Background
The coronavirus disease 2019 (COVID‐19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low‐dose corticosteroids have proven clinical ...benefit in patients with severe COVID‐19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID‐19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID‐19 is unclear.
Methods
The COVID STEROID 2 trial is an investigator‐initiated, international, parallel‐grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID‐19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all‐cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health‐related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol.
Discussion
The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID‐19 patients with severe hypoxia with important implications for patients, their relatives and society.
Disks in binary systems can cause exotic eclipsing events. MWC 882 (BD -22 4376, EPIC 225300403) is such a disk-eclipsing system identified from observations during Campaign 11 of the K2 mission. We ...propose that MWC 882 is a post-Algol system with a B7 donor star of mass in a 72-day orbit around an A0 accreting star of mass . The disk around the accreting star occults the donor star once every orbit, inducing 19-day long, 7% deep eclipses identified by K2 and subsequently found in pre-discovery All-Sky Automated Survey and All Sky Automated Survey for Supernovae observations. We coordinated a campaign of photometric and spectroscopic observations for MWC 882 to measure the dynamical masses of the components and to monitor the system during eclipse. We found the photometric eclipse to be gray to 1%. We found that the primary star exhibits spectroscopic signatures of active accretion, and we observed gas absorption features from the disk during eclipse. We suggest that MWC 882 initially consisted of a 3.6 M donor star transferring mass via Roche lobe overflow to a 2.1 M accretor in a 7-day initial orbit. Through angular momentum conservation, the donor star is pushed outward during mass transfer to its current orbit of 72 days. The observed state of the system corresponds with the donor star having left the red giant branch ∼0.3 Myr ago, terminating active mass transfer. The present disk is expected to be short-lived (102 yr) without an active feeding mechanism, presenting a challenge to this model.
Repeated attempts to lose weight by temporary dieting may result in weight cycling, eventually further gain of body fat, and possible metabolic adaptation. We tested this with a controlled experiment ...in C57BL/6J mice subjected to four weight cycles (WC), continuous hypercaloric feeding (HF), or low-fat feeding (LF). To search for genes involved in an adaptive mechanism to former weight cycling and avoid acute effects of the last cycle, the last hypercaloric feeding period was prolonged by an additional 2 wk before euthanization. Total energy intake was identical in WC and HF. However, compared with HF, the WC mice gained significantly more total body mass and fat mass and showed increased levels of circulating leptin and lipids in liver. Both the HF and WC groups showed increased adipocyte size and insulin resistance. Despite these effects, we also observed an interesting maintenance of circulating adiponectin and free fatty acid levels after WC, whereas changes in these parameters were observed in HF mice. Global gene expression was analyzed by microarrays. Weight-cycled mice were characterized by a downregulation of several clock genes (Dbp, Tef, Per1, Per2, Per3, and Nr1d2) in adipose tissues, which was confirmed by quantitative PCR. In 3T3-L1 cells, we found reduced expression of Dbp and Tef early in adipogenic differentiation, which was mediated via cAMP-dependent signaling. Our data suggest that clock genes in adipose tissue may play a role in metabolic adaptation to weight cycling.
Circulating adiponectin levels are decreased in pregnant women with obesity or gestational diabetes, and this is believed to contribute to the insulin resistance and increased risk of fetal ...overgrowth associated with these conditions. However, the molecular mechanisms regulating adiponectin secretion from maternal adipose tissues in pregnancy are poorly understood.
We tested the hypothesis that obesity in pregnancy is associated with adipose tissue insulin resistance and increased adiponectin ubiquitination and degradation, caused by inflammation and endoplasmic reticulum (ER) stress.
Visceral adipose tissues were collected from lean and obese pregnant humans and mice. Total and ubiquitinated adiponectin, and markers of inflammation, ER stress, and insulin resistance were examined in adipose tissues. The role of insulin, inflammation, and ER stress in mediating adiponectin ubiquitination and degradation was examined using 3T3L-1 adipocytes.
Obesity in pregnancy is associated with adipose tissue inflammation, ER stress, insulin resistance, increased adiponectin ubiquitination, and decreased total abundance of adiponectin. Adiponectin ubiquitination was increased in visceral fat of obese pregnant women as compared to lean pregnant women. We further observed that insulin prevents, whereas ER stress and inflammation promote, adiponectin ubiquitination and degradation in differentiated 3T3-L1 adipocytes.
We have identified adiponectin ubiquitination as a key mechanism by which obesity diminishes adiponectin secretion in pregnancy. This information will help us better understand the mechanisms controlling maternal insulin resistance and fetal growth in pregnancy and may provide a foundation for the development of strategies aimed at improving adiponectin production in pregnant women with obesity or gestational diabetes.
Aims
The effect on left ventricular (LV) systolic function and LV dyssynchrony by alternative right ventricular (RV) lead position in cardiac resynchronization therapy (CRT) is unclear. In the ...present study, RV apical (RV‐A) was compared with RV high posterior septal (RV‐HS) lead position in CRT.
Methods and results
In 85 consecutive CRT patients (mean age 66 ±11 years) the RV lead placement was randomized to RV‐A (n = 43) or RV‐HS (n = 42). The LV lead was targeted to the latest activated LV segment (concordant LV lead), identified by two‐dimensional speckle tracking radial strain (ST‐RS) echocardiography. Concordant LV leads were obtained in 72%, similar in RV‐A and RV‐HS (79% vs. 64%; P = 0.13). Six months after CRT, no difference was found in LV reverse remodelling (reduction of LV end‐systolic volume ≥15%) according to RV‐A and RV‐HS leads 26 (65%) vs. 25 (64%); P = 0.93. Superior LV reverse remodelling was observed in concordant LV leads compared with discordant LV leads 41 (73%) vs. 10 (43%); P = 0.01. At 6‐month follow‐up, LV reverse dyssynchrony (reduction of anteroseptal to posterior delay ≥50%) using ST‐RS imaging was similar in RV‐A and RV‐HS 25 (63%) vs. 24 (62%); P = 0.93. More LV reverse dyssynchrony was found in concordant LV leads vs. discordant LV leads 39 (70%) vs. 10 (43%); P = 0.03. A concordant LV lead was an independent predictor of LV reverse remodelling (odds ratio, 3.65; P = 0.01) and LV reverse dyssynchrony (odds ratio, 4.22; P = 0.02) 6 months after CRT.
Conclusion
RV‐A and RV‐HS in CRT demonstrated similar LV reverse remodelling and LV reverse dyssynchrony at 6‐month follow‐up. Concordant LV leads provided superior LV reverse remodelling and LV reverse dyssynchrony.
Trial registration: NCT01035489
This study describes the clinical and histopathological findings in dogs with mammary gland tumours, and compares the histopathological and clinical evidence consistent with progression from benign ...to malignant to human breast cancer epidemiology. Clinical and histopathological data on 90 female dogs with 236 tumours was included. Dogs with malignant tumours were significantly older than dogs with benign tumours (9.5 versus 8.5 years), P = 0.009. Malignant tumours were significantly larger than benign tumours (4.7 versus 2.1 cm), P = 0.0002. Sixty-six percent had more than one tumour, and evidence of histological progression was noted with increasing tumour size. Dogs with malignant tumours were significantly more likely to develop new primary tumours than dogs with benign tumours, P = 0.015. These findings suggest that canine mammary tumours progress from benign to malignant; malignant tumours may be the end stage of a histological continuum with clinical and histopathological similarities to human breast carcinogenesis.
Aims.
We introduce a novel way to identify new compact hierarchical triple stars by exploiting the huge potential of
Gaia
DR3 and also its future data releases. We aim to increase the current number ...of compact hierarchical triple systems significantly.
Methods.
We used several eclipsing binary catalogs from different sky surveys that list a total of more than 1 million targets to search for
Gaia
DR3 non-single-star orbital solutions with periods substantially longer than the eclipsing periods of the binaries. Those solutions in most cases are likely to belong to outer orbits of tertiary stars in those systems. We also attempted to validate some of our best-suited candidates using TESS eclipse timing variations.
Results.
We find 403 objects with suitable
Gaia
orbital solutions of which 27 are already known triple systems, leaving 376 newly identified hierarchical triple system candidates in our sample. We find the cumulative probability distribution of the outer orbit eccentricities to be very similar to those found in earlier studies based on observations of the
Kepler
and OGLE missions. We find measurable nonlinear eclipse timing variations or third-body eclipses in the TESS data for 192 objects which we also consider to be confirmed candidates. Of these, we construct analytical light-travel time effect models for the eclipse timing variations of 22 objects with wellsampled TESS observations. We compare the outer orbital parameters from our solutions with those from the
Gaia
solutions and find that the most reliable orbital parameter is the orbital period, while the values of the other parameters should be used with caution.
Background
In recent years, a variety of innovative therapeutics for castration-resistant prostate cancer have been developed, including novel anti-androgenic drugs, such as abiraterone or VPC-13566. ...Therapeutic monitoring of these pharmaceuticals is performed either by measuring PSA levels in serum or by imaging. PET using PSMA ligands labeled with Fluor-18 or Gallium-68 is the most sensitive and specific imaging modality for detection of metastases in advanced prostate cancer. To date, it remains unclear how PSMA expression is modulated by anti-hormonal treatment and how it correlates with PSA secretion.
Methods
We analyzed modulation of PSMA-mRNA and protein expression,
68
Ga–PSMA uptake and regulation of PSA secretion by abiraterone or VPC-13566 in LNCaP cells in vitro.
Results
We found that abiraterone and VPC-13566 upregulate PSMA protein and mRNA expression but block PSA secretion in LNCaP cells. Both anti-androgens also enhanced
68
Ga–PSMA uptake normalized by the number of cells, whereas abiraterone and VPC-13566 reduced
68
Ga–PSMA uptake in total LNCaP monolayers treated due to cell death.
Conclusion
Our data indicate that PSA secretion and PSMA expression are differentially regulated upon anti-androgen treatment. This finding might be important for the interpretation of
68
Ga–PSMA PET images in monitoring therapies with abiraterone and VPC-13566 in prostate cancer patients, but needs to be validated in vivo.
Abstract
New sets of young M dwarfs with complex, sharp-peaked, and strictly periodic photometric modulations have recently been discovered with Kepler/K2 (scallop shells) and TESS (complex ...rotators). All are part of star-forming associations, are distinct from other variable stars, and likely belong to a unified class. Suggested hypotheses include starspots, accreting dust disks, corotating clouds of material, magnetically constrained material, spots and misaligned disks, and pulsations. Here, we provide a comprehensive overview and add new observational constraints with TESS and SPECULOOS Southern Observatory photometry. We scrutinize all hypotheses from three new angles: (1) We investigate each scenario’s occurrence rates via young star catalogs, (2) we study the feature’s longevity using over one year of combined data, and (3) we probe the expected color dependency with multicolor photometry. In this process, we also revisit the stellar parameters accounting for activity effects, study stellar flares as activity indicators over year-long timescales, and develop toy models to simulate typical morphologies. We rule out most hypotheses, and only (i) corotating material clouds and (ii) spots and misaligned disks remain feasible—with caveats. For (i), corotating dust might not be stable enough, while corotating gas alone likely cannot cause percentage-scale features and (ii) would require misaligned disks around most young M dwarfs. We thus suggest a unified hypothesis, a superposition of large-amplitude spot modulations and sharp transits of corotating gas clouds. While the complex rotators’ mystery remains, these new observations add valuable pieces to the puzzle going forward.
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