COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. ...PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.
Since the beginning of the COVID -19 pandemic, many contact sport teams are facing major challenges to safely continue training and competition. We present the design and implementation of a ...structured monitoring concept for the Austrian national football league. 146 professional players from five clubs of the professional Austrian football league were monitored for a period of 12 weeks. Subjective health parameters, PCR- test results and data obtained from a geo-tracking app were collected. Simulations modelling the consequences of a COVID-19 case with increasing reproduction number were computed. No COVID -19 infection occurred during the observation period in the players. Infections in the nearer surroundings lead to increased perceived risk of infection. Geo tracking was particularly hindered due to technical problems and reluctance of users. Simulation models suggested a hypothetical shut-down of all training and competition activities. A structured monitoring concept can help to continue contact sports safely in times of a pandemic. Cooperation of all involved is essential. Trial registration: ID: DRKS00022166 15/6/2020 https://www.who.int/ictrp/search/en/ .
Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a ...disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid > 5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives.
Objective
Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) ...with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used 11CUCB‐J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity.
Methods
Eleven participants with clinically probable bvFTD and 25 age‐ and sex‐matched healthy controls were included. Participants underwent dynamic 11CUCB‐J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared 11CUCB‐J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected 11CUCB‐J binding potential from regions of interest (ROIs).
Results
Patients with bvFTD showed severe synaptic loss compared to controls. 11CUCB‐J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI‐based analyses mirrored the voxelwise results.
Interpretation
In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. 11CUCB‐J PET could support translational studies and experimental medicine strategies for new disease‐modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142–154
RESUMEN Pimelodus grosskopfii, es un Siluriforme importante en la pesca continental en Colombia y de interés en la acuicultura. La presente investigación tuvo como objetivo clonar y determinar las ...secuencias codificantes de las subunidades GP-α y LHβ de la gonadotropina luteinizante de esta especie. Para lograr lo anterior, el ARN total de glándulas pituitarias fue extraído y se realizó síntesis de cDNA. Los productos de PCR purificados de GP-α y LHβ fueron ligados en pJET1.2/blunt® seguido de la transformación de Escherichia coli DH5α® y posterior secuenciación de fragm&os de interés. El marco abierto de lectura de las subunidades GP-α y LHβ fue de 351 pb (116 aminoácidos) y 423 pb (140 aminoácidos), respectivam&e. Se encontró una alta homología (aminoácidos) en la subunidad GP-α con otras familias de Siluriformes (87-99%) y menor homología con órdenes como Perciformes, Salmoniformes y Cypriniformes (66-90%). De igual manera para la subunidad LHβ, la homología (aminoácidos) fue alta al interior del orden Siluriformes (91-97%) y menor con otros ordenes (65-86%). Los resultados obtenidos en el presnte estudio ofrecen información básica sobre las secuencias de las gonadotropinas en bagres neotropicales y pueden ser utilizados para el desarrollo de hormonas recombinantes para optimizar el control reproductivo en P. grosskopfii.
Aims
Penumbral selection is best‐evidence practice for thrombectomy in the 6‐24 hour window. Moreover, it helps to identify the best responders to thrombolysis. Multimodal computed tomography (mCT) ...at the primary centre—including noncontrast CT, CT perfusion, and CT angiography—may enhance reperfusion therapy decision‐making. We developed a network with five spoke primary stroke sites and assessed safety, feasibility, and influence of mCT in rural hospitals on decision‐making for thrombolysis.
Methods
Consecutive patients assessed via telemedicine from April 2013 to June 2018. Clinical outcomes were measured, and decision‐making compared using theoretical models for reperfusion therapy applied without mCT guidance. Symptomatic intracranial hemorrhage (sICH) was assessed according to Safe Implementation of Treatments in Stroke Thrombolysis Registry criteria.
Results
A total of 334 patients were assessed, 240 received mCT, 58 were thrombolysed (24.2%). The mean age of thrombolysed patients was 70 years, median baseline National Institutes of Health Stroke Scale was 10 (IQR 7‐18) and 23 (39.7%) had a large vessel occlusion. 1.7% had sICH and 3.5% parenchymal hematoma. Three months poststroke, 55% were independent, compared with 70% in the non‐thrombolysed group.
Conclusion
Implementation of CTP in rural centers was feasible and led to high thrombolysis rates with low rates of sICH.
Background. The etiologic inference of identifying a pathogen in the upper respiratory tract (URT) of children with pneumonia is unclear. To determine if viral load could provide evidence of ...causality of pneumonia, we compared viral load in the URT of children with World Health Organization–defined severe and very severe pneumonia and age-matched community controls. Methods. In the 9 developing country sites, nasopharyngeal/oropharyngeal swabs from children with and without pneumonia were tested using quantitative real-time polymerase chain reaction for 17 viruses. The association of viral load with case status was evaluated using logistic regression. Receiver operating characteristic (ROC) curves were constructed to determine optimal discriminatory viral load cutoffs. Viral load density distributions were plotted. Results. The mean viral load was higher in cases than controls for 7 viruses. However, there was substantial overlap in viral load distribution of cases and controls for all viruses. ROC curves to determine the optimal viral load cutoff produced an area under the curve of <0.80 for all viruses, suggesting poor to fair discrimination between cases and controls. Fatal and very severe pneumonia cases did not have higher viral load than less severe cases for most viruses. Conclusions. Although we found higher viral loads among pneumonia cases than controls for some viruses, the utility in using viral load of URT specimens to define viral pneumonia was equivocal. Our analysis was limited by lack of a gold standard for viral pneumonia.
Background: Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), continues to pose a significant clinical and scientific challenge. The most significant finding of recent years is ...that PDAC tumours harbour their specific microbiome, which differs amongst tumour entities and is distinct from healthy tissue. This review aims to evaluate and summarise all PDAC studies that have used the next-generation technique, 16S rRNA gene amplicon sequencing within each bodily compartment. As well as establishing a causal relationship between PDAC and the microbiome. Materials and Methods: This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. A comprehensive search strategy was designed, and 1727 studies were analysed. Results: In total, 38 studies were selected for qualitative analysis and summarised significant PDAC bacterial signatures. Despite the growing amount of data provided, we are not able to state a universal 16S rRNA gene microbial signature that can be used for PDAC screening. This is most certainly due to the heterogeneity of the presentation of results, lack of available datasets and the intrinsic selection bias between studies. Conclusion: Several key studies have begun to shed light on causality and the influence the microbiome constituents and their produced metabolites could play in tumorigenesis and influencing outcomes. The challenge in this field is to shape the available microbial data into targetable signatures. Making sequenced data readily available is critical, coupled with the coordinated standardisation of data and the need for consensus guidelines in studies investigating the microbiome in PDAC.
Studies report that the microstructural integrity of the uncinate fasciculus (UF; connecting the anterior temporal lobe to the orbitofrontal cortex) is abnormal in adults with psychopathy and ...children with conduct problems (CP), especially those with high callous-unemotional (CU) traits. However, it is unknown if these abnormalities are 'fixed' or 'reversible'. Therefore, we tested the hypothesis that a reduction in CP symptoms, following a parenting intervention, would be associated with altered microstructural integrity in the UF. Using diffusion tensor imaging tractography we studied microstructural differences (mean diffusivity (MD) and radial diffusivity (RD)) in the UF of 43 typically developing (TD) and 67 boys with CP before and after a 14-week parenting intervention. We also assessed whether clinical response in CP symptoms or CU traits explained changes in microstructure following the intervention. Prior to intervention, measures of MD and RD in the UF were increased in CP compared to TD boys. Following intervention, we found that the CP group had a significant reduction in RD and MD. Further, these microstructural changes were driven by the group of children whose CU traits improved (but not CP symptoms as hypothesized). No significant microstructural changes were observed in the TD group. Our findings suggest, for the first time, that microstructural abnormalities in the brains of children with CP may be reversible following parenting intervention.
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