Impact of the first COVID lockdown on accident- and injury-related pediatric intensive care admissions in Germany - a multicenter study

Children’s and adolescents’ lives drastically changed during COVID lockdowns worldwide. To compare accident- and injury-related admissions to pediatric intensive care units (PICU) during the first German COVID lockdown with previous years, we conducted a retrospective multicenter study among 37 PICUs (21.5% of German PICU capacities). A total of 1444 admissions after accidents or injuries during the first lockdown period and matched periods of 2017–2019 were reported and standardized morbidity ratios (SMR) were calculated. Total PICU admissions due to accidents/injuries declined from an average of 366 to 346 (SMR 0.95 (CI 0.85–1.05)). Admissions with trauma increased from 196 to 212 (1.07 (0.93–1.23). Traffic accidents and school/kindergarten accidents decreased (0.77 (0.57–1.02 and 0.26 (0.05–0.75)), whereas household and leisure accidents increased (1.33 (1.06–1.66) and 1.34 (1.06–1.67)). Less neurosurgeries and more visceral surgeries were performed (0.69 (0.38–1.16) and 2.09 (1.19–3.39)). Non-accidental non-suicidal injuries declined (0.73 (0.42–1.17)). Suicide attempts increased in adolescent boys (1.38 (0.51–3.02)), but decreased in adolescent girls (0.56 (0.32–0.79)). In summary, changed trauma mechanisms entailed different surgeries compared to previous years. We found no evidence for an increase in child abuse cases requiring intensive care. The increase in suicide attempts among boys demands investigation

Over 40 Years of Fosmidomycin Drug Research: A Comprehensive Review and Future Opportunities

To address the continued rise of multi-drug-resistant microorganisms, the development of novel drugs with new modes of action is urgently required. While humans biosynthesize the essential isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) via the established mevalonate pathway, pathogenic protozoa and certain pathogenic eubacteria use the less well-known methylerythritol phosphate pathway for this purpose. Important pathogens using the MEP pathway are, for example, Plasmodium falciparum, Mycobacterium tuberculosis, Pseudomonas aeruginosa and Escherichia coli. The enzymes of that pathway are targets for antiinfective drugs that are exempt from target-related toxicity. 2C-Methyl-D-erythritol 4-phosphate (MEP), the second enzyme of the non-mevalonate pathway, has been established as the molecular target of fosmidomycin, an antibiotic that has so far failed to be approved as an anti-infective drug. This review describes the development and anti-infective properties of a wide range of fosmidomycin derivatives synthesized over the last four decades. Here we discuss the DXR inhibitor pharmacophore, which comprises a metal-binding group, a phosphate or phosphonate moiety and a connecting linker. Furthermore, non-fosmidomycin-based DXRi, bisubstrate inhibitors and several prodrug concepts are described. A comprehensive structure–activity relationship (SAR) of nearly all inhibitor types is presented and some novel opportunities for further drug development of DXR inhibitors are discussed

Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases

Purpose Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody–drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. Methods This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. Results In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. Conclusion HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important

Binding Modes of Reverse Fosmidomycin Analogs toward the Antimalarial Target IspC

1-Deoxy-d-xylulose 5-phosphate reductoisomerase of Plasmodium falciparum (<i>Pf</i>IspC, <i>Pf</i>Dxr), believed to be the rate-limiting enzyme of the nonmevalonate pathway of isoprenoid biosynthesis (MEP pathway), is a clinically validated antimalarial target. The enzyme is efficiently inhibited by the natural product fosmidomycin. To gain new insights into the structure activity relationships of reverse fosmidomycin analogs, several reverse analogs of fosmidomycin were synthesized and biologically evaluated. The 4-methoxyphenyl substituted derivative <b>2c</b> showed potent inhibition of <i>Pf</i>IspC as well as of P. falciparum growth and was more than one order of magnitude more active than fosmidomycin. The binding modes of three new derivatives in complex with <i>Pf</i>IspC, reduced nicotinamide adenine dinucleotide phosphate, and Mg²⁺ were determined by X-ray structure analysis. Notably, <i>Pf</i>IspC selectively binds the <i>S</i>-enantiomers of the study compounds

Divided access and the spatial polarization of housing wealth

Recent research has pointed to increasingly divided housing access across advanced economies. This reflects growing labor market inequality and rising intergenerational divides amplifying the importance of parental resources. At the same time, an increasing spatial polarization of housing markets has driven divergence between high-gain versus low-gain submarkets. This paper confronts how divided access to housing collides with growing spatial inequality in housing markets. The research turns to the Netherlands, drawing on full-population register data. First, GIS mapping exposes spatial polarization in house-value development. Second, household-level modeling demonstrates the impact of income, employment position and parental wealth in divided access to housing submarkets. Taken together, spatial polarization and differentiated access appear fundamental to driving inequalities in housing wealth accumulation

Sekundärdaten in der Diabetes-Surveillance – Kooperationsprojekte und Referenzdefinition zur administrativen Diabetesprävalenz

Neben den Gesundheitssurveys des Robert Koch-Instituts ist die zusätzliche Verwendung von Ergebnissen aus Sekundärdatenanalysen für die Zielsetzung einer wiederkehrenden und umfassenden Beschreibung des Diabetesgeschehens im Rahmen der Diabetes-Surveillance am Robert Koch-Institut unerlässlich. Die wesentlichen Gründe hierfür liegen im großen Stichprobenumfang und der routinemäßigen Erfassung der Sekundärdaten, die tief stratifizierte Auswertungen in zeitlich dichter Folge erlauben. Aufgrund der fragmentierten Datenlage sind verschiedene Sekundärdatenquellen notwendig, um die Indikatoren der vier Handlungsfelder der Diabetes-Surveillance mit Ergebnissen zu befüllen. Somit war ein Meilenstein im Projekt, die Eignung verschiedener Datenquellen auf ihre Nutzbarkeit hin zu prüfen und Analysen durchzuführen. Für diese Aufgabe wurden im Rahmen der Diabetes-Surveillance gezielt Kooperationsprojekte gefördert. In diesem Beitrag werden die Ergebnisse der Kooperationsprojekte aus den Jahren 2016 bis 2018 vorgestellt, die thematisch von der Prüfung der Eignung von Sekundärdaten bis hin zur statistischen Modellierung der Entwicklung epidemiologischer Kennzahlen reichen. Daneben wurden auf Grundlage aller rund 70 Millionen gesetzlich Krankenversicherten erste dokumentierte Prävalenzen des Typ-2-Diabetes für die Jahre 2010 und 2011 geschätzt. Um diese Prävalenzen über die Jahre vergleichbar in die Diabetes-Surveillance zu integrieren, wurde zusammen mit externer Expertise eine Referenzdefinition abgestimmt.Peer Reviewe

Secondary data in diabetes surveillance – co-operation projects and definition of references on the documented prevalence of diabetes

In addition to the Robert Koch Institute’s health surveys, analyses of secondary data are essential to successfully developing a regular and comprehensive description of the progression of diabetes as part of the Robert Koch Institute’s diabetes surveillance. Mainly, this is due to the large sample size and the fact that secondary data are routinely collected, which allows for highly stratified analyses in short time intervals. The fragmented availability of data means that various sources of secondary data are required in order to provide data for the indicators in the four fields of action for diabetes surveillance. Thus, a milestone in the project was to check the suitability of different data sources for their usability and to carry out analyses. Against this backdrop, co-operation projects were specifically funded in the context of diabetes surveillance. This article presents the results that were achieved in co-operation projects between 2016 and 2018 that focused on a range of topics: from evaluating the usability of secondary data to statistically modelling the development of epidemiological indices. Moreover, based on the data of the around 70 million people covered by statutory health insurance, an initial estimate was calculated for the documented prevalence of type 2 diabetes for the years 2010 and 2011. To comparably integrate these prevalences over the years in diabetes surveillance, a reference definition was established with external expertise.Peer Reviewe

IspC as Target for Antiinfective Drug Discovery: Synthesis, Enantiomeric Separation, and Structural Biology of Fosmidomycin Thia Isosters

The emergence and spread of multidrug-resistant pathogens are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the synthesis and properties of “reverse” thia analogs of fosmidomycin, which inhibit the first committed enzyme of a metabolic pathway that is essential for the causative agents of tuberculosis and malaria but is absent in the human host. Notably, IspC displays a high level of enantioselectivity for an α-substituted fosmidomycin derivative

Peak and Fixed-Time High-Sensitive Troponin for Prediction of Infarct Size, Impaired Left Ventricular Function, and Adverse Outcomes in Patients With First ST-Segment Elevation Myocardial Infarction Receiving Percutaneous Coronary Intervention

The clinical use of advanced imaging modalities for early determination of infarct size and prognosis is limited. As a specific indicator of myocardial necrosis, cardiac troponin T(cTnT) can be used as a surrogate measure for this purpose. The present study sought to investigate the use of peak and serial 6-hour fixed-time high-sensitive (hs) cTnT for estimation of infarct size, left ventricular (LV) function, and prognosis in consecutive patients with ST-segment elevation myocardial infarction. The infarct size was expressed as the 48-hour cumulative creatine kinase release. LV function at 3 months was assessed using the echocardiographic wall motion score index and LV ejection fraction using radionuclide ventriculography. Adverse outcomes, comprising all-cause death, implantable cardioverter-defibrillator implantation, or hospitalization for heart failure, were recorded at 1 year of follow-up. In 188 patients, the peak and all fixed-time values correlated significantly with the 48-hour cumulative creatine kinase release, wall motion score index, and LV ejection fraction. The hs-cTnT value at 24 hours demonstrated the greatest correlation (r= 0.86, r=0.47, and r=−0.59, respectively; p <0.001 for all). In the multivariate regression models adjusted for the clinical parameters, almost all were independently associated with the 48-hour cumulative creatine kinase release, wall motion score index, and LV ejection fraction, with the hs-cTnT value at 24 hours having the largest effect. Moreover, all cTnT values independently predicted adverse outcomes, again, with the hs-cTnT value at 24hours showing the largest influence (hazard ratio 3.77, 95% confidence interval 2.12 to 6.73, p<0.001). In conclusion, not only peak, but all fixed-time hs-cTnT values were associated with infarct size, LV function at 3 months, and adverse outcomes 1 year after ST-segment elevation myocardial infarction. The value 24 hours after the onset of symptoms had the closest associations with all outcomes. Therefore, serial sampling for a peak value might be redundant.Cardiolog