MCPH1 is a causal gene for the neurodevelopmental disorder, human primary microcephaly (MCPH1, OMIM251200). Most pathogenic mutations are located in the N-terminal region of the gene, which encodes a BRCT domain, suggesting an important function of this domain in brain size determination. To investigate the specific function of the N-terminal BRCT domain in vivo, we generated a mouse model lacking the N’-BRCT domain of MCPH1 (referred as Mcph1-ΔBR1). These mutant mice are viable, but exhibit reduced brain size, with a thinner cortex due to a reduction of neuroprogenitor populations and premature neurogenic differentiation. Mcph1-ΔBR1 mice (both male and female) are infertile; however, almost all female mutants develop ovary tumours. Mcph1-ΔBR1 MEF cells exhibit a defect in DNA damage response and DNA repair, and show the premature chromosome condensation (PCC) phenotype, a hallmark of MCPH1 patient cells and also Mcph1 knockout cells. In comparison with Mcph1 complete knockout mice, Mcph1-ΔBR1 mice faithfully reproduce all phenotypes, indicating an essential role of the N-terminal BRCT domain for the physiological function of MCPH1 in the control of brain size and gonad development as well as in multiple cellular processes.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) frequently cause nosocomial outbreaks. To investigate these, tracing focused on patients with related CPE strains and spatiotemporal contact (e.g. contact with each other in a room or on a ward during overlapping periods) has limitations. Moreover, as widely available molecular typing methods cannot detect plasmid-related transmissions, carbapenemase gene transfer across enteric bacteria through plasmids in hospitals remains poorly understood. AIM: Because whole-genome sequencing (WGS), particularly long-read sequencing, can offer insights into bacterial relationships both at core-genome and plasmid levels, we tested its utility, using VIM-CPE as example, to investigate plasmid and CPE spread in a hospital beyond outbreaks. METHODS: We included inpatient episodes from 2018 to 2021 involving bla _VIM-bearing CPE isolates. Short- and long-read WGS data were combined with patient movement information to identify genomically related hospital-acquired VIM-CPE and putative transmission routes. RESULTS: Among 43 included inpatient episodes, 27 isolates were hospital-acquired, with 23 genomically related based on core-genome or plasmid analyses. For 14 of these 23 isolates, patient movement data supported suspected transmission events. Plasmid and core-genome level analyses revealed that most transmission events did not temporally concur, occurring over up to 33 months. Thus, conventional infection tracing methods focusing on concurrent spatiotemporal contact missed a substantial proportion of transmission events. CONCLUSION: With our findings, we advocate for broader epidemiological investigations of temporal connections if genomic data suggest relatedness. We emphasise considering plasmid transfer alongside analyses of core-genome relatedness of bacteria beyond patient contact events to study CPE and resistance spread, and guide infection control strategies.

Healthcare professionals are particularly vulnerable to mental health issues during epidemics, as evidenced by the COVID-19 crisis. German public health authorities, crucial for disease prevention, faced significant strain from chronic understaffing and resource limitations exacerbated by the pandemic. The study was designed as a cross-sectional, observational online survey. This study conducted an online needs assessment survey among heads of municipal public health authorities in Thuringia, Saxony, North Rhine-Westphalia, Bavaria, and Berlin between June and November 2023. Of the 191 contacted authorities, 74 responses (38.7%) were analyzed, focusing on professional demands, recognition, stress resilience, general life satisfaction, operational organization, and communication during the pandemic. Validated scales such as ERI, RS-13, L-1, and the COVID-19 add-on module of the COPSOQ were utilized. Statistical tests included descriptive statistics, correlation coefficients, Chi-Square tests, linear regression, T-tests, and ANOVA with a significance level set at p < 0.05. Respondents were mainly from North Rhine-Westphalia (43.3%) and Bavaria (24.3%), predominantly female (54.1%), and had a mean age of 52.7 years. The majority were medical specialists (71.9%). The RS-13 mean score was 72.66 (SD = 12.42), with 58.9% demonstrating high stress resilience. Public health degree holders showed the highest resilience. The ER-ratio indicated high effort versus reward for 96.7% of heads. Larger districts showed lower ER-ratios, suggesting resilient organizational structures. The study highlights high psychosocial workload and resilience among German public health authority heads during COVID-19, suggesting the need for optimized crisis management and scalable staffing for future pandemics and crises.