We report the discovery of a 200 mHz quasi-periodic oscillation (QPO) in the X-ray emission from a bright ultraluminous X-ray source (ULX), Holmberg IX X-1, using a long XMM-Newton observation. The ...QPO has a centroid at sub(QPO) = 202.5 sub(3.8) super(+4.9) mHz, a coherence Q = sub(QPO)/ logical or sub(FWHM) -9.3, and an amplitude (rms) of 6% in the 0.2-10 keV band. This is only the second detection of a QPO from a ULX, after M82 X-1, and provides strong evidence against beaming. The power spectrum is well fitted by a power law with an index of -0.7. The total integrated power (rms) is -9.4% in the 0.001-1 Hz range. The X-ray spectrum shows clear evidence of a soft X-ray excess component that is well described by a multicolor disk blackbody (kT sub(in) 60.3 keV) and a high-energy curvature that can be modeled either by a cutoff power law ( 6 1; E sub(cutoff) = 9 keV) or as a strongly Comptonized continuum in an optically thick (t - 7.3) and cool (kT sub(e) - 3 keV) plasma. Both the presence of the QPO and the shape of the X-ray spectrum strongly suggest that the ULX is not in the high/soft or thermally dominated state. A truncated disk and inner optically thick corona may explain the observed X-ray spectrum and the presence of the QPO.
Background
This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma.
Methods
A ...questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy. Records of consecutive patients undergoing oesophagogastric resection at seven centres between January 2000 and December 2013 were reviewed. Pathological response to neoadjuvant chemotherapy was assessed using the Mandard Tumour Regression Grade (TRG) and lymph node downstaging.
Results
TRG (8 of 11 centres) was the most widely used system to assess response to neoadjuvant chemotherapy, but there was discordance on how it was used in practice. Of 1392 patients, 1293 had TRG assessment; data were available for clinical and pathological nodal status (cN and pN) in 981 patients, and TRG, cN and pN in 885. There was a significant difference in survival between responders (TRG 1–2; median overall survival (OS) not reached) and non‐responders (TRG 3–5; median OS 2·22 (95 per cent c.i. 1·94 to 2·51) years; P < 0·001); the hazard ratio was 2·46 (95 per cent c.i. 1·22 to 4·95; P = 0·012). Among local non‐responders, the presence of lymph node downstaging was associated with significantly improved OS compared with that of patients without lymph node downstaging (median OS not reached versus 1·92 (1·68 to 2·16) years; P < 0·001).
Conclusion
A clinically meaningful local response to neoadjuvant chemotherapy was restricted to the small minority of patients (14·8 per cent) with TRG 1–2. Among local non‐responders, a subset of patients (21·3 per cent) derived benefit from neoadjuvant chemotherapy by lymph node downstaging and their survival mirrored that of local responders.
Response associated with survival
Summary Background Very few over‐the‐counter cosmetic ‘anti‐ageing’ products have been subjected to a rigorous double‐blind, vehicle‐controlled trial of efficacy. Previously we have shown that ...application of a cosmetic ‘anti‐ageing’ product to photoaged skin under occlusion for 12 days can stimulate the deposition of fibrillin‐1. This observation infers potential to repair and perhaps clinically improve photoaged skin.
Objective We examined another similar over‐the‐counter cosmetic ‘anti‐ageing’ product using both the patch test assay and a 6‐month double‐blind, randomized controlled trial (RCT), with a further 6‐month open phase to assess clinical efficacy in photoaged skin.
Methods For the patch test, a commercially available test product and its vehicle were applied occluded for 12 days to photoaged forearm skin (n = 10) prior to biopsy and immunohistochemical assessment of fibrillin‐1; all‐trans retinoic acid (RA) was used as a positive control. Sixty photoaged subjects were recruited to the RCT (test product, n = 30 vs. vehicle, n = 30; once daily for 6 months, face and hands) with clinical assessments performed at recruitment and following 1, 3 and 6 months of use. Twenty‐eight volunteers had skin biopsies (dorsal wrist) at baseline and at 6 months treatment for immunohistochemical assessment of fibrillin‐1 (test product, n = 15; vehicle, n = 13). All volunteers received the test product for a further 6 months. Final clinical assessments were performed at the end of this open period.
Results In the 12‐day patch test assay, we observed significant immunohistological deposition of fibrillin‐1 in skin treated with the test product and RA compared with the untreated baseline (P = 0·005 and 0·015, respectively). In the clinical RCT, at 6 months, the test product produced statistically significant improvement in facial wrinkles as compared to baseline assessment (P = 0·013), whereas vehicle‐treated skin was not significantly improved (P = 0·11). After 12 months, there was a significant benefit of the test product over that projected for the vehicle (70% vs. 33% of subjects improving; combined Wilcoxon rank tests, P = 0·026). There was significant deposition of fibrillin‐1 in skin treated for 6 months with the test product (mean ± SE) vehicle 1·84 ± 0·23; test product 2·57 ± 0·19; ancovaP = 0·019).
Conclusions In a double‐blind RCT, an over‐the‐counter cosmetic ‘anti‐ageing’ product resulted in significant clinical improvement in facial wrinkles, which was associated with fibrillin‐1 deposition in treated skin. This study demonstrates that a cosmetic product can produce significant improvement in the appearance of wrinkles and further supports the use of fibrillin‐1 as a robust biomarker for the repair of photoaged dermis.
We report the detection of an ultra-bright fast radio burst (FRB) from a modest, 3.4-day pilot survey with the Australian Square Kilometre Array Pathfinder. The survey was conducted in a wide-field ...fly's-eye configuration using the phased-array-feed technology deployed on the array to instantaneously observe an effective area of 160 deg2, and achieve an exposure totaling 13200 deg2 hr . We constrain the position of FRB 170107 to a region in size (90% containment) and its fluence to be 58 6 Jy ms. The spectrum of the burst shows a sharp cutoff above 1400 MHz, which could be due to either scintillation or an intrinsic feature of the burst. This confirms the existence of an ultra-bright ( Jy ms) population of FRBs.
A UMo powellite glass–ceramic designed by French workers to immobilise Mo-rich intermediate-level waste was found to be quite leach resistant in water at 90°C with the dissolution of Cs, Mo, Na, B ...and Ca not exceeding 2g/L in normalised PCT tests. 133Cs solid state nuclear magnetic resonance and scanning electron microscopy (SEM) showed the Cs to inhabit the glass phase. The microstructures were not greatly affected by cooling rates between 1 and 5°C/min or by introducing 10times as much Cs and Sr. Protracted leach tests at 90°C showed surface alteration as evidenced by SEM and particularly transmission electron microscopy; the main alteration phase was a Zn aluminosilicate but several other alteration phases were evident. Voidage in the alteration layers was indicated from enhanced lifetimes in positron annihilation lifetime spectroscopy.
Human cytomegalovirus (HCMV) remains an important cause of morbidity after allotransplantation, causing a range of direct effects including hepatitis, pneumonitis, enteritis and retinitis. A dominant ...risk factor for HCMV disease is high level viral replication in blood but it remains unexplained why only a subset of patients develop such diseases. In this detailed study of 25 renal transplant recipients, we show that functional impairment of HCMV specific CD8 T cells in the production of interferon gamma was associated with a 14‐fold increased risk of progression to high level replication. The CD8 T‐cell impairment persisted during the period of high level replication and was more prominent in patients above 40 years of age (odds ratio = 1.37, p = 0.01) and was also evident in dialysis patients. Threshold levels of functional impairment were associated with an increased risk of future HCMV replication and there was a direct relationship between the functional capacity of HCMV ppUL83 CD8 T cells and HCMV load (R2= 0.83). These results help to explain why a subset of seropositive individuals develop HCMV replication and are at risk of end‐organ disease and may facilitate the early identification of individuals who would benefit from targeted anti‐HCMV therapy after renal transplantation.
In 25 renal transplant recipients, functional impairment of HCMV‐specific CD8 T cells in production of interferon‐γ was associated with an increased risk of progression to high level replication of CMV in blood.
A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this ...intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis.
For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D
, vitamin D
, or 25-hydroxyvitamin D (25OHD) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units IU vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633.
We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 61·3% of 23 364 participants) than in the placebo group (14 217 62·3% of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I
=35·6%, p
=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 95% CI 0·65-0·94; 19 studies; I
=53·5%, p
=0·003), at daily dose equivalents of 400-1000 IU (0·70 0·55-0·89; ten studies; I
=31·2%, p
=0·16), for a duration of 12 months or less (0·82 0·72-0·93; 29 studies; I
=38·1%, p
=0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 0·57-0·90; 15 studies; I
=46·0%, p
=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 0·86-1·07; 36 studies; I
=0·0%, p
=0·99). Risk of bias within individual studies was assessed as being low for all but three trials.
Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation.
None.
Androgen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and ...oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer.
The PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE NCT00268476 platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately.
Recruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of -3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3-13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80-1.53; P = 0.54). Oncological outcomes are awaited.
Efficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure - overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway.
We present a systematic X-ray study of eight active galactic nuclei (AGNs) with intermediate-mass black holes (image M sub(image)) based on 12 XMM-Newton observations. The sample includes the two ...prototype AGNs in this class-NGC 4395 and POX 52 and six other AGNs discovered with the Sloan Digitized Sky Survey. These AGNs show some of the strongest X-ray variability, with the normalized excess variances being the largest and the power density break timescales being the shortest observed among radio-quiet AGNs. The excess-variance-luminosity correlation appears to depend on both the BH mass and the Eddington luminosity ratio. The break timescale-black hole mass relations for AGN with IMBHs are consistent with that observed for massive AGNs. We find that the FWHM of the H beta /H alpha line is uncorrelated with the BH mass, but shows strong anticorrelation with the Eddington luminosity ratio. Four AGNs show clear evidence for soft X-ray excess emission (image eV). X-ray spectra of three other AGNs are consistent with the presence of the soft excess emission. NGC 4395 with lowest L/L sub(Edd) lacks the soft excess emission. Evidently small black mass is not the primary driver of strong soft X-ray excess emission from AGNs. The X-ray spectral properties and optical-to-X-ray spectral energy distributions of these AGNs are similar to those of Seyfert 1 galaxies. The observed X-ray/UV properties of AGNs with IMBHs are consistent with these AGNs being low-mass extensions of more massive AGNs, those with high Eddington luminosity ratio looking more like narrow-line Seyfert 1 s and those with low L/L sub(Edd) looking more like broad-line Seyfert 1 galaxies.
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