Three dimensional adaptive mesh refinement on a spherical shell for atmospheric models with lagrangian coordinates

One of the most important advances needed in global climate models is the development of atmospheric General Circulation Models (GCMs) that can reliably treat convection. Such GCMs require high resolution in local convectively active regions, both in the horizontal and vertical directions. During previous research we have developed an Adaptive Mesh Refinement (AMR) dynamical core that can adapt its grid resolution horizontally. Our approach utilizes a finite volume numerical representation of the partial differential equations with floating Lagrangian vertical coordinates and requires resolving dynamical processes on small spatial scales. For the latter it uses a newly developed general-purpose library, which facilitates 3D block-structured AMR on spherical grids. The library manages neighbor information as the blocks adapt, and handles the parallel communication and load balancing, freeing the user to concentrate on the scientific modeling aspects of their code. In particular, this library defines and manages adaptive blocks on the sphere, provides user interfaces for interpolation routines and supports the communication and load-balancing aspects for parallel applications. We have successfully tested the library in a 2-D (longitude-latitude) implementation. During the past year, we have extended the library to treat adaptive mesh refinement in the vertical direction. Preliminary results are discussed. This research project is characterized by an interdisciplinary approach involving atmospheric science, computer science and mathematical/numerical aspects. The work is done in close collaboration between the Atmospheric Science, Computer Science and Aerospace Engineering Departments at the University of Michigan and NOAA GFDL.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58181/2/jpconf7_78_012072.pd

Surgical outcomes after neoadjuvant ablative dose radiation among patients with borderline resectable and locally advanced pancreas cancer from the multi-institutional phase 2 Stereotactic MR-Guided Adaptive Radiation Therapy (SMART) trial

Background: Acute grade 3+ toxicity was rare in the multi-institutional phase 2 stereotactic MR-guided on-table adaptive radiation therapy (SMART) trial (NCT03621644) for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC). Surgery may be considered after ablative SMART although the feasibility and safety of this is not well understood. Postoperative outcomes of the subset of patients in the SMART trial are examined here. Methods: Trial eligibility included BRPC or LAPC without metastases after a minimum of 3 months of induction chemotherapy. All patients received SMART prescribed to 50 Gy in 5 fractions using an integrated 0.35T MR-radiation therapy device equipped with cutting edge soft tissue tracking, automatic beam gating, and on-table adaptive replanning. Surgery was permitted after SMART, often after multi-disciplinary review. Perioperative details and postoperative outcomes, including morbidity, mortality, and overall survival (OS), were analyzed. Results: 136 patients across 13 sites were enrolled between 2019-2022. 44 patients (32.4%) had surgery after SMART (33 BRPC, 11 LAPC). Surgical procedures included pancreaticoduodenectomy (81.8%), distal pancreatectomy with splenectomy (9.1%), total pancreatectomy (6.8%), and distal pancreatectomy with celiac axis resection (2.3%). 52.3% required vascular resection/reconstruction, a majority of which were venous resections (65.2%), with a smaller proportion needing both venous/ arterial (21.7%), or arterial (13%). Surgery was performed after a mean 51.4 ± 52.8 days from SMART. Postoperative hospitalization was 10.5 ± 8.9 days. Nine patients (20.5%) had Clavien-Dindo complications of grade III or higher; 3 deaths resulted from post-pancreatectomy hemorrhage in patients who had portal vein resection. One-year OS in patients who had surgery versus no surgery after SMART was 66% vs. 43%, respectively. Conclusions: These are the first prospectively evaluated surgical outcomes after 5-fraction ablative SMART for BRPC/LAPC. The rate of surgery for BRPC compares favorably to radiated patients on the Alliance A021501 trial. Despite the use of ablative radiation dose and frequent need for vascular resection, the incidence of serious surgical complications was similar to what is reported after non-ablative radiation therapy. However, several deaths occurred after surgery and we therefore we urge caution when considering surgery after ablative radiation therapy. Further analysis of other variables such as the time between SMART and surgery, approaches to vascular resections, and discrete events such as delayed gastric emptying, operative duration, and post-operative pancreatic fistula are needed to better understand the surgical morbidity seen in these patients

Intracellular CD24 disrupts the ARF–NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation

CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels. These data provide a general mechanism for functional inactivation of ARF and reveal an important cellular context for genetic and viral inactivation of TP53. P53 is a tumour suppressor that is frequently mutated or downregulated in cancer. Here, Wang et al. show that CD24, a molecule frequently overexpressed in cancer, promotes p53 degradation by disrupting a regulatory ARF–MDM2 interaction, and silencing CD24 prevents the downregulation of p53

Novel Structurally Designed Vaccine for S. aureus α-Hemolysin: Protection against Bacteremia and Pneumonia

Staphylococcus aureus (S. aureus) is a human pathogen associated with skin and soft tissue infections (SSTI) and life threatening sepsis and pneumonia. Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism. S. aureus alpha-hemolysin (Hla) is a pore-forming toxin expressed by most S. aureus strains and reported to play a key role in the pathogenesis of SSTI and pneumonia. Here we report a novel recombinant subunit vaccine candidate for Hla, rationally designed based on the heptameric crystal structure. This vaccine candidate, denoted AT-62aa, was tested in pneumonia and bacteremia infection models using S. aureus strain Newman and the pandemic strain USA300 (LAC). Significant protection from lethal bacteremia/sepsis and pneumonia was observed upon vaccination with AT-62aa along with a Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) that is currently in clinical trials. Passive transfer of rabbit immunoglobulin against AT-62aa (AT62-IgG) protected mice against intraperitoneal and intranasal challenge with USA300 and produced significant reduction in bacterial burden in blood, spleen, kidney, and lungs. Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection. AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action. This remarkable efficacy makes this Hla-based vaccine a prime candidate for inclusion in future multivalent S. aureus vaccine. Furthermore, identification of protective epitopes within AT-62aa could lead to novel immunotherapy for S. aureus infection

A plea for equitable global access to COVID‐19 diagnostics, vaccination and therapy: The NeuroCOVID‐19 Task Force of the European Academy of Neurology

Coronavirus disease 2019 (COVID‐19), a multi‐organ disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), continues to challenge health and care systems around the globe. The pandemic has disrupted acute neurology services and routine patient care and has impacted the clinical course in patients with chronic neurological disease. COVID‐19 appears to have exposed inequalities of societies and healthcare systems and had a disproportionate impact on already vulnerable communities. The next challenge will be to set up initiatives to stop disparities in all aspects related to COVID‐19. From the medical perspective, there is a need to consider inequalities in prevention, treatment and long‐term consequences. Some of the issues of direct relevance to neurologists are summarised. With this appraisal, the European Academy of Neurology NeuroCOVID‐19 Task Force intends to raise awareness of the potential impact of COVID‐19 on inequalities in healthcare and calls for action to prevent disparity at individual, national and supranational levels

Management of intra-abdominal infections : recommendations by the WSES 2016 consensus conference

This paper reports on the consensus conference on the management of intra-abdominal infections (IAIs) which was held on July 23, 2016, in Dublin, Ireland, as a part of the annual World Society of Emergency Surgery (WSES) meeting. This document covers all aspects of the management of IAIs. The Grading of Recommendations Assessment, Development and Evaluation recommendation is used, and this document represents the executive summary of the consensus conference findings.Peer reviewe

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease