Low frequency dynamics of the nitrogenase MoFe protein via femtosecond pump probe spectroscopy - Observation of a candidate promoting vibration

We have used femtosecond pump-probe spectroscopy (FPPS) to study the FeMo-cofactor within the nitrogenase (N2ase) MoFe protein from Azotobacter vinelandii. A sub-20-fs visible laser pulse was used to pump the sample to an excited electronic state, and a second sub-10-fs pulse was used to probe changes in transmission as a function of probe wavelength and delay time. The excited protein relaxes to the ground state with a ~1.2ps time constant. With the short laser pulse we coherently excited the vibrational modes associated with the FeMo-cofactor active site, which are then observed in the time domain. Superimposed on the relaxation dynamics, we distinguished a variety of oscillation frequencies with the strongest band peaks at ~84, 116, 189, and 226cm(-1). Comparison with data from nuclear resonance vibrational spectroscopy (NRVS) shows that the latter pair of signals comes predominantly from the FeMo-cofactor. The frequencies obtained from the FPPS experiment were interpreted with normal mode calculations using both an empirical force field (EFF) and density functional theory (DFT). The FPPS data were also compared with the first reported resonance Raman (RR) spectrum of the N2ase MoFe protein. This approach allows us to outline and assign vibrational modes having relevance to the catalytic activity of N2ase. In particular, the 226cm(-1) band is assigned as a potential 'promoting vibration' in the H-atom transfer (or proton-coupled electron transfer) processes that are an essential feature of N2ase catalysis. The results demonstrate that high-quality room-temperature solution data can be obtained on the MoFe protein by the FPPS technique and that these data provide added insight to the motions and possible operation of this protein and its catalytic prosthetic group

Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations: an overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO)

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included

Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort

Objectives:We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies.Methods: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries.Results: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT(> MIC) (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving beta-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P=0.012]. Additionally, in patients with a SOFA score of >= 9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P=0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P=0.025].Conclusions: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections

Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials

Background Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. Methods In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 mu g or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. Findings In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. Interpretation Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients

Variation in the COVID-19 infection-fatality ratio by age, time, and geography during the pre-vaccine era: a systematic analysis

Background The infection-fatality ratio (IFR) is a metric that quantifies the likelihood of an individual dying once infected with a pathogen. Understanding the determinants of IFR variation for COVID-19, the disease caused by the SARS-CoV-2 virus, has direct implications for mitigation efforts with respect to clinical practice, non-pharmaceutical interventions, and the prioritisation of risk groups for targeted vaccine delivery. The IFR is also a crucial parameter in COVID-19 dynamic transmission models, providing a way to convert a population's mortality rate into an estimate of infections.Methods We estimated age-specific and all-age IFR by matching seroprevalence surveys to total COVID-19 mortality rates in a population. The term total COVID-19 mortality refers to an estimate of the total number of deaths directly attributable to COVID-19. After applying exclusion criteria to 5131 seroprevalence surveys, the IFR analyses were informed by 2073 all-age surveys and 718 age-specific surveys (3012 age-specific observations). When seroprevalence was reported by age group, we split total COVID-19 mortality into corresponding age groups using a Bayesian hierarchical model to characterise the non-linear age pattern of reported deaths for a given location. To remove the impact of vaccines on the estimated IFR age pattern, we excluded age-specific observations of seroprevalence and deaths that occurred after vaccines were introduced in a location. We estimated age-specific IFR with a non-linear meta-regression and used the resulting age pattern to standardise all-age IFR observations to the global age distribution. All IFR observations were adjusted for baseline and waning antibody-test sensitivity. We then modelled age-standardised IFR as a function of time, geography, and an ensemble of 100 of the top-performing covariate sets. The covariates included seven clinical predictors (eg, age-standardised obesity prevalence) and two measures of health system performance. Final estimates for 190 countries and territories, as well as subnational locations in 11 countries and territories, were obtained by predicting age-standardised IFR conditional on covariates and reversing the age standardisation.Findings We report IFR estimates for April 15, 2020, to January 1, 2021, the period before the introduction of vaccines and widespread evolution of variants. We found substantial heterogeneity in the IFR by age, location, and time. Age-specific IFR estimates form a J shape, with the lowest IFR occurring at age 7 years (0-0023%, 95% uncertainty interval [UI] 0-0015-0-0039) and increasing exponentially through ages 30 years (0-0573%, 0-0418-0-0870), 60 years (1-0035%, 0-7002-1-5727), and 90 years (20-3292%, 14-6888-28-9754). The countries with the highest IFR on July 15, 2020, were Portugal (2-085%, 0-946-4-395), Monaco (1-778%, 1-265-2-915), Japan (1-750%, 1-302-2-690), Spain (1-710%, 0-991-2-718), and Greece (1-637%, 1-155-2-678). All-age IFR varied by a factor of more than 30 among 190 countries and territories.After age standardisation, the countries with the highest IFR on July 15, 2020, were Peru (0-911%, 0-636-1-538), Portugal (0-850%, 0-386-1-793), Oman (0-762%, 0-381-1-399), Spain (0-751%, 0-435-1-193), and Mexico (0-717%, 0-426-1-404). Subnational locations with high IFRs also included hotspots in the UK and southern and eastern states of the USA. Sub-Saharan African countries and Asian countries generally had the lowest all-age and age-standardised IFRs. Population age structure accounted for 74% of logit-scale variation in IFRs estimated for 39 in-sample countries on July 15, 2020. A post-hoc analysis showed that high rates of transmission in the care home population might account for higher IFRs in some locations. Among all countries and territories, we found that the median IFR decreased from 0-466% (interquartile range 0-223-0-840) to 0-314% (0-143-0-551) between April 15, 2020, and Jan 1, 2021.Interpretation Estimating the IFR for global populations helps to identify relative vulnerabilities to COVID-19. Information about how IFR varies by age, time, and location informs clinical practice and non-pharmaceutical interventions like physical distancing measures, and underpins vaccine risk stratification. IFR and mortality risk form a J shape with respect to age, which previous research, such as that by Glynn and Moss in 2020, has identified to be a common pattern among infectious diseases. Understanding the experience of a population with COVID-19 mortality requires consideration for local factors; IFRs varied by a factor of more than 30 among 190 countries and territories in this analysis. In particular, the presence of elevated age-standardised IFRs in countries with well resourced health-care systems indicates that factors beyond health-care capacity are important. Potential extenuating circumstances include outbreaks among care home residents, variable burdens of severe cases, and the population prevalence of comorbid conditions that increase the severity of COVID-19 disease. During the pre-vaccine period, the estimated 33% decrease in median IFR over 8 months suggests that treatment for COVID-19 has improved over time. Estimating IFR for the pre-vaccine era provides an important baseline for describing the progression of COVID-19 mortality patterns.Funding Bill &amp; Melinda Gates Foundation, J Stanton, T Gillespie, and J and E Nordstrom Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

Scaling the state: Egypt in the third millennium BC

Discussions of the early Egyptian state suffer from a weak consideration of scale. Egyptian archaeologists derive their arguments primarily from evidence of court cemeteries, elite tombs, and monuments of royal display. The material informs the analysis of kingship, early writing, and administration but it remains obscure how the core of the early Pharaonic state was embedded in the territory it claimed to administer. This paper suggests that the relationship between centre and hinterland is key for scaling the Egyptian state of the Old Kingdom (ca. 2,700-2,200 BC). Initially, central administration imagines Egypt using models at variance with provincial practice. The end of the Old Kingdom demarcates not the collapse, but the beginning of a large-scale state characterized by the coalescence of central and local models

Population genetics of sexual conflict in the genomic era

Sexual conflict occurs when selection acts in opposing directions on males and females. Case studies in both vertebrates and invertebrates indicate that sexual conflict maintains genetic diversity through balancing selection, which might explain why many populations show more genetic variation than expected. Recent population genomic approaches based on different measures of balancing selection have suggested that sexual conflict can arise over survival, not just reproductive fitness as previously thought. A fuller understanding of sexual conflict will provide insight into its contribution to adaptive evolution and will reveal the constraints it might impose on populations

SSRI’s en depressieve klachten bij schizofrenie : een systematische review

BACKGROUND: Patients with schizophrenia frequently have depressive symptoms. Current guidelines do not provide specific recommendations regarding the treatment of these symptoms, nor do they mention the role that selective serotonin reuptake inhibitors (ssris) can play in the treatment. AIM: To investigate whether ssris are more effective than placebo in treating depressive symptoms in patients with schizophrenia. METHOD: We searched the literature systematically using PubMed, embase, Cochrane Library and Psycinfo. We selected articles on the basis of inclusion and exclusion criteria and the methodologies used and compared the severity of patients symptoms before and after treatment. RESULTS: We found only four published studies of randomised, double blind, placebo-controlled trials. These showed that an ssri was significantly more effective than a placebo (the difference being 0.4 - 6.7 points on the Hamilton Depression Rating Scale and 0.2 - 2.6 on the Calgary Depression Scale for Schizophrenia). CONCLUSION: There are indications that ssris are effective for the treatment of depressive symptoms in patients with schizophrenia. However, the total sample size was limited and individual studies had several methodological limitations

SSRI’s en depressieve klachten bij schizofrenie : een systematische review

BACKGROUND: Patients with schizophrenia frequently have depressive symptoms. Current guidelines do not provide specific recommendations regarding the treatment of these symptoms, nor do they mention the role that selective serotonin reuptake inhibitors (ssris) can play in the treatment. AIM: To investigate whether ssris are more effective than placebo in treating depressive symptoms in patients with schizophrenia. METHOD: We searched the literature systematically using PubMed, embase, Cochrane Library and Psycinfo. We selected articles on the basis of inclusion and exclusion criteria and the methodologies used and compared the severity of patients symptoms before and after treatment. RESULTS: We found only four published studies of randomised, double blind, placebo-controlled trials. These showed that an ssri was significantly more effective than a placebo (the difference being 0.4 - 6.7 points on the Hamilton Depression Rating Scale and 0.2 - 2.6 on the Calgary Depression Scale for Schizophrenia). CONCLUSION: There are indications that ssris are effective for the treatment of depressive symptoms in patients with schizophrenia. However, the total sample size was limited and individual studies had several methodological limitations