[After the pandemic is before the pandemic: And how interdisciplinary research can help here]. / Nach der Pandemie ist vor der Pandemie: Und wie interdisziplinäre Forschung hier helfen kann.

Aviation is among the social sectors most impacted by the COVID-19 pandemic, and at the same time has contributed to the rapid global spread of the SARS-CoV-2 virus. SARS-CoV-2 is one of the coronaviruses that have led to outbreaks such as MERS-CoV in the past. This group of pathogens, as well as others that may be unknown at this time, will continue to challenge our society in the future. In order to be able to react better, a research training group was established at DLR in cooperation with 6 institutes, which will develop interdisciplinary approaches to researching and combating current and future pandemics. Engineers, physicists, software developers, biologists and physicians are working closely together on new concepts and the development of interdisciplinary knowledge in order to better control and contain future pandemics and to be able to react in a more targeted manner. One focus is the reduction of germ contamination in airplanes but also in other means of public transport such as buses and trains. In this review, we provide an overview of the baseline situation and possible approaches to address future pandemic challenges.

Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500).

ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.

Neonatal and postneonatal tetanus at a referral hospital in Kamsar, Guinea: a retrospective audit of paediatric records (2014-2018).

BACKGROUND: Tetanus is a vaccine-preventable disease caused by the bacterium Clostridium tetani. In 2018, all of Guinea was considered to be at risk of the disease and the country is currently in the elimination phase. METHODS: A 5-y audit (1 January 2014-31 December 2018) of all admissions to the neonatal and general paediatric units of Kamsar Hospital (Western Guinea) was undertaken to identify cases of neonatal tetanus (NNT) and postneonatal tetanus (PNNT). RESULTS: There were 5670 admissions during the study period, of which 39 (0.7%) were due to tetanus (22 NNT and 17 PNNT). Among NNT patients, the bacterial entry site was the umbilical cord (n=20) or wound following circumcision (n=2). For PNNT, the entry site was surface wound (n=12), limb fracture (n=1) or could not be established (n=4). A majority of the patients (36/39, 92.3%) were born to unvaccinated mothers or those who received suboptimal vaccination during pregnancy. Overall, 21 (53.8%) children died within 7 d of admission with a higher mortality observed among neonates (16/22, 72.7%) compared with postneonates (5/17, 29.4%). CONCLUSIONS: Tetanus was a rare cause of admission at Kamsar Hospital with a very high case fatality rate. The disease primarily occurred among children born to mothers who were unvaccinated/inadequately vaccinated during pregnancy.

Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306.

PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound 1 was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.

Multiple criteria decision analysis approach to consider therapeutic innovations in the emergency department: The methoxyflurane organizational impact in acute trauma pain.

BACKGROUND: Acute trauma pain is poorly managed in the emergency department (ED). The reasons are partly organizational: ED crowding and rare trauma care pathways contribute to oligoanalgesia. Anticipating the organizational impact of an innovative care procedure might facilitate the decision-making process and help to optimize pain management. METHODS: We used a multiple criteria decision analysis (MCDA) approach to consider the organizational impact of methoxyflurane (self-administered) in the ED, introduced alone or supported by a trauma care pathway. A MCDA experiment was designed for this specific context, 8 experts in emergency trauma care pathways (leading physicians and pharmacists working in French urban tertiary hospitals) were recruited. The study involved four steps: (i) Selection of organizational criteria for evaluating the innovation's impact; (ii) assessment of the relative weight of each criterion; (iii) choice of appropriate scenarios for exploring the organizational impact of MEOX under various contexts; and (iv) software-assisted simulation based on pairwise comparisons of the scenarios. The final outcome measure was the expected overall organizational impact of methoxyflurane on a 0-to-100 scale (score >50: positive impact). RESULTS: Nine organizational criteria were selected. "Mean length of stay in the ED" was the most weighted. Methoxyflurane alone obtained 59 as a total score, with a putative positive impact for eight criteria, and a neutral effect on one. When a trauma care pathway was introduced concomitantly, the impact of methoxyflurane was greater overall (score: 75) and for each individual criterion. CONCLUSIONS: Our model highlighted the putative positive organizational impact of methoxyflurane in the ED-particularly when supported by a trauma care pathway-and the relevance of expert consensus in this particular pharmacoeconomic context. The MCDA approach could be extended to other research fields and healthcare challenges in emergency medicine.

[Epidemiological and clinical profile of children with Coronavirus disease (COVID-19) at the Center for the Treatment of Epidemics and Infection Prevention (CTEIP) of the University Hospital of Donka in Conakry]. / Profil épidémiologique et clinique des enfants atteints de la maladie à coronavirus (COVID-19) au Centre de Traitement des Epidémies et Prévention des Infections (CTEPI) du CHU de Donka à Conakry.

COVID-19 is caused by SARS-CoV-2 virus, which is genetically similar to severe acute respiratory syndrome (SARS) virus. In pediatrics, it has a benign clinical course. Since the outbreak of COVID-19 pandemic in Guinea, whose epicenter was Conakry, pediatric cases have been reported at the CTEIP in Donka. The purpose of this study was to determine their epidemiological profile. We conducted a descriptive cross-sectional study of children aged 0-16 years admitted to the CTEIP, Donka, over a period of four months. Out of 7308 patients, coming predominantly from 5 communes of Conakry and hospitalized in the CTEPI, 189 were aged between 0 and 16 years (2 .59%). The majority of patients were within the age-group 0-4-years (38.62%) with a sex-ratio (F/M) of 1.52; 62.96% were students, 70% of children lived in Conakry, 28.57% of mothers were traders and contact persons (39.68%); 37.57% of fathers were civil servants, 2.65% of children had a history of sickle cell disease and 1.59% had allergic rhinitis. Asymptomatic patients accounted for 52.38% of cases and diagnosed patients were 74.6%. Symptoms included fever, rhinorrhea, headache, cough, abdominal pain, sneezing, diarrhea, physical asthenia. The incidence of COVID-19 among children hospitalized in the CTEIP of Donka is low. Children aged 5 years and older are more affected and nearly 50% are asymptomatic. Common symptoms are fever, headache, rhinorrhea, cough, abdominal pain, sneezing, diarrhea, physical asthenia.