Further Evidence for Collimated Particle Beams from Pulsars, and Precession

We follow up on our (Radhakrishnan & Deshpande, 2001: RD01) radically different interpretation of the observed structures and morphologies in the x-ray observations of the nebulae around young pulsars (PWNe). In our general model for PWNe (RD01), originally motivated by the Chandra observations of the Vela X-ray nebula, the bright arcs, the jet-like feature and the diffuse components in such nebulae can be explained together in detail, wherein the arcs are understood as traces of the particle beams from the two magnetic poles at the shock front. We consider this as important evidence for collimated particle beams from pulsars' magnetic poles. In this paper, we discuss the variability in the features in the Vela X-ray nebula observed by Pavlov et al. (2003), and assess the relevance and implication of our model to the observations on the Crab and other remnants. Our basic picture after incorporating the signatures of free precession of the central compact object can readily account for the variability and significant asymmetries, including the bent jet-like features, in the observed morphologies. The implications of these findings are discussed.Comment: Minor revision; 12 (9+3) pages, 3 figures; To appear in Ap

Science from "Solar X-ray spectrometer (SOXS)" - proposed payload onboard Indian satellite

It is proposed to fly a high spectral and temporal resolution "Solar X-ray Spectrometer (SOXS)" onboard Indian satellite to understand the mechanisms of energy release and particle acceleration in solar flares. The SOXS will provide the disk integrated flux in the energy range 2 keV-10 MeV. The proposed SOXS will consist of two detector modules - SOXS Low Energy Detector (SLD) and SOXS High Energy Detector (SHD). The proposed instrument will enable us to measure precisely the low energy cut-off below 60 keV to estimate the total energy release in the flare. It is proposed that high spectral and temporal resolution efficiencies of our detectors will reveal, perhaps for the first time, the observed break below 60 keV in the characteristic double power-law shape of hard X-ray spectrum. Whether electrons and protons are accelerated simultaneously may be also answered by correlating high temporal spectra of SLD and SHD. The high temporal and sub-keV resolution spectra from SLD will be capable to investigate the nature of micro/nano flares considered responsible to heat the chromosphere and corona. It is proposed to use the observations from this space borne instrument, along with extensive simultaneous ground based high spatial and time resolution observations in optical and radio wavebands for better understanding of the flare phenomena

Failure analysis using X-ray computed tomography of composite sandwich panels subjected to full-scale blast loading

The tailorable mechanical properties and high strength-to-weight ratios of composite sandwich panels make them of interest to the commercial marine and naval sector, however, further investigation into their blast resilience is required. The experiments performed in this study aimed to identify whether alterations to the composite skins or core of a sandwich panel can yield improved blast resilience both in air and underwater. Underwater blast loads using 1.28 kg TNT equivalent charge at a stand-off distance of 1 m were performed on four different composite sandwich panels. Results revealed that implementing a stepwise graded density foam core, with increasing density away from the blast, reduces the deflection of the panel and damage sustained. Furthermore, the skin material affects the extent of panel deflection and damage, the lower strain to failure of carbon-fibre reinforced polymer (CFRP) skins reduces deflection but increases skin debonding. A further two panels were subjected to a 100 kg TNT air blast loading at a 15 m stand-off to compare the effect of a graded density core and the results support the underwater blast results. Future modelling of these experiments will aid the design process and should aim to include material damage mechanisms to identify the most suitable skins

Floating Drug Delivery of Nevirapine as a Gastroretentive System

A multiple-unit floating drug delivery system based on gas formation technique was developed, in order to prolong the gastric residence time and to increase the overall bioavailability of the dosage form. The floating bead formulations were prepared by dispersing nevirapine together with calcium carbonate in a mixture of sodium alginate and hydroxypropyl methylcellulose solution and then dripping the dispersion into an acidified solution of calcium chloride. Calcium alginate beads were formed, as the alginate underwent ionotropic gelation by calcium ions, and carbon dioxide developed from the reaction of carbonate salts with acid. The obtained beads were able to float due to CO2-gas formation and the gas entrapment by the polymeric membrane. The prepared beads were evaluated for percent drug loading, drug entrapment efficiency, morphology, surface topography, buoyancy, in-vitro release, and release kinetics. The formulations were optimized for different weight ratios of the gas-forming agent and sodium alginate. The beads containing higher amounts of calcium carbonate demonstrated an instantaneous, complete, and excellent floating ability over a period of 24 hours. The increased amount of the gas forming agent did not affect the time to float, but increased the drug release from the floating beads, while increasing the coating level of the gas-entrapped membrane, increased the time to float, and slightly retarded the drug release. Good floating properties and sustained drug release were achieved. Finally, these floating beads seemed to be a promising gastroretentive drug delivery system

Advancing sepsis clinical research: harnessing transcriptomics for an omics-based strategy - a comprehensive scoping review

Sepsis continues to be recognized as a significant global health challenge across all ages and is characterized by a complex pathophysiology. In this scoping review, PRISMA-ScR guidelines were adhered to, and a transcriptomic methodology was adopted, with the protocol registered on the Open Science Framework. We hypothesized that gene expression analysis could provide a foundation for establishing a clinical research framework for sepsis. A comprehensive search of the PubMed database was conducted with a particular focus on original research and systematic reviews of transcriptomic sepsis studies published between 2012 and 2022. Both coding and non-coding gene expression studies have been included in this review. An effort was made to enhance the understanding of sepsis at the mRNA gene expression level by applying a systems biology approach through transcriptomic analysis. Seven crucial components related to sepsis research were addressed in this study: endotyping (n = 64), biomarker (n = 409), definition (n = 0), diagnosis (n = 1098), progression (n = 124), severity (n = 451), and benchmark (n = 62). These components were classified into two groups, with one focusing on Biomarkers and Endotypes and the other oriented towards clinical aspects. Our review of the selected studies revealed a compelling association between gene transcripts and clinical sepsis, reinforcing the proposed research framework. Nevertheless, challenges have arisen from the lack of consensus in the sepsis terminology employed in research studies and the absence of a comprehensive definition of sepsis. There is a gap in the alignment between the notion of sepsis as a clinical phenomenon and that of laboratory indicators. It is potentially responsible for the variable number of patients within each category. Ideally, future studies should incorporate a transcriptomic perspective. The integration of transcriptomic data with clinical endpoints holds significant potential for advancing sepsis research, facilitating a consensus-driven approach, and enabling the precision management of sepsis

Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted. (C) 2022 by American Society of Clinical Oncolog

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Axitinib: The evidence of its potential in the treatment of advanced thyroid cancer.

IntroductionThyroid cancer is a rare disease with an incidence of around 37,000 cases per year. However, its incidence is rising faster than many other cancers and for men this disease ranks highest overall in the rate of increase (2.4% annual increase) in cancer deaths. As the number of radioactive iodine-resistant thyroid cancers increases, the need for newer treatments has become more important. Axitinib is one of many new small molecule inhibitors of growth factor receptors that have shown promise in the treatment of many cancers. It targets the vascular endothelial growth factor receptors 1, 2 and 3.AimsThe goal of this article is to review the published evidence for the use of axitinib in the treatment of thyroid cancer and define its therapeutic potential.Evidence reviewThe major evidence of axitinib activity has appeared in meeting report abstracts. One phase II study has been published. This included patients with any histological type of thyroid cancer that was not amenable to treatment with radioactive iodine.Clinical potentialTo date, in phase II clinical studies axitinib has demonstrated antitumor activity in advanced refractory thyroid cancer. As a monotherapy it resulted in a 30% response rate with another 38% of patients having stable disease. Axitinib appears to have a good tolerability profile, with hypertension being the most common grade 3 or greater side effect