Staatliche Beeinflussung des Krankenstandes? Eine Untersuchung der Krankschreibungspraxis eines frei praktizierenden Arztes in Ost-Berlin nach Einführung der Ärzteberatungskommissionen in den 1950er Jahren

Hintergrund: Mit dem Anstieg des Krankenstandes in Ost-Berlin und der Deutschen Demokratischen Republik überstiegen 1952 erstmals die Ausgaben des Gesundheitswesen dessen Einnahmen; gleichzeitig verursachte der Ausfall von Arbeitskräften ökonomische Verluste. In Ost-Berlin wurden ab 1954 Ärzteberatungskommissionen (ÄBKen) eingesetzt, um einerseits die Qualität der medizinischen Versorgung der Bevölkerung zu verbessern und andererseits die Krankschreibungspraxis von Ärzt*innen zu kontrollieren. Diesen Kommissionen mussten bis 1958 alle Patient*innen mit einer Krankschreibungsdauer ≥11 Tage vorgestellt werden. Ziel der Arbeit: Durch die Auswertung von Patientenkarteikarten konnte, am Fallbeispiel des Ost-Berliner Hausarztes Georg Bresan, untersucht werden, inwieweit die ÄBKen Einfluss auf die Krankschreibungspraxis von Ärzten hatten. Methoden: Es wurden alle Patientenkarteikarten des Hausarztes Georg Bresan erfasst, die Eintragungen zwischen 1. Januar 1957 und 31. Dezember 1958 sowie 1. Januar 1960 und 31. Dezember 1961 hatten. Dabei wurden erhoben: Alter, Geschlecht, Wohnort der Patient*innen, Grund, Dauer, Häufigkeit einer Krankschreibung und Vorstellung bei einer Ärzteberatungskommission. Maximal fünf Krankschreibungen wurden pro Patient*in mit Grund und Häufigkeit erhoben. Zur einheitlichen Bezeichnung der Krankschreibungsgründe wurde das Verzeichnis der Krankheiten und Todesursachen für Zwecke der Medizinalstatistik verwendet. Ergebnisse: Ausgewertet wurden Patientenkarteikarten von 1545 Patient*innen; 961 (62%) waren weiblich. In allen vier Jahren suchten mehr Frauen als Männer die Praxis auf. Bezüglich der Krankschreibung von Patient*innen im Arbeitsalter (Patientinnen: 15-60 Jahren, Patienten: 15-65 Jahren) zeigte sich folgendes: Die Krankschreibungsquote war bei Patienten höher als bei Patientinnen. Krankschreibungen dauerten 1957/58 und 1960/61 häufiger ≥ 11 Tage. 1960/61 war dieser Anteil bei Patientinnen höher als 1957/58. Patient*innen zwischen 40-60 Jahren bzw. 40-65 Jahren wurden häufiger ≥ 11 Tage krankgeschrieben als jüngere Patient*innen. Krankschreibungen mit einer Dauer von ≥22 Tagen gab es häufiger bei Frauen zwischen 25-39 Jahren und bei Männern zwischen 40-65 Jahren. Krankschreibungen ≥ 22 Tage führten eher zur ÄBK-Vorstellung als jene mit einer Dauer von 11-21 Tagen. Patient*innen zwischen 40-60 bzw. 40-65 Jahren wurden öfter einer ÄBK vorgestellt als Patient*innen anderer Altersgruppen. Ferner wurden Patientinnen dieser Altersgruppe eher einer ÄBK vorgestellt als Patienten; häufigster Vorstellungsgrund bei einer ÄBK waren Krankschreibungen wegen Herz-Kreislauf-Erkrankungen. Zusammenfassung: Einzelne Ergebnisse der vorliegenden Untersuchung legen nahe, dass die ÄBK-Arbeit Einfluss auf die Krankschreibungspraxis von Georg Bresan hatte. Das Krankenstandsniveau in Ost-Berlin konnte jedoch, nach offiziellen Statistiken, durch die Einführung der ÄBK-Arbeit nicht gesenkt werden. Stattdessen kam es zu einer Verkürzung der Krankschreibungsdauer bei gleichzeitig steigender Anzahl von Krankschreibungen; diese Entwicklung war im untersuchten Patientenkollektiv nicht nachzuvollziehen. Aspekte, wie die Alters- und Geschlechterstruktur des Patientenkollektivs, hatten vermutlich einen größeren Einfluss auf die Krankschreibungspraxis von Georg Bresan.Background: In 1952, increased absence from work due to sick leave (SL) caused the costs of East-Berlin’s health care system to exceed its revenues. Also the absenteeism due to SL led to economic losses. In 1954, physician advisory committees (PACs) were introduced to improve the quality of health care and to exert more control over SL certifications; until 1958, all patients with SL of 11 days had to be presented to a PAC. Objective: Taking the practice of East-Berlin General Practitioner Georg Bresan as an example, it was evaluated through the analysis of his patient records whether the PACs influenced his issuing of SL certificates. Methods: All patient record cards of Georg Bresan that contained entries from Januar 1957 until Dezember 1958 and from Januar 1960 until Dezember 1961 were analyzed concerning the patient’s age, sex, place of residence as well as the duration and frequency of SL and PAC-evaluation. For the recording of SL reasons, the Verzeichnis der Krankheiten und Todesursachen für Zwecke der Medizinalstatistik was used. Results: Patient records of 1545 patients were evaluated; 961 (62%) were female. In all four years, women consulted Georg Bresan more frequently than men. Results concerning SL certifications for patients of working age (women 15-60 years, men 15-65 years): The rate of SL certifications was higher among men. SL duration 11 days was common in all years; 1960/61 the proportion of SL 11 days among women was higher than in 1957/58. Patients in working age 40 years more frequently got SL 11 days. SL 22 days was issued mostly to women between 25-39 years and men between 40-65 years. SL 22 days resulted in a PAC-evaluation more often than SL of 11-21 days. Patients in working age 40 years were more frequently evaluated by a PAC whereby women were more frequently evaluated than men. The most common reason for SL in patients who went to a PAC were Cardiovascular diseases. Conclusions: Some results of this study suggest that PACs had an influence on the work of Georg Bresan. However, aspects like the age and gender distribution of the patient collective may have been more important factors. The overall rate of absence from work due to SL in East-Berlin did not decline after the PACs were introduced; instead, the mean duration of SL showed a decline while the frequency of SL certifications rose - this development could not be seen in this study

Day care study showed no differences in long-term symptoms in children who were and were not infected during COVID-19 outbreaks

Peer Reviewe

The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5

G protein-coupled receptor kinase 5 (GRK5) is a regulator of cardiac performance and a potential therapeutic target in heart failure in the adult. Additionally, we have previously classified GRK5 as a determinant of left-right asymmetry and proper heart development using zebrafish. We thus aimed to identify GRK5 variants of functional significance by analysing 187 individuals with laterality defects (heterotaxy) that were associated with a congenital heart defect (CHD). Using Sanger sequencing we identified two moderately frequent variants in GRK5 with minor allele frequencies <10%, and seven very rare polymorphisms with minor allele frequencies <1%, two of which are novel variants. Given their evolutionarily conserved position in zebrafish, in-depth functional characterisation of four variants (p.Q41L, p.G298S, p.R304C and p.T425M) was performed. We tested the effects of these variants on normal subcellular localisation and the ability to desensitise receptor signalling as well as their ability to correct the left-right asymmetry defect upon Grk5l knockdown in zebrafish. While p.Q41L, p.R304C and p.T425M responded normally in the first two aspects, neither p.Q41L nor p.R304C were capable of rescuing the lateralisation phenotype. The fourth variant, p.G298S was identified as a complete loss-of-function variant in all assays and provides insight into the functions of GRK5

SARS-CoV-2 Transmissibility Within Day Care Centers—Study Protocol of a Prospective Analysis of Outbreaks in Germany

Introduction: Until today, the role of children in the transmission dynamics of SARS-CoV-2 and the development of the COVID-19 pandemic seems to be dynamic and is not finally resolved. The primary aim of this study is to investigate the transmission dynamics of SARS-CoV-2 in child day care centers and connected households as well as transmission-related indicators and clinical symptoms among children and adults. Methods and Analysis: COALA (“Corona outbreak-related examinations in day care centers”) is a day care center- and household-based study with a case-ascertained study design. Based on day care centers with at least one reported case of SARS-CoV-2, we include one- to six-year-old children and staff of the affected group in the day care center as well as their respective households. We visit each child's and adult's household. During the home visit we take from each household member a combined mouth and nose swab as well as a saliva sample for analysis of SARS-CoV-2-RNA by real-time reverse transcription polymerase chain reaction (real-time RT-PCR) and a capillary blood sample for a retrospective assessment of an earlier SARS-CoV-2 infection. Furthermore, information on health status, socio-demographics and COVID-19 protective measures are collected via a short telephone interview in the subsequent days. In the following 12 days, household members (or parents for their children) self-collect the same respiratory samples as described above every 3 days and a stool sample for children once. COVID-19 symptoms are documented daily in a symptom diary. Approximately 35 days after testing the index case, every participant who tested positive for SARS-CoV-2 during the study is re-visited at home for another capillary blood sample and a standardized interview. The analysis includes secondary attack rates, by age of primary case, both in the day care center and in households, as well as viral shedding dynamics, including the beginning of shedding relative to symptom onset and viral clearance. Discussion: The results contribute to a better understanding of the epidemiological and virological transmission-related indicators of SARS-CoV-2 among young children, as compared to adults and the interplay between day care and households.Peer Reviewe

SARS-CoV-2 seroconversion in children attending daycare versus adults in Germany between October 2020 and June 2021

Abstract Background: Data on seroconversion rates after SARS-CoV-2 infection in young children (<6 years) is scarce. The present study compares seroconversion rates between young children and adults and identifies associated factors. Methods: The COALA study (“Corona-outbreak-related examinations in daycare centers”) investigated transmission dynamics of SARS-CoV-2 in daycare centers and associated households (10/2020-06/2021). 114 individuals tested positive for SARS-CoV-2 through PCR either prior to the study period by health authorities or in PCR testing during the study period. Two capillary blood samples were obtained within five weeks consecutively and tested for SARS-CoV-2 IgG-antibodies (second sampling depending on positive PCR). Results from 91 participants (38 young children 1–6 years, 53 adults) were included in the analyses. Results: Seroconversion rate in young children is significantly higher than in adults (97.4% versus 66%). High viral load and longer time interval between the probable date of infection and antibody testing are associated with seroconversion. Conclusions: Our findings depict substantial development of specific antibodies in young children after SARS-CoV-2 infection. This may provide temporary protection from re-infection for young children or severe disease for this age group

Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males

Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype-phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level

Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95% CI: 2.67-4.94), CDH1 (OR: 17.04, 95% CI: 3.54-82), CHEK2 (OR: 2.93, 95% CI: 2.29-3.75), PALB2 (OR: 9.53, 95% CI: 6.25-14.51), and TP53 (OR: 7.30, 95% CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR: 1.39, 95% CI: 0.73-2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors

Deafness in LIMP2-deficient mice due to early loss of the potassium channel KCNQ1/KCNE1 in marginal cells of the stria vascularis

Our previous studies revealed a critical role of the lysosomal membrane protein LIMP2 in the regulation of membrane transport processes in the endocytic pathway. Here we show that LIMP2-deficient mice display a progressive high-frequency hearing loss and decreased otoacoustic emissions as early as 4 weeks of age. In temporal overlap to hearing impairment, fluorescence immunohistochemical studies revealed that the potassium channel KCNQ1 and its β-subunit KCNE1 were almost completely lost in the luminal part of marginal cells in the stria vascularis, affecting first higher and later also lower frequency processing cochlear turns. Concomitant with this, the expression of megalin, a multiligand endocytic receptor, was reduced in luminal surfaces of marginal cells within the stria vascularis. KCNQ1/KCNE1 and megalin were also lost in the dark cells of the vestibular system. Although LIMP2 is normally expressed in all cells of the stria vascularis, in the organ of Corti and cochlear neurons, the lack of LIMP2 preferentially caused a loss of KCNQ1/KCNE1 and megalin, and structural changes were only seen months later, indicating that these proteins are highly sensitive to disturbances in the lysosomal pathway. The spatio-temporal correlation of the loss of KCNQ1/KCNE1 surface expression and loss of hearing thresholds supports the notion that the decline of functional KCNQ1/KCNE1 is likely to be the primary cause of the hearing loss. Our findings suggest an important role for LIMP2 in the control of the localization and the level of apically expressed membrane proteins such as KCNQ1, KCNE1 and megalin in the stria vascularis