Characteristics of Patients with Oseltamivir-Resistant Pandemic (H1N1) 2009, United States

During April 2009–June 2010, thirty-seven (0.5%) of 6,740 pandemic (H1N1) 2009 viruses submitted to a US surveillance system were oseltamivir resistant. Most patients with oseltamivir-resistant infections were severely immunocompromised (76%) and had received oseltamivir before specimen collection (89%). No evidence was found for community circulation of resistant viruses; only 4 (unlinked) patients had no oseltamivir exposure

Skunk River Review Fall 1997, Vol 9

https://openspace.dmacc.edu/skunkriver/1018/thumbnail.jp

Displaying the heterogeneity of the SN 2002CX-like subclass of type IA supernovae with observations of the pan-starrs-1 discovered sn 2009ku

SN 2009ku, discovered by Pan-STARRS-1, is a Type Ia supernova (SN Ia), and a member of the distinct SN 2002cx-like class of SNe Ia. Its light curves are similar to the prototypical SN 2002cx, but are slightly broader and have a later rise to maximum in g. SN 2009ku is brighter (∼0.6 mag) than other SN 2002cx-like objects, peaking at MV = −18.4 mag — which is still significantly fainter than typical SNe Ia. SN 2009ku, which had an ejecta velocity of ∼2000 km s−1 at 18 days after maximum brightness is spectroscopically most similar to SN 2008ha, which also had extremely lowvelocity ejecta. However, SN 2008ha had an exceedingly low luminosity, peaking at MV = −14.2 mag, ∼4 mag fainter than SN 2009ku. The contrast of high luminosity and low ejecta velocity for SN 2009ku is contrary to an emerging trend seen for the SN 2002cx class. SN 2009ku is a counter-example of a previously held belief that the class was more homogeneous than typical SNe Ia, indicating that the class has a diverse progenitor population and/or complicated explosion physics. As the first example of a member of this class of objects from the new generation of transient surveys, SN 2009ku is an indication of the potential for these surveys to find rare and interesting objects.Astronom

Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate and high-risk early stage triple negative breast cancer

Background: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK-TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected (ctDNA+). Patients and methods: c-TRAK-TN, a multi-centre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or, stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three monthly blood sampling to 12 months (18 months if samples were missed due to COVID), and ctDNA+ patients were randomised 2:1; intervention:observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16/09/2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were i) ctDNA detection rate ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). Results: 208 patients registered between 30/01/18 - 06/12/19, 185 had tumour sequenced, 171 (92·4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27·3% (44/161,95%CI:20·6-34·9). Seven patients relapsed without prior ctDNA detection. 45 patients entered the therapeutic component (intervention n=31; observation n=14; 1 observation patient was re-allocated to intervention following protocol amendment). Of patients allocated intervention, 72% (23/32) had metastases on staging at time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. Conclusion: c-TRAK-TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes

Toward Characterization of the Type IIP Supernova Progenitor Population: A Statistical Sample of Light Curves from Pan-STARRS1

In recent years, wide-field sky surveys providing deep multiband imaging have presented a new path for indirectly characterizing the progenitor populations of core-collapse supernovae (SNe): systematic light-curve studies. We assemble a set of 76 grizy-band Type IIP SN light curves from Pan-STARRS1, obtained over a constant survey program of 4 yr and classified using both spectroscopy and machine-learning-based photometric techniques. We develop and apply a new Bayesian model for the full multiband evolution of each light curve in the sample. We find no evidence of a subpopulation of fast-declining explosions (historically referred to as "Type IIL" SNe). However, we identify a highly significant relation between the plateau phase decay rate and peak luminosity among our SNe IIP. These results argue in favor of a single parameter, likely determined by initial stellar mass, predominantly controlling the explosions of red supergiants. This relation could also be applied for SN cosmology, offering a standardizable candle good to an intrinsic scatter of lesssim 0.2 mag. We compare each light curve to physical models from hydrodynamic simulations to estimate progenitor initial masses and other properties of the Pan-STARRS1 Type IIP SN sample. We show that correction of systematic discrepancies between modeled and observed SN IIP light-curve properties and an expanded grid of progenitor properties are needed to enable robust progenitor inferences from multiband light-curve samples of this kind. This work will serve as a pathfinder for photometric studies of core-collapse SNe to be conducted through future wide-field transient searches.Astronom

Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Michael J. Fox Foundation for Parkinson's Research. Grant Number: ID 15015.02. NIHR Cambridge Biomedical Research Centre. Grant Number: BRC-1215-20014info:eu-repo/semantics/publishedVersio

Systematic Uncertainties Associated with the Cosmological Analysis of the First Pan-STARRS1 Type Ia Supernova Sample

We probe the systematic uncertainties from the 113 Type Ia supernovae (SN Ia) in the Pan-STARRS1 (PS1) sample along with 197 SN Ia from a combination of low-redshift surveys. The companion paper by Rest et al. (2013) describes the photometric measurements and cosmological inferences from the PS1 sample. The largest systematic uncertainty stems from the photometric calibration of the PS1 and low-z samples. We increase the sample of observed Calspec standards from 7 to 10 used to define the PS1 calibration system. The PS1 and SDSS-II calibration systems are compared and discrepancies up to ∼ 0.02 mag are recovered. We find uncertainties in the proper way to treat intrinsic colors and reddening produce differences in the recovered value of w up to 3%. We estimate masses of host galaxies of PS1 supernovae and detect an insignificant difference in distance residuals of the full sample of 0.037±0.031 mag for host galaxies with high and low masses. Assuming flatness and including systematic uncertainties in our analysis of only SNe measurements, we find w =−1.120+0.360 −0.206(Stat)+0.269 −0.291(Sys). With additional constraints from BAO, CMB (Planck) and H0 measurements, we find w = −1.166+0.072 −0.069 and Ωm = 0.280+0.013 −0.012 (statistical and systematic errors added in quadrature). Significance of the inconsistency with w = −1 depends on whether we use Planck or WMAP measurements of the CMB: wBAO+H0+SN+WMAP = −1.124+0.083−0.065.Astronom

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

Exploiting in silico modelling to enhance translation of liver cell therapies from bench to bedside

Cell therapies are emerging as promising treatments for a range of liver diseases but translational bottlenecks still remain including: securing and assessing the safe and effective delivery of cells to the disease site; ensuring successful cell engraftment and function; and preventing immunogenic responses. Here we highlight three therapies, each utilising a different cell type, at different stages in their clinical translation journey: transplantation of multipotent mesenchymal stromal/signalling cells, hepatocytes and macrophages. To overcome bottlenecks impeding clinical progression, we advocate for wider use of mechanistic in silico modelling approaches. We discuss how in silico approaches, alongside complementary experimental approaches, can enhance our understanding of the mechanisms underlying successful cell delivery and engraftment. Furthermore, such combined theoretical-experimental approaches can be exploited to develop novel therapies, address safety and efficacy challenges, bridge the gap between in vitro and in vivo model systems, and compensate for the inherent differences between animal model systems and humans. We also highlight how in silico model development can result in fewer and more targeted in vivo experiments, thereby reducing preclinical costs and experimental animal numbers and potentially accelerating translation to the clinic. The development of biologically-accurate in silico models that capture the mechanisms underpinning the behaviour of these complex systems must be reinforced by quantitative methods to assess cell survival post-transplant, and we argue that non-invasive in vivo imaging strategies should be routinely integrated into transplant studies

Targeting Focal Adhesion Kinase Suppresses the Malignant Phenotype in Rhabdomyosarcoma Cells

Despite the tremendous advances in the treatment of childhood solid tumors, rhabdomyosarcoma (RMS) continues to provide a therapeutic challenge. Children with metastatic or relapsed disease have a disease-free survival rate under 30%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumorigenesis. Signaling pathways both upstream and downstream to FAK have been found to be important in sarcoma tumorigenesis, leading us to hypothesize that FAK would be present in RMS and would impact cellular survival. In the current study, we showed that FAK was present and phosphorylated in pediatric alveolar and embryonal RMS tumor specimens and cell lines. We also examined the effects of FAK inhibition upon two RMS cell lines utilizing parallel approaches including RNAi and small molecule inhibitors. FAK inhibition resulted in decreased cellular survival, invasion, and migration and increased apoptosis. Furthermore, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse RMS xenograft model. The findings from this study will help to further our understanding of the regulation of tumorigenesis in RMS and may provide desperately needed novel therapeutic strategies for these difficult-to-treat tumors