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Do supernovae indicate an accelerating universe?
No full textIn the late 1990’s, observations of two directionally-skewed samples of, in total, 93 Type Ia supernovae were analysed in the framework of the Friedmann–Lemaître–Robertson–Walker (FLRW) cosmology. Assuming these to be ‘standard(isable) candles’ it was inferred that the Hubble expansion rate is accelerating as if driven by a positive Cosmological Constant Λ in Einstein’s theory of gravity. This is still the only direct evidence for the ‘dark energy’ that is the dominant component of today’s standard ΛCDM cosmological model. Other data such as baryon acoustic oscillations (BAO) in the large-scale distribution of galaxies, temperature fluctuations in the cosmic microwave background (CMB), measurement of stellar ages, the rate of growth of structure, etc are all ‘concordant’ with this model but do not provide independent evidence for accelerated expansion. The recent discussions about whether the inferred acceleration is real rests on analysis of a larger sample of 740 SNe Ia which shows that these are not quite standard candles, and more importantly highlights the ‘corrections’ that are applied to analyse the data in the FLRW framework. The latter holds in the reference frame in which the CMB is isotropic, whereas observations are carried out in our heliocentric frame in which the CMB has a large dipole anisotropy. This is assumed to be of kinematic origin i.e. due to our non-Hubble motion driven by local inhomogeneity in the matter distribution which has grown under gravity from primordial density perturbations traced by the CMB fluctuations. The ΛCDM model predicts how this peculiar velocity should fall off as the averaging scale is raised and the universe becomes sensibly homogeneous. However observations of the local ‘bulk flow’ are inconsistent with this expectation and convergence to the CMB frame is not seen. Moreover, the kinematic interpretation implies a corresponding dipole in the sky distribution of high redshift quasars, which is rejected by observations at 4.9σ. Hence the peculiar velocity corrections employed in supernova cosmology are inconsistent and discontinuous within the data. The acceleration of the Hubble expansion rate is in fact anisotropic at 3.9σ and aligned with the bulk flow. Thus dark energy could be an artefact of analysing data assuming that we are idealised observers in an FLRW universe, when in fact the real universe is inhomogeneous and anisotropic out to distances large enough to impact on cosmological analyses
Formation of supermassive black hole seeds in nuclear star clusters via gas accretion and runaway collisions
No full textMore than 200 supermassive black holes (SMBHs) of masses ≳109M⊙≳109M⊙ have been discovered at z ≳ 6. One promising pathway for the formation of SMBHs is through the collapse of supermassive stars (SMSs) with masses ∼103−105M⊙∼103−105M⊙ into seed black holes which could grow upto few times 109M⊙109M⊙ SMBHs observed at z ∼ 7. In this paper, we explore how SMSs with masses ∼103−105M⊙∼103−105M⊙ could be formed via gas accretion and runaway stellar collisions in high-redshift, metal-poor nuclear star clusters (NSCs) using idealized N-body simulations. We explore physically motivated accretion scenarios, e.g. Bondi–Hoyle–Lyttleton accretion and Eddington accretion, as well as simplified scenarios such as constant accretions. While gas is present, the accretion time-scale remains considerably shorter than the time-scale for collisions with the most massive object (MMO). However, overall the time-scale for collisions between any two stars in the cluster can become comparable or shorter than the accretion time-scale, hence collisions still play a crucial role in determining the final mass of the SMSs. We find that the problem is highly sensitive to the initial conditions and our assumed recipe for the accretion, due to the highly chaotic nature of the problem. The key variables that determine the mass growth mechanism are the mass of the MMO and the gas reservoir that is available for the accretion. Depending on different conditions, SMSs of masses ∼103−105M⊙∼103−105M⊙ can form for all three accretion scenarios considered in this work
Mindfulness-based programmes to reduce stress and enhance well-being at work: a realist review
No full textObjectives To understand how and why workplace mindfulness-based programmes (MBPs) work or do not work.
Design A realist review.
Eligibility criteria for selection We considered any studies (experimental quasi-experimental, observational, qualitative and mixed-methods studies) of workplace MBPs as long as they provided data to explain our programme theories. All MBP formats and delivery modes were included.
Analysis Consistent with realist review methodology, we systematically screened and analysed data to explain how and why workplace MBPs work or do not work. These explanations were consolidated into a programme theory augmented by theories from organisational literature, such as conservation of resources theory.
Results Findings from 75 primary studies suggest that workplace MBPs enable participants (including healthcare professionals) to deal more skillfully with stressful events and improve their well-being. The mechanisms involved can be grouped around awareness/self-regulation, acceptance/compassion, feeling permitted to take care of self, sense of growth and promise of goal attainment. In order for professionals to invest in an MBP and benefit from it, it is important that they feel safe to engage with self-care at work and share emotional difficulties among peers. It is also important that employees are able to link the programme and its activities to existing goals and practices. Concerns of being non-productive, of not getting work done or of being exposed in front of colleagues can result in strategic use of brief mindfulness exercises, non-adherence or drop-out.
Conclusions Simply offering an MBP to (healthcare) professionals in order to reduce stress and enhance well-being does not suffice. A supportive environment must exist in order for the programme’s benefits to be reaped.
PROSPERO registration number CRD42018086280
Cognitive, behavioural and familial maintenance mechanisms in childhood obsessive compulsive disorders: a systematic review
No full textCognitive Behavioural Therapy (CBT) for preadolescent children with obsessive compulsive disorder (OCD) is typically derived from adult cognitive behavioural models of OCD; however, it is unknown whether these adult models apply to preadolescent children. This systematic review examined whether 11 cognitive, behavioural and familial maintenance mechanisms identified from adult cognitive behavioural models of OCD and descriptions of how family factors may maintain OCD applied to preadolescent children with obsessive compulsive symptoms/disorder (OCS/OCD; Prospero:CRD42019153371). PsycINFO, MEDLINE and Web of Science Core Collection were searched in March 2019, with forward citation handsearching conducted in March/April 2020. Twenty-nine studies were synthesised. Studies were identified for only six of the 11 proposed maintenance factors. Of the cognitive and behavioural factors, only inflated responsibility and meta-cognitive beliefs showed evidence of independent and/or specific associations with childhood OCS. Of the family factors, only less frequent displays of parental confidence, positive problem solving and rewarding of children’s independence showed some evidence of specificity to childhood OCD. Notably, findings across studies were inconsistent and existing studies have considerable methodological limitations. Experimental and prospective longitudinal studies are needed to determine whether the proposed factors maintain childhood OCS/OCD, to improve the effectiveness and efficiency of CBT for preadolescent children with OCD
Testing models of diffusion of morphosyntactic innovations in Twitter data
No full textEstablished models of the spatial diffusion of linguistic innovations vary in their relationship to population density. Differences in prediction between the gravity models (Trudgill 1974), in which probability of diffusion is sensitive to settlement size, and the traditional wave models can be challenging to test due to the difficulty of large-scale and finely-grained geographical sampling. This paper tests the suitability of data derived from Twitter in establishing diffusion patterns. Using two case studies from British English – variation in the realisation of ditransitives, and preposition drop with go – we propose that the correlation between (local) population density and linguistic similarity to geographical neighbours can be used as a measure of hierarchical patterning for an individual innovation
Variable short duration treatment versus standard treatment, with and without adjunctive ribavirin, for chronic hepatitis C: the STOP-HCV-1 non-inferiority, factorial RCT
No full textObjectives: To compare cure rates using variable ultrashort first-line treatment stratified by baseline viral load followed by retreatment, with a fixed 8-week first-line treatment with retreatment with or without adjunctive ribavirin.
Design: An open-label, multicentre, factorial randomised controlled trial.
Randomisation: Randomisation was computer generated, with patients allocated in a 1:1 ratio using a factorial design to each of biomarker-stratified variable ultrashort strategy or fixed duration and adjunctive ribavirin (or not), using a minimisation algorithm with a probabilistic element.
Setting: NHS.
Participants: A total of 202 adults (aged ≥ 18 years) infected with chronic hepatitis C virus genotype 1a/1b or 4 for ≥ 6 months, with a detectable plasma hepatitis C viral load and no significant fibrosis [FibroScan® (Echosens, Paris, France) score F0–F1 or biopsy-proven minimal fibrosis], a hepatitis C virus viral load 24 weeks on anti-human immunodeficiency virus drugs.
Interventions: Fixed-duration 8-week first-line therapy compared with variable ultrashort first-line therapy, initially for 4–6 weeks (continuous scale) stratified by screening viral load (variable ultrashort strategy 1, mean 32 days of treatment) and then, subsequently, for 4–7 weeks (variable ultrashort strategy 2 mean 39 days of duration), predominantly with ombitasvir, paritaprevir, ritonavir (Viekirax®; AbbVie, Chicago, IL, USA), and dasabuvir (Exviera®; AbbVie, Chicago, IL, USA) or ritonavir. All patients in whom first-line treatment was unsuccessful were immediately retreated with 12 weeks’ sofosbuvir, ledipasvir (Harvoni®, Gilead Sciences, Inc., Foster City, CA, USA) and ribavirin.
Main outcome measure: The primary outcome was overall sustained virological response (persistently undetectable) 12 weeks after the end of therapy (SVR12).
Results: A total of 202 patients were analysed. All patients in whom the primary outcome was evaluable achieved SVR12 overall [100% (197/197), 95% confidence interval 86% to 100%], demonstrating non-inferiority between fixed- and variable-duration strategies (difference 0%, 95% confidence interval –3.8% to 3.7%, prespecified non-inferiority margin 4%). A SVR12 following first-line treatment was achieved in 91% (92/101; 95% confidence interval 86% to 97%) of participants randomised to the fixed-duration strategy and by 48% (47/98; 95% confidence interval 39% to 57%) allocated to the
variable-duration strategy. However, the proportion achieving SVR12 was significantly higher among those allocated to variable ultrashort strategy 2 [72% (23/32), 95% confidence interval 56% to 87%] than among those allocated to variable ultrashort strategy 1 [36% (24/66), 95% confidence interval 25% to 48%]. Overall, a SVR12 following first-line treatment was achieved by 72% (70/101) (95% confidence interval 65% to 78%) of patients treated with ribavirin and by 68% (69/98) (95% confidence interval 61% to 76%) of those not treated with ribavirin. A SVR12 with variable ultrashort strategies 1 and 2 was 52% (25/48) (95% confidence interval 38% to 65%) with ribavirin, compared with 44% (22/50) (95% confidence interval 31% to 56) without. However, at treatment failure, the emergence of viral resistance was lower with ribavirin [12% (3/26), 95% confidence interval 2% to 30%] than without [38% (11/29), 95% confidence interval 21% to 58%; p = 0.01]. All 10 individuals who became undetectable at day 3 of treatment achieved first-line SVR12 regardless of treatment duration. Five participants in the variable-duration arm and five in the fixed-duration arm experienced serious adverse events (p = 0.69),
as did five participants receiving ribavirin and five participants receiving no ribavirin.
Conclusions: SVR12 rates were significantly higher when ultrashort treatment varied between 4 and 7 weeks, rather than between 4 and 6 weeks. We found no evidence of ribavirin significantly affecting first-line SVR12, with unsuccessful first-line short-course therapy also not compromising subsequent retreatment with sofosbuvir, ledipasvir and ribavirin.
Future work: A priority for future work needs to be the development and evaluation of robust predictive measures to identify those patients who can be cured with ultrashort courses of therapy.
Trial registration: Current Controlled Trials ISRCTN37915093, EudraCT 2015-005004-28 and CTA 19174/0370/001-0001.
Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 17. See the NIHR Journals Library website for further project information
Multiple sensors provide spatiotemporal oxygen regulation of gene expression in a Rhizobium-legume symbiosis
No full textRegulation by oxygen (O2) in rhizobia is essential for their symbioses with plants and involves multiple O2 sensing proteins. Three sensors exist in the pea microsymbiont Rhizobium leguminosarum Rlv3841: hFixL, FnrN and NifA. At low O2 concentrations (1%) hFixL signals via FxkR to induce expression of the FixK transcription factor, which activates transcription of downstream genes. These include fixNOQP, encoding the high-affinity cbb3-type terminal oxidase used in symbiosis. In free-living Rlv3841, the hFixL-FxkR-FixK pathway was active at 1% O2, and confocal microscopy showed hFixL-FxkR-FixK activity in the earliest stages of Rlv3841 differentiation in nodules (zones I and II). Work on Rlv3841 inside and outside nodules showed that the hFixL-FxkR-FixK pathway also induces transcription of fnrN at 1% O2 and in the earliest stages of Rlv3841 differentiation in nodules. We confirmed past findings suggesting a role for FnrN in fixNOQP expression. However, unlike hFixL-FxkR-FixK, Rlv3841 FnrN was only active in the near-anaerobic zones III and IV of pea nodules. Quantification of fixNOQP expression in nodules showed this was driven primarily by FnrN, with minimal direct hFixL-FxkR-FixK induction. Thus, FnrN is key for full symbiotic expression of fixNOQP. Without FnrN, nitrogen fixation was reduced by 85% in Rlv3841, while eliminating hFixL only reduced fixation by 25%. The hFixL-FxkR-FixK pathway effectively primes the O2 response by increasing fnrN expression in early differentiation (zones I-II). In zone III of mature nodules, near-anaerobic conditions activate FnrN, which induces fixNOQP transcription to the level required for wild-type nitrogen fixation activity. Modelling and transcriptional analysis indicates that the different O2 sensitivities of hFixL and FnrN lead to a nuanced spatiotemporal pattern of gene regulation in different nodule zones in response to changing O2 concentration. Multi-sensor O2 regulation is prevalent in rhizobia, suggesting the fine-tuned control this enables is common and maximizes the effectiveness of the symbioses
Long-term real-world experience with ipilimumab and non-ipilimumab therapies in advanced melanoma: the IMAGE study
No full textBackground: Ipilimumab has shown long-term overall survival (OS) in patients with advanced melanoma in clinical trials, but robust real-world evidence is lacking. We present long-term outcomes from the IMAGE study (NCT01511913) in patients receiving ipilimumab and/or non-ipilimumab (any approved treatment other than ipilimumab) systemic therapies.
Methods: IMAGE was a multinational, prospective, observational study assessing adult patients with advanced melanoma treated with ipilimumab or non-ipilimumab systemic therapies between June 2012 and March 2015 with ≥ 3 years of follow-up. Adjusted OS curves based on multivariate Cox regression models included covariate effects. Safety and patient-reported outcomes were assessed.
Results: Among 1356 patients, 1094 (81%) received ipilimumab and 262 (19%) received non-ipilimumab index therapy (systemic therapy [chemotherapy, anti–programmed death 1 antibodies, or BRAF ± MEK inhibitors], radiotherapy, and radiosurgery). In the overall population, median age was 64 years, 60% were male, 78% were from Europe, and 78% had received previous treatment for advanced melanoma. In the ipilimumab-treated cohort, 780 (71%) patients did not receive subsequent therapy (IPI-noOther) and 314 (29%) received subsequent non-ipilimumab therapy (IPI-Other) on study. In the non-ipilimumab–treated cohort, 205 (78%) patients remained on or received other subsequent non-ipilimumab therapy (Other-Other) and 57 (22%) received subsequent ipilimumab therapy (Other-IPI) on study. Among 1151 patients who received ipilimumab at any time during the study (IPI-noOther, IPI-Other, and Other-IPI), 296 (26%) reported CTCAE grade ≥ 3 treatment-related adverse events, most occurring in year 1. Ipilimumab-treated and non-ipilimumab–treated patients who switched therapy (IPI-Other and Other-IPI) had longer OS than those who did not switch (IPI-noOther and Other-Other). Patients with prior therapy who did not switch therapy (IPI-noOther and Other-Other) showed similar OS. In treatment-naive patients, those in the IPI-noOther group tended to have longer OS than those in the Other-Other group. Patient-reported outcomes were similar between treatment cohorts.
Conclusions: With long-term follow-up (≥ 3 years), safety and OS in this real-world population of patients treated with ipilimumab 3 mg/kg were consistent with those reported in clinical trials. Patient-reported quality of life was maintained over the study period. OS analysis across both pretreated and treatment-naive patients suggested a beneficial role of ipilimumab early in treatment
Postoperative short course content delphi process study
No full textThe data contained herein is the raw data from three rounds of a Delphi Process (xls and R files
Bedside monitoring of lung volume available for gas exchange
No full textBackground
Bedside measurement of lung volume may provide guidance in the personalised setting of respiratory support, especially in patients with the acute respiratory distress syndrome at risk of ventilator-induced lung injury. We propose here a novel operator-independent technique, enabled by a fibre optic oxygen sensor, to quantify the lung volume available for gas exchange. We hypothesised that the continuous measurement of arterial partial pressure of oxygen (PaO2) decline during a breath-holding manoeuvre could be used to estimate lung volume in a single-compartment physiological model of the respiratory system.
Methods
Thirteen pigs with a saline lavage lung injury model and six control pigs were studied under general anaesthesia during mechanical ventilation. Lung volumes were measured by simultaneous PaO2 rate of decline (VPaO2) and whole-lung computed tomography scan (VCT) during apnoea at different positive end-expiratory and end-inspiratory pressures.
Results
A total of 146 volume measurements was completed (range 134 to 1869 mL). A linear correlation between VCT and VPaO2 was found both in control (slope = 0.9, R2 = 0.88) and in saline-lavaged pigs (slope = 0.64, R2 = 0.70). The bias from Bland–Altman analysis for the agreement between the VCT and VPaO2 was − 84 mL (limits of agreement ± 301 mL) in control and + 2 mL (LoA ± 406 mL) in saline-lavaged pigs. The concordance for changes in lung volume, quantified with polar plot analysis, was − 4º (LoA ± 19°) in control and − 9° (LoA ± 33°) in saline-lavaged pigs.
Conclusion
Bedside measurement of PaO2 rate of decline during apnoea is a potential approach for estimation of lung volume changes associated with different levels of airway pressure