The Peak of the Fallback Rate from Tidal Disruption Events: Dependence on Stellar Type

A star completely destroyed in a tidal disruption event (TDE) ignites a luminous flare that is powered by the fallback of tidally stripped debris to a supermassive black hole (SMBH) of mass $M_{\bullet}$. We analyze two estimates for the peak fallback rate in a TDE, one being the "frozen-in" model, which predicts a strong dependence of the time to peak fallback rate, $t_{\rm peak}$, on both stellar mass and age, with $15\textrm{ days} \lesssim t_{\rm peak} \lesssim 10$ yr for main sequence stars with masses $0.2\le M_{\star}/M_{\odot} \le 5$ and $M_{\bullet} = 10^6M_{\odot}$. The second estimate, which postulates that the star is completely destroyed when tides dominate the maximum stellar self-gravity, predicts that $t_{\rm peak}$ is very weakly dependent on stellar type, with $t_{\rm peak} = \left(23.2\pm4.0\textrm{ days}\right)\left(M_{\bullet}/10^6M_{\odot}\right)^{1/2}$ for $0.2\le M_{\star}/M_{\odot} \le 5$, while $t_{\rm peak} = \left(29.8\pm3.6\textrm{ days}\right)\left(M_{\bullet}/10^6M_{\odot}\right)^{1/2}$ for a Kroupa initial mass function truncated at $1.5 M_{\odot}$. This second estimate also agrees closely with hydrodynamical simulations, while the frozen-in model is discrepant by orders of magnitude. We conclude that (1) the time to peak luminosity in complete TDEs is almost exclusively determined by SMBH mass, and (2) massive-star TDEs power the largest accretion luminosities. Consequently, (a) decades-long extra-galactic outbursts cannot be powered by complete TDEs, including massive-star disruptions, and (b) the most highly super-Eddington TDEs are powered by the complete disruption of massive stars, which -- if responsible for producing jetted TDEs -- would explain the rarity of jetted TDEs and their preference for young and star-forming host galaxies.Comment: 10 pages, 4 figures, ApJL accepte

High salt intake activates the hypothalamic-pituitary-adrenal axis, amplifies the stress response, and alters tissue glucocorticoid exposure in mice

Aims: High salt intake is common and contributes to poor cardiovascular health. Urinary sodium excretion correlates directly with glucocorticoid excretion in humans and experimental animals. We hypothesized that high salt intake activates the hypothalamic-pituitary-adrenal axis activation and leads to sustained glucocorticoid excess. Methods and results: In male C57BL/6 mice, high salt intake for 2-8 weeks caused an increase in diurnal peak levels of plasma corticosterone. After 2 weeks, high salt increased Crh and Pomc mRNA abundance in the hypothalamus and anterior pituitary, consistent with basal hypothalamic-pituitary-adrenal axis activation. Additionally, high salt intake amplified glucocorticoid response to restraint stress, indicative of enhanced axis sensitivity. The binding capacity of Corticosteroid-Binding Globulin was reduced and its encoding mRNA downregulated in the liver. In the hippocampus and anterior pituitary, Fkbp5 mRNA levels were increased, indicating increased glucocorticoid exposure. The mRNA expression of the glucocorticoid-regenerating enzyme, 11β-hydroxysteroid dehydrogenase Type 1, was increased in these brain areas and in the liver. Sustained high salt intake activated a water conservation response by the kidney, increasing plasma levels of the vasopressin surrogate, copeptin. Increased mRNA abundance of Tonebp and Avpr1b in the anterior pituitary suggested that vasopressin signalling contributes to hypothalamic-pituitary-adrenal axis activation by high salt diet. Conclusion: Chronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells.</p

Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

OBJECTIVE To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. METHODS Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. RESULTS We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. CONCLUSION Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions

Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV):an open-label randomised controlled phase 3 trial

Background The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy. Methods We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1: 1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m(2) on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m(2) loading dose followed by seven weekly infusions of 250 mg/m(2)). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080. Findings Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4.8 [95% CI 4.2-5.4] with cisplatin vs 4.8 [4.2-5.4] with cetuximab; p=0.98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29.2 [95% CI 27.3-31.0] with cisplatin vs 30.1 [28.3-31.9] with cetuximab; p=0.49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97.5% vs 89.4%, hazard ratio 5.0 [95% CI 1.7-14.7]; p=0.001) and 2-year recurrence (6.0% vs 16.1%, 3.4 [1.6-7.2]; p=0.0007). Interpretation Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. Funding Cancer Research UK. Copyright (c) 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Humility, Self-Awareness, and Religious Ambivalence: Another Look at Beckett's ‘Humanistic Quietism’

This is the accepted manuscript. The final version is available from Edinburgh University Press at http://www.euppublishing.com/doi/abs/10.3366/jobs.2014.0104. This article provides a commentary on the opaque and often contradictory arguments of ‘Humanistic Quietism’, Samuel Beckett's 1934 review of Thomas MacGreevy's Poems. Using Beckett's complicated relationship to both his own Protestant upbringing and the Catholicism of MacGreevy as a starting point, the article proposes new ways of understanding Beckett's ambivalent comments about MacGreevy's interiority, prayer-like poetry, humility, and quietism. It draws on Beckett's comments on Rilke, André Gide, and Arnold Geulincx, as well as his familiarity with Dante, to unpack the review's dense allusions and make sense of Beckett's aesthetic allegiances. </jats:p

Evaluating the effect of a digital health intervention to enhance physical activity in people with chronic kidney disease (Kidney BEAM): a multicentre, randomised controlled trial in the UK

BACKGROUND: Remote digital health interventions to enhance physical activity provide a potential solution to improve the sedentary behaviour, physical inactivity, and poor health-related quality of life that are typical of chronic conditions, particularly for people with chronic kidney disease. However, there is a need for high-quality evidence to support implementation in clinical practice. The Kidney BEAM trial evaluated the clinical effect of a 12-week physical activity digital health intervention on health-related quality of life. METHODS: In a single-blind, randomised controlled trial conducted at 11 centres in the UK, adult participants (aged ≥18 years) with chronic kidney disease were recruited and randomly assigned (1:1) to the Kidney BEAM physical activity digital health intervention or a waiting list control group. Randomisation was performed with a web-based system, in randomly permuted blocks of six. Outcome assessors were masked to treatment allocation. The primary outcome was the difference in the Kidney Disease Quality of Life Short Form version 1.3 Mental Component Summary (KDQoL-SF1.3 MCS) between baseline and 12 weeks. The trial was powered to detect a clinically meaningful difference of 3 arbitrary units (AU) in KDQoL-SF1.3 MCS. Outcomes were analysed by an intention-to-treat approach using an analysis of covariance model, with baseline measures and age as covariates. The trial was registered with ClinicalTrials.gov, NCT04872933. FINDINGS: Between May 6, 2021, and Oct 30, 2022, 1102 individuals were assessed for eligibility, of whom 340 participants were enrolled and randomly assigned to the Kidney BEAM intervention group (n=173) or the waiting list control group (n=167). 268 participants completed the trial (112 in the Kidney BEAM group and 156 in the waiting list control group). All 340 randomly assigned participants were included in the intention-to treat population. At 12 weeks, there was a significant improvement in KDQoL-SF.13 MCS score in the Kidney BEAM group (from mean 44·6 AU [SD 10·8] at baseline to 47·0 AU [10·6] at 12 weeks) compared with the waiting list control group (from 46·1 AU [10·5] to 45·0 AU [10·1]; between-group difference of 3·1 AU [95% CI 1·8-4·4]; p<0·0001). INTERPRETATION: The Kidney BEAM physical activity platform is an efficacious digital health intervention to improve mental health-related quality of life in patients with chronic kidney disease. These findings could facilitate the incorporation of remote digital health interventions into clinical practice and offer a potential intervention worthy of investigation in other chronic conditions. FUNDING: Kidney Research UK

Minor Body Science with the Nancy Grace Roman Space Telescope

n/

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (Pten BRF1 ) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In Pten BRF1 tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis