Differential molecular response in mice and human thymocytes exposed to a combined-dose radiation regime

In the quest for more effective radiation treatment options that can improve both cell killing and healthy tissue recovery, combined radiation therapies are lately in the spotlight. The molecular response to a combined radiation regime where exposure to an initial low dose (priming dose) of ionizing radiation is administered prior to a subsequent higher radiation dose (challenging dose) after a given latency period have not been thoroughly explored. In this study we report on the differential response to either a combined radiation regime or a single challenging dose both in mouse in vivo and in human ex vivo thymocytes. A differential cell cycle response including an increase in the subG1 fraction on cells exposed to the combined regime was found. Together with this, a differential protein expression profiling in several pathways including cell cycle control (ATM, TP53, p21CDKN1A), damage response (γH2AX) and cell death pathways such as apoptosis (Cleaved Caspase-3, PARP1, PKCδ and H3T45ph) and ferroptosis (xCT/GPX4) was demonstrated. This study also shows the epigenetic regulation following a combined regime that alters the expression of chromatin modifiers such as DNMTs (DNMT1, DNMT2, DNMT3A, DNMT3B, DNMT3L) and glycosylases (MBD4 and TDG). Furthermore, a study of the underlying cellular status six hours after the priming dose alone showed evidence of retained modifications on the molecular and epigenetic pathways suggesting that the priming dose infers a “radiation awareness phenotype” to the thymocytes, a sensitization key to the differential response seen after the second hit with the challenging dose. These data suggest that combined-dose radiation regimes could be more efficient at making cells respond to radiation and it would be interesting to further investigate how can these schemes be of use to potential new radiation therapie

Short-term prognosis of polypharmacy in elderly patients treated in emergency departments: results from the EDEN project

Background: Polypharmacy is a growing phenomenon among elderly individuals. However, there is little information about the frequency of polypharmacy among the elderly population treated in emergency departments (EDs) and its prognostic effect. This study aims to determine the prevalence and short-term prognostic effect of polypharmacy in elderly patients treated in EDs. Methods: A retrospective analysis of the Emergency Department Elderly in Needs (EDEN) project's cohort was performed. This registry included all elderly patients who attended 52 Spanish EDs for any condition. Mild and severe polypharmacy was defined as the use of 5-9 drugs and >10 drugs, respectively. The assessed outcomes were ED revisits, hospital readmissions, and mortality 30 days after discharge. Crude and adjusted logistic regression analyses, including the patient's comorbidities, were performed. Results: A total of 25,557 patients were evaluated [mean age: 78 (IQR: 71-84) years]; 10,534 (41.2%) and 5678 (22.2%) patients presented with mild and severe polypharmacy, respectively. In the adjusted analysis, mild polypharmacy and severe polypharmacy were associated with an increase in ED revisits [odds ratio (OR) 1.13 (95% confidence interval (CI): 1.04-1.23) and 1.38 (95% CI: 1.24-1.51)] and hospital readmissions [OR 1.18 (95% CI: 1.04-1.35) and 1.36 (95% CI: 1.16-1.60)], respectively, compared to non-polypharmacy. Mild and severe polypharmacy were not associated with increased 30-day mortality [OR 1.05 (95% CI: 0.89-2.26) and OR 0.89 (95% CI: 0.72-1.12)], respectively. Conclusion: Polypharmacy was common among the elderly treated in EDs and associated with increased risks of ED revisits and hospital readmissions 10 drugs. In these patients comorbidities were associated with an increase in the number of drugs. In the patients with severe polypharmacy (>10 drugs), diuretics were the most frequently drugs prescribed, followed by antihypertensives and statins. The results obtained indicate that polypharmacy is a frequent phenomenon among the elderly population treated in Emergency departments, being antihypertensives the most frequently used drugs in this population. Those patients who takes >10 drugs have a higher risk of new visits to the emergency room and hospital readmissions in short term period

ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19

The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use