 5% (1–8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83–1·07]; p=0·323), which translates to an absolute improvement in survival of 2% (−3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 [66%] of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 [0·89–1·18]; p=0·724) or zoledronic acid (0·98 [0·82–1·16]; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials. The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small. Medical Research Council UK.

Background Most evidence about what works in transitional care comes from small studies in single clinical specialties. We tested the hypothesis that exposures to nine recommended features of transitional healthcare were associated with better outcomes for young people with long-term conditions during transition from child-centred to adult-oriented health services. Methods This is a longitudinal, observational cohort study in UK secondary care including 374 young people, aged 14–18.9 years at recruitment, with type 1 diabetes ( n = 150), cerebral palsy ( n = 106) or autism spectrum disorder with an associated mental health problem ( n = 118). All were pre-transfer and without significant learning disability. We approached all young people attending five paediatric diabetes centres, all young people with autism spectrum disorder attending four mental health centres, and randomly selected young people from two population-based cerebral palsy registers. Participants received four home research visits, 1 year apart and 274 participants (73%) completed follow-up. Outcome measures were Warwick Edinburgh Mental Wellbeing Scale, Mind the Gap Scale (satisfaction with services), Rotterdam Transition Profile (Participation) and Autonomy in Appointments. Results Exposure to recommended features was 61% for ‘coordinated team’, 53% for ‘age-banded clinic’, 48% for ‘holistic life-skills training’, 42% for ‘promotion of health self-efficacy’, 40% for ‘meeting the adult team before transfer’, 34% for ‘appropriate parent involvement’ and less than 30% for ‘written transition plan’, ‘key worker’ and ‘transition manager for clinical team’. Three features were strongly associated with improved outcomes. (1) ‘Appropriate parent involvement’, example association with Wellbeing (b = 4.5, 95% CI 2.0–7.0, p  = 0.001); (2) ‘Promotion of health self-efficacy’, example association with Satisfaction with Services (b = − 0.5, 95% CI – 0.9 to – 0.2, p  = 0.006); (3) ‘Meeting the adult team before transfer’, example associations with Participation (arranging services and aids) (odds ratio 5.2, 95% CI 2.1–12.8, p  < 0.001) and with Autonomy in Appointments (average 1.7 points higher, 95% CI 0.8–2.6, p  < 0.001). There was slightly less recruitment of participants from areas with greater socioeconomic deprivation, though not with respect to family composition. Conclusions Three features of transitional care were associated with improved outcomes. Results are likely to be generalisable because participants had three very different conditions, attending services at many UK sites. Results are relevant for clinicians as well as for commissioners and managers of health services. The challenge of introducing these three features across child and adult healthcare services, and the effects of doing so, should be assessed.

The sensitivity of microwave kinetic inductance detectors (MKIDs) using dissipation readout is limited by the noise temperature of the cryogenic amplifier, usually a HEMT with T n ∼ 5 K. A lower noise amplifier is required to improve NEP and reach the photon noise limit at millimeter wavelengths. Eom et al. have proposed a kinetic inductance traveling wave (KIT) parametric amplifier (also called the dispersion-engineered travelling wave kinetic inductance parametric amplifier) that utilizes the nonlinearity with very low dissipation of NbTiN. This amplifier has the promise to achieve quantum limited noise, broad bandwidth, and high dynamic range, all of which are required for ideal MKID dissipation readout. We have designed a KIT amplifier which consists of a 2.2 m long coplanar waveguide transmission line fabricated in a double spiral format, with periodic loadings and impedance transformers at the input/output ports on a 2 by 2 cm Si chip. The design was fabricated with 20 nm NbTiN films. The device has shown over 10 dB of gain from 4 to 11 GHz. We have found the maximum gain is limited by abrupt breakdown at defects in the transmission line in the devices. By cascading two devices, more than 20 dB of gain was achieved from 4.5 to 12.5 GHz, with a peak of ∼ 27 dB.

The vast majority of systematic reviews are planned retrospectively, once most eligible trials have completed and reported, and are based on aggregate data that can be extracted from publications. Prior knowledge of trial results can introduce bias into both review and meta-analysis methods, and the omission of unpublished data can lead to reporting biases. We present a collaborative framework for prospective, adaptive meta-analysis (FAME) of aggregate data to provide results that are less prone to bias. Also, with FAME, we monitor how evidence from trials is accumulating, to anticipate the earliest opportunity for a potentially definitive meta-analysis. We developed and piloted FAME alongside 4 systematic reviews in prostate cancer, which allowed us to refine the key principles. These are to: (1) start the systematic review process early, while trials are ongoing or yet to report; (2) liaise with trial investigators to develop a detailed picture of all eligible trials; (3) prospectively assess the earliest possible timing for reliable meta-analysis based on the accumulating aggregate data; (4) develop and register (or publish) the systematic review protocol before trials produce results and seek appropriate aggregate data; (5) interpret meta-analysis results taking account of both available and unavailable data; and (6) assess the value of updating the systematic review and meta-analysis. These principles are illustrated via a hypothetical review and their application to 3 published systematic reviews. FAME can reduce the potential for bias, and produce more timely, thorough and reliable systematic reviews of aggregate data.

An array of 488 Josephson junctions that amplifies and squeezes noise beyond conventional quantum limits should prove useful in the study and development of superconducting qubits and other quantum devices. It has recently become possible to encode the quantum state of superconducting qubits and the position of nanomechanical oscillators into the states of microwave fields 1 , 2 . However, to make an ideal measurement of the state of a qubit, or to detect the position of a mechanical oscillator with quantum-limited sensitivity, requires an amplifier that adds no noise. If an amplifier adds less than half a quantum of noise, it can also squeeze the quantum noise of the electromagnetic vacuum. Highly squeezed states of the vacuum can be used to generate entanglement or to realize back-action-evading measurements of position 3 , 4 . Here we introduce a general-purpose parametric device, which operates in a frequency band between 4 and 8 GHz. It adds less than half a noise quantum, it amplifies quantum noise above the added noise of commercial amplifiers and it squeezes quantum fluctuations by 10 dB.

A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence. Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomisation were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence. One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0·82 [0·71-0·95, p = 0·008]] and sarilumab [0·80 [0·61-1·04, p = 0·09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 [95%CI 0·81-1·32, p = 0·80]. The p-value for the global test of inconsistency was 0·28. Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.

IntroductionAutism is a neurodevelopmental disorder characterized by deficits in the ability to initiate and maintain social interaction, as well as a set of restricted and inflexible behavior patterns and interests. Individuals with Autism Spectrum Disorder (ASD) are at increased risk of suicidal behavior, including suicidal ideation, suicide attempts and death by suicide, as compared to the general population. Among the underlying causes, the co-occurrence of other psychiatric disorders, such as depression and anxiety, is common and can contribute to the reduction of the quality of life, as well as a worse prognosis of the disease.ObjectivesCase report and brief review of risk factors associated with suicidal behavior in individuals with ASD.MethodsReview of the patients clinical file; Brief non-sistematic literature review of articles indexed to Pubmed with the key words: “Autism Spectrum Disorder”, “Suicide”, ”Suicidal behaviour”, ”Mood disorder”.ResultsJ., 18 years old, male, with ASD, the best student at school, with above-average results since childhood. Two years ago he showed a non-reciprocal love interest. Since then, he has had multiple visits to the emergency department and successive hospitalizations, mostly because of mood and behaviour alterations, with suicidal ideation. After 1 month with depressive and anxious symptoms, he ended up making a suicide attempt through voluntary intoxication by prescribed medication. He was taken to the emergency room. Examination of mental status highlighted depressed mood, elevated anxiety levels, hypoprosody, and active suicidal ideation. Blood tests and CE-CT scan without changes. He was admitted in the psychiatry ward and treated with fluvoxamine, risperidone and lorazepam. He showed a good evolution of the psychopathological condition. Discharged at day 44, he was referred to a psychiatric and psychological outpatient clinics.ConclusionsMood disorders have a significant impact on the well-being of individuals with ASD, contributing to a worse quality of life and higher suicide mortality. Cognition has been associated with different levels of death by suicide, and individuals with ASD without intellectual disability, such as this patient, are at increased risk of suicide, which may be due to a greater awareness of their own difficulties. The role of genetics has been a subject of interest. The overlap of genes strongly associated with suicidal behavior and ASD has been described. However, there is still need of large scale genetic studies, for a better understanding of the genetic mechanisms involved in this association. The identification of vulnerable individuals and early initiation of preventive and therapeutic strategies is essential to improve the prognosis of ASD.Disclosure of InterestNone Declared

Background It is unclear how to disseminate the results of randomised controlled trials effectively to health professionals and policymakers to improve treatment, care or prevention through changing policy and practice. This systematic review examined the effectiveness of different methods of dissemination of clinical research results to professional audiences. Methods We systematically reviewed the published and grey literature from 2000 to 2022 for studies assessing different approaches for disseminating clinical study results to professional audiences (health professionals, policymakers and guideline developers). Two reviewers assessed potentially relevant full texts for inclusion. We grouped studies by intervention type, synthesising findings using effect direction plots. Outcomes were grouped into out-takes (e.g. awareness, knowledge, understanding), outcomes (e.g. attitude changes) and impact (changes in policy/practice). The quality of evidence was assessed using GRADE. Results Our search identified 13,264 unique records, of which 416 full texts were assessed for eligibility. Of 60 studies that were identified as eligible for inclusion, 20 evaluated the effectiveness of interventions to disseminate clinical research results (13 RCTs, 2 observational studies, 3 pre- and post-intervention surveys and 2 cross-sectional surveys). Studies were grouped by intervention: 7 studies that involved face-to-face meetings between the target audience and trained educators were classified as ‘outreach interventions’; 5 studies that provided a summary format for systematic review findings (e.g. summary of findings tables) were grouped together. There was high certainty evidence of a small beneficial impact of outreach interventions on health and moderate certainty evidence of impact on practice (mostly prescribing). There was no evidence of impact on policy and very low certainty around benefits on outcomes and out-takes. We found no consistent benefits of summary formats for systematic review results on outcomes or out-takes (moderate quality evidence). Other interventions with less evidence are reported in the Additional Materials. Conclusions Outreach interventions to disseminate clinical research results can lead to changes in practice and improvements in health. However, these interventions can be resource-intensive. Investment is vital to identify and implement effective and cost-effective ways to disseminate results, so that the potential benefits of trials to patients can be realised. Trial registration International Prospective Register of Systematic Reviews (PROSPERO), CRD42019137364.