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Yong Du,1 Jens Baumert,1 Stefan Damerow,1 Alexander Rommel,1 Hannelore Neuhauser,1,2 Christin Heidemann1 1Department of Epidemiology and Health Monitoring, Robert Koch Institute, Berlin, Germany; 2German Centre for Cardiovascular Research (DZHK), Berlin, GermanyCorrespondence: Yong Du, Department of Epidemiology and Health Monitoring, Robert Koch Institute, General-Pape-Str. 62-66, Berlin, D-12101, Germany, Tel +49-30-18754 3199, Fax +49 − 30-18754 3211, Email duy@rki.dePurpose: Fear of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and lockdown measures may have an impact on health care utilization particularly for people with chronic diseases. We investigated changes in outpatient utilization behavior in pandemic phases among people with selected chronic diseases in Germany.Methods: The nationwide population-based telephone surveys German Health Update (GEDA) 2019/2020 (April 2019 to September 2020) and GEDA 2021 (July to December 2021) covered 4 out of 7 pandemic phases from the pre-pandemic to the 4th pandemic wave. Data on hypertension, diabetes and major cardiovascular diseases (CVD) in the past 12 months and visiting a general practitioner (GP) or a specialist (excluding dentist) in the past 4 weeks was collected using a standardized questionnaire. Proportions and odds ratios were derived from logistic regression models adjusted for age, sex, education and federal states.Results: Among 27,967 participants aged ≥ 16 years, 8,449, 2,497 and 1,136 individuals had hypertension, diabetes and major CVD. Participants with these chronic diseases visited a GP or specialist significantly more often than the overall study population, irrespective of pandemic phases. Compared to the pre-pandemic phase, a significant reduction in specialist-visiting was found in the first pandemic wave among people with hypertension (34.3% vs 24.1%), diabetes (39.5% vs 25.5%) and major CVD (41.9% vs 25.6%). GP-visiting was lower only among people with hypertension (53.0% vs 46.0%). No difference in GP or specialist visiting was found in the 4th pandemic wave compared to the pre-pandemic phase.Conclusion: The observed decrease particularly in specialist utilization among people with the selected chronic diseases at the beginning of the pandemic was not observed for the second half of 2021 despite the ongoing pandemic. Further studies are required to examine whether the temporary changes in the utilization of ambulatory health care have affected the disease management of people with chronic diseases.Keywords: health service utilization, outpatients, SARS-CoV-2, chronic disease, cardiometabolic diseases, diabetes, Germany

Cryptosporidiosis is a diarrheal disease caused by infection with Cryptosporidium spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population. Additional safe therapeutics are urgently required to tackle this unmet medical need. However, the development of anti-cryptosporidial drugs is hindered by a lack of understanding of the optimal compound properties required to treat this gastrointestinal infection. To address this knowledge gap, a diverse set of potent lysyl-tRNA synthetase inhibitors was profiled to identify optimal physicochemical and pharmacokinetic properties required for efficacy in a chronic mouse model of infection. The results from this comprehensive study illustrated the importance of balancing solubility and permeability to achieve efficacy in vivo. Our results establish in vitro criteria for solubility and permeability that are predictive of compound efficacy in vivo to guide the optimization of anti-cryptosporidial drugs. Two compounds from chemically distinct series (DDD489 and DDD508) were identified as demonstrating superior efficacy and prioritized for further evaluation. Both compounds achieved marked parasite reduction in immunocompromised mouse models and a disease-relevant calf model of infection. On the basis of these promising data, these compounds have been selected for progression to preclinical safety studies, expanding the portfolio of potential treatments for this neglected infectious disease.

Background: The panel infrastructure Health in Germany, which is currently being set up, is geared towards the needs of public health research in Germany. The panel will consist of extensive probability and non-probability samples. This infrastructure will be used to collect survey data, measurement data and laboratory data to describe the health situation on an ongoing basis and make them available promptly., Methods: For the initial drawing of the probability sample, the sampling frame of the residents' registration offices (EMA) established in Germany is used. The study design follows a mixed-mode approach in which the invited persons can choose whether to participate in the survey online or in paper form. Four surveys per year are planned for the regular operation of the panel (regular annual wave). Ad-hoc studies on specific topics or acute issues are also possible., Conclusions: The panel provides a new infrastructure for continuous epidemiological studies to monitor the health of the population in Germany. This data basis strengthens the health monitoring and health reporting of the federal government, enabling a prompt and adaptable response to emerging data needs., Competing Interests: Conflicts of interest Patrick Schmich declares he has been delegated working for the Federal Ministry of Health since March 2023. The others authors declared no conflicts of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

In the course of the COVID-19 pandemic and the implementation of associated non-pharmaceutical containment measures, the need for continuous monitoring of the mental health of populations became apparent. When the pandemic hit Germany, a nationwide Mental Health Surveillance (MHS) was in conceptual development at Germany's governmental public health institute, the Robert Koch Institute. To meet the need for high-frequency reporting on population mental health we developed a prototype that provides monthly estimates of several mental health indicators with smoothing splines. We used data from the telephone surveys German Health Update (GEDA) and COVID-19 vaccination rate monitoring in Germany (COVIMO). This paper provides a description of the highly automated data pipeline that produces time series data for graphical representations, including details on data collection, data preparation, calculation of estimates, and output creation. Furthermore, statistical methods used in the weighting algorithm, model estimations for moving three-month predictions as well as smoothing techniques are described and discussed. Generalized additive modelling with smoothing splines best meets the desired criteria with regard to identifying general time trends. We show that the prototype is suitable for a population-based high-frequency mental health surveillance that is fast, flexible, and able to identify variation in the data over time. The automated and standardized data pipeline can also easily be applied to other health topics or other surveys and survey types. It is highly suitable as a data processing tool for the efficient continuous health surveillance required in fast-moving times of crisis such as the Covid-19 pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Junker, Damerow, Walther and Mauz.)

Background: Times of crisis such as the COVID-19 pandemic are expected to compromise mental health. Despite a large number of studies, evidence on the development of mental health in general populations during the pandemic is inconclusive. One reason may be that representative data spanning the whole pandemic and allowing for comparisons to pre-pandemic data are scarce., Methods: We analyzed representative data from telephone surveys of Germany's adults. Three mental health indicators were observed in ~1,000 and later up to 3,000 randomly sampled participants monthly until June 2022: symptoms of depression (observed since April 2019, PHQ-2), symptoms of anxiety (GAD-2), and self-rated mental health (latter two observed since March 2021). We produced time series graphs including estimated three-month moving means and proportions of positive screens (PHQ/GAD-2 score ≥ 3) and reports of very good/excellent mental health, as well as smoothing curves. We also compared time periods between years. Analyses were stratified by sex, age, and level of education., Results: While mean depressive symptom scores declined from the first wave of the pandemic to summer 2020, they increased from October 2020 and remained consistently elevated throughout 2021 with another increase between 2021 and 2022. Correspondingly, the proportion of positive screens first decreased from 11.1% in spring/summer 2019 to 9.3% in the same period in 2020 and then rose to 13.1% in 2021 and to 16.9% in 2022. While depressive symptoms increased in all subgroups at different times, developments among women (earlier increase), the youngest (notable increase in 2021) and eldest adults, as well as the high level of education group (both latter groups: early, continuous increases) stand out. However, the social gradient in symptom levels between education groups remained unchanged. Symptoms of anxiety also increased while self-rated mental health decreased between 2021 and 2022., Conclusion: Elevated symptom levels and reduced self-rated mental health at the end of our observation period in June 2022 call for further continuous mental health surveillance. Mental healthcare needs of the population should be monitored closely. Findings should serve to inform policymakers and clinicians of ongoing dynamics to guide health promotion, prevention, and care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor WR declared a shared affiliation with the author SS at the time of review., (Copyright © 2023 Mauz, Walther, Junker, Kersjes, Damerow, Eicher, Hölling, Müters, Peitz, Schnitzer and Thom.)

Background: Study results on the impact of the COVID-19 pandemic on mental health in the first year of the pandemic are contradictory. The GEDA 2019/2020 study makes it possible to examine changes in depressive symptoms in the population., Methods: A standardised telephone interview was used to survey a random sample of the population in Germany aged 15 and older. To exclude seasonal effects, 10,220 interviewees from the period April 2019 to January 2020 were compared with 11,900 from the period April 2020 to January 2021. Depressive symptoms were assessed with the internationally established 8-item Patient Health Questionnaire (PHQ-8)., Results: The prevalence of depressive symptoms decreased from 9.2% to 7.6% in the first year of the pandemic. Changes differ between women and men as well as between age and education groups. The analysis of individual symptoms suggests that it is not about a reduction of mental disorders of the depressive type in the narrower sense, but rather a decrease in stress-associated individual symptoms., Conclusions: The decrease in stress-associated depressive symptoms in parts of the population can be interpreted as an indication that pandemic-related changes in everyday life and the working environment may have had a positive effect on individual areas of mental health in certain groups, at least temporarily in the first year of the pandemic. The continuing strong social inequality in depressive symptoms to the disadvantage of low education groups confirms that the need for social situation-related health promotion and prevention with regard to the living and working conditions of socially disadvantaged people must not be lost sight of in times of pandemic. For groups in the population that partly showed a worsening of symptoms in this phase of the pandemic, e.g. the diminished ability to concentrate of very old men, targeted support options should be created in the future., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

Background: Measures for containing the COVID-19 pandemic in 2020 and 2021 resulted in drastic changes in physical activity and dietary habits that also impacted body weight., Methods: The representative study German Health Update (GEDA 2021) includes self-reported information about body weight and body height for adults aged 18 years and older (n=2,985) from July to October 2021. In addition, the study asked about changes in body weight since the beginning of the COVID-19 pandemic., Results: For 59% of participants, body weight has not changed since the beginning of the COVID-19 pandemic, 26% report weight gain, and 15% report weight loss. Younger people indicate weight gain more often than older people, and individuals with obesity report weight gain more often than individuals without obesity. 1.5 years after the beginning of the COVID-19 pandemic, the average weight change within the population is approximately +0.34kg., Conclusions: The effects of restrictions in everyday life with regard to the possible negative impacts on body weight should be given greater consideration and should be monitored in the future., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

Objective: To investigate SARS-COV-2 viral clearance and viral load kinetics in the course of infection in children aged 1-6 years in comparison with adults., Methods: Prospective cohort study of infected daycare children and staff and their close contacts in households from 11/2020 to 06/2021. Adult participants took upper respiratory tract specimen from themselves and/or their children, for PCR tests on SARS-CoV-2. Data on symptoms and exposure were used to determine the date of probable infection for each participant. We determined (a) viral clearance, and (b) viral load dynamics over time. Samples were taken from day 4-6 to day 16-18 after diagnosis of the index case in the respective daycare group (5 samples per participant)., Results: We included 40 children (1-6 years) and 67 adults (18-77 years) with SARS-CoV-2 infection. Samples were available at a mean of 4.3 points of time per participant. Among the participants, the 12-day study period fell in different periods within the individual course of infection, ranging from day 5-17 to day 15-26 after assumed infection.Children reached viral clearance at a median of 20 days after assumed infection (95% CI 17-21 days, Kaplan-Meier Analysis), adults at 23 days (95% CI 20-25 days, difference not significant). In both children and adults, viral load decreased over time with trajectories of the mean viral load not being statistically different between groups. Kaplan-Meier calculations show that from day 15 (95% CI 13-15), 50% of all participants had a viral load <1 million copies/ml, i.e. were no longer infectious or negative., Conclusion: Children aged 1-6 and adults infected with SARS-CoV-2 (wild type and Alpha variant) did not differ significantly in terms of viral load kinetics and time needed to clear the virus. Therefore, containment measures are important also in the daycare settings as long as the pandemic continues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Sandoni, Schaffrath Rosario, Michel, Kuttig, Wurm, Damerow, Iwanowski, Finkel, Schrick, Buchholz, Haas, Varnaccia, Kubisch, Jordan, Schienkiewitz, Nitsche and Loss.)

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold., (© 2022. The Author(s).)

In daycare centres, the close contact of children with other children and employees favours the transmission of infections. The majority of children <6 years attend daycare programmes in Germany, but the role of daycare centres in the SARS-CoV-2 pandemic is unclear. We investigated the transmission risk in daycare centres and the spread of SARS-CoV-2 to associated households. 30 daycare groups with at least one recent laboratory-confirmed SARS-CoV-2 case were enrolled in the study (10/2020-06/2021). Close contact persons within daycare and households were examined over a 12-day period (repeated SARS-CoV-2 PCR tests, genetic sequencing of viruses, symptom diary). Households were interviewed to gain comprehensive information on each outbreak. We determined primary cases for all daycare groups. The number of secondary cases varied considerably between daycare groups. The pooled secondary attack rate (SAR) across all 30 daycare centres was 9.6%. The SAR tended to be higher when the Alpha variant was detected (15.9% vs. 5.1% with evidence of wild type). The household SAR was 53.3%. Exposed daycare children were less likely to get infected with SARS-CoV-2 than employees (7.7% vs. 15.5%). Containment measures in daycare programmes are critical to reduce SARS-CoV-2 transmission, especially to avoid spread to associated households.

The spread of the coronavirus SARS-CoV-2 in 2020 and the containment measures associated therewith have changed many aspects of daily life. An impact on health even beyond infections itself is assumed as well. The health situation of the population in the first phase of the pandemic was thus analysed using data from the German Health Update (GEDA 2019/2020-EHIS). By continuing the survey, the analyses for 2020 are completed (n=26,507 participants), whereby the focus is now on the third phase of the pandemic (second wave of infection, gradual reintroduction of containment measures). The health indicators are presented on a monthly basis. As in the first phase of the pandemic, no pandemic-related changes were observed for tobacco smoking/ second-hand smoke exposure and for received/lack of/provided support. In contrast to the first phase of the pandemic, declines in utilisation of medical services and depressive symptoms are not observed in the third phase. The increase in body weight/body mass index after the first phase of the pandemic did not continue. The survey period allows for a comparison of the periods before and as of the pandemic situation. A decrease in the medical services utilisation and depressive symptoms as well as an increase in the body weight/body mass index is observed in the period from March 2020 to January 2021 compared to the pre-pandemic period from April 2019 to March 2020., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schienkiewitz, Jordan, Hornbacher, Perlitz, Zeisler, Sandoni, Kubisch, Wess, Kuttig, Schaffrath-Rosario, Damerow, Rattay, Varnaccia, Loer, Wormsbächer, Cohrdes, Wetzstein, Albrecht, Hey, Michel, Schrick, Gößwald, Allen, Schlaud, Busch, Butschalowsky, Wernitz, Otte im Kampe, Buchholz, Haas, Schaade, Wieler, Ziese, Lampert and Loss.)

Between April 2019 and September 2020, 23,001 people aged 15 or over responded to questions about their health and living conditions for the German Health Update (GEDA 2019/2020-EHIS). The results are representative of the German resident population aged 15 or above. The response rate was 21.6%. The study used a questionnaire based on the third wave of the European Health Interview Survey (EHIS), which was carried out in all EU member states. EHIS consists of four modules on health status, health care provision, health determinants, and socioeconomic variables. The data are collected in a harmonised manner and therefore have a high degree of international comparability. They constitute an important source of information for European health policy and health reporting and are made available by the Statistical Office of the European Union (Eurostat). They also form the basis of the Federal Health Reporting undertaken in Germany. Data collection began in April 2019, just under a year before the beginning of the SARS-CoV-2 pandemic, and continued into its initial phase, as of March 2020. As such, data from the current GEDA wave can also be used to conduct research into the health impact of the SARS-CoV-2 pandemic., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

Fucose is a common component of eukaryotic cell-surface glycoconjugates, generally added by Golgi-resident fucosyltransferases. Whereas fucosylated glycoconjugates are rare in kinetoplastids, the biosynthesis of the nucleotide sugar GDP-Fuc has been shown to be essential in Trypanosoma brucei . Here we show that the single identifiable T. brucei fucosyltransferase (TbFUT1) is a GDP-Fuc: β-D-galactose α-1,2-fucosyltransferase with an apparent preference for a Galβ1,3GlcNAcβ1-O-R acceptor motif. Conditional null mutants of TbFUT1 demonstrated that it is essential for both the mammalian-infective bloodstream form and the insect vector-dwelling procyclic form. Unexpectedly, TbFUT1 was localized in the mitochondrion of T. brucei and found to be required for mitochondrial function in bloodstream form trypanosomes. Finally, the TbFUT1 gene was able to complement a Leishmania major mutant lacking the homologous fucosyltransferase gene (Guo et al., 2021). Together these results suggest that kinetoplastids possess an unusual, conserved and essential mitochondrial fucosyltransferase activity that may have therapeutic potential across trypanosomatids., Competing Interests: GB, SD, HG, AM, JP, SB, MF none, MS None, (© 2021, Bandini et al.)

Glycoconjugates play major roles in the infectious cycle of the trypanosomatid parasite Leishmania While GDP-Fucose synthesis is essential, fucosylated glycoconjugates have not been reported in Leishmania major [H. Guo et al., J. Biol. Chem. 292, 10696-10708 (2017)]. Four predicted fucosyltransferases appear conventionally targeted to the secretory pathway; SCA1/2 play a role in side-chain modifications of lipophosphoglycan, while gene deletion studies here showed that FUT2 and SCAL were not essential. Unlike most eukaryotic glycosyltransferases, the predicted α 1-2 fucosyltransferase encoded by FUT1 localized to the mitochondrion. A quantitative "plasmid segregation" assay, expressing FUT1 from the multicopy episomal pXNG vector in a chromosomal null ∆ fut1 - background, established that FUT1 is essential. Similarly, "plasmid shuffling" confirmed that both enzymatic activity and mitochondrial localization were required for viability, comparing import-blocked or catalytically inactive enzymes, respectively. Enzymatic assays of tagged proteins expressed in vivo or of purified recombinant FUT1 showed it had a broad fucosyltransferase activity including glycan and peptide substrates. Unexpectedly, a single rare ∆ fut1 - segregant ( ∆fut1 s ) was obtained in rich media, which showed severe growth defects accompanied by mitochondrial dysfunction and loss, all of which were restored upon FUT1 reexpression. Thus, FUT1 along with the similar Trypanosoma brucei enzyme TbFUT1 [G. Bandini et al., bioRxiv, https://www.biorxiv.org/content/10.1101/726117v2 (2021)] joins the eukaryotic O-GlcNAc transferase isoform as one of the few glycosyltransferases acting within the mitochondrion. Trypanosomatid mitochondrial FUT1s may offer a facile system for probing mitochondrial glycosylation in a simple setting, and their essentiality for normal growth and mitochondrial function renders it an attractive target for chemotherapy of these serious human pathogens., Competing Interests: Competing interest statement: One of the reviewers (G.W.H.) and one of the authors (M.A.J.F.) are coauthors on chapter 12 in Essentials of Glycobiology (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, ed. 3, 2015–2017).

People with diabetes regularly need outpatient medical care due to their disease and possible concomitant and secondary illnesses. Using data from the nationwide GEDA 2019/2020-EHIS survey conducted from April 2019 to September 2020, the present study examines developments in outpatient utilisation behaviour during the measures put in place to contain the SARS-CoV-2 pandemic. During the observation period, people with diabetes had a significantly higher rate of utilisation of medical services provided by general practitioners (GPs) and specialists than the population as a whole. In the spring of 2020, when the restrictions were put in place, utilisation of specialist medical services by people with diabetes decreased temporarily by 46% compared to the 2019 reference period. In contrast, no relevant decline in the utilisation of medical services provided by GPs was observed, but this could be related to adaptations of care provision through telephone consultations for people with regularly requiring GP office visits. The issue examined here requires further observations in view of the renewed containment measures., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

[This corrects the article on p. 3-20 in vol. 5.]., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

The German Health Interview and Examination Survey for Children and Adolescents (KiGGS) provides comprehensive and reliable data on the health situation of the upcoming generation. The KiGGS cohort accompanies participants from the KiGGS baseline study (2003-2006) into adulthood. Until now, two follow-up surveys of the cohort have been implemented with KiGGS Wave 1 (2009-2012) and KiGGS Wave 2 (2014-2017). In KiGGS Wave 2, the cohort was supplemented by the in-depth study 'Family and care-specific factors influencing the development, trajectories and effects of mental disorders (especially ADHD), obesity and allergic diseases (especially asthma)'. One aim of the study was to identify individual trajectories of these health disorders. For this purpose, probabilities for typical transitions from the KiGGS baseline study to KiGGS Wave 2 were calculated. An important result is that many participants who had asthma, obesity or ADHD at KiGGS baseline still had the disease more than ten years later: Over a third still had asthma (35%) or ADHD (37%), and almost half were still affected by obesity (47%). The results point to the need for early preventive measures to stop these potentially chronic diseases from developing in childhood and adolescence., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

Background: No standards exist for the handling and reporting of data quality in health research. This work introduces a data quality framework for observational health research data collections with supporting software implementations to facilitate harmonized data quality assessments., Methods: Developments were guided by the evaluation of an existing data quality framework and literature reviews. Functions for the computation of data quality indicators were written in R. The concept and implementations are illustrated based on data from the population-based Study of Health in Pomerania (SHIP)., Results: The data quality framework comprises 34 data quality indicators. These target four aspects of data quality: compliance with pre-specified structural and technical requirements (integrity); presence of data values (completeness); inadmissible or uncertain data values and contradictions (consistency); unexpected distributions and associations (accuracy). R functions calculate data quality metrics based on the provided study data and metadata and R Markdown reports are generated. Guidance on the concept and tools is available through a dedicated website., Conclusions: The presented data quality framework is the first of its kind for observational health research data collections that links a formal concept to implementations in R. The framework and tools facilitate harmonized data quality assessments in pursue of transparent and reproducible research. Application scenarios comprise data quality monitoring while a study is carried out as well as performing an initial data analysis before starting substantive scientific analyses but the developments are also of relevance beyond research.

Carotid intima-media thickness (cIMT) and carotid stiffness (CS) are important markers of atherosclerotic risk in the young. We assessed a novel third-generation method for its applicability in large population-based epidemiologic studies to determine strengths, limitations, completeness and predictors of unsuccessful measurement. Four thousand seven hundred ninety-eight 14- to 31-y-old participants of the German KiGGS cohort, which is based on a nationally representative sample with 11-y follow-up, underwent B-mode ultrasound examinations of the left and right common carotid artery with semi-automatic edge detection and automatic electrocardiogram-gated real-time quality control based on a sophisticated snake algorithm and subpixel interpolation. Overall completeness was 98% for far wall cIMT and 89% for CS parameters. Plane-specific completeness varied from 92%-96% for far wall and from 64%-69% for near-wall cIMT. Obesity independently predicted unsuccessful cIMT and CS measurements with odds ratios of 12.67 (95% confidence interval: 5.50-29.19) and 7.30 (4.87-10.94) compared with non-overweight after adjustment for blood pressure, cholesterol, smoking, hazardous drinking, age, sex and sonographer. Inter- and intra-rater reliabilities of cIMT and CS parameters in a sample of 15 young adults were good or excellent. Third-generation cIMT and CS measurements in the young with semi-automatic edge-detection and automatic real-time quality control has been successfully standardized with high reliability and very high completeness in a national survey setting. This provides a strong methodological foundation for further validation of the predictive value of cIMT and CS for atherosclerotic risk in the young., Competing Interests: Conflict of interest disclosure The authors report no conflicts of interest., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.

SARS-CoV-2, the novel coronavirus, has posed major challenges in Germany in 2020. It is unclear whether the pandemic and containment measures will have an impact on the health of the population beyond the point of infection. The German Health Update (GEDA 2019/2020-EHIS) is a nationwide survey of the population aged 15 years and older (n=23,001) that was conducted between April 2019 and September 2020. The focus of the analysis was on indicators for which pandemic-related changes could be expected. Based on regression models, adjusted proportions and mean values were estimated as trends over time. Any differences in the values found for the time period of containment measures in spring 2020 and the reference period 2019 were statistically tested. Since the implementation of containment measures, both body weight and body mass index (BMI) have increased. The utilisation of general and specialist medical services decreased temporarily. The number of tobacco smokers during the observation period also decreased, yet without revealing a clear link to the pandemic situation. No differences were found in the general population for depressive symptoms and household assistance received and provided. During the period of containment measures, changes to the health situation beyond the occurrence of infections can be observed. However, a more differentiated explanation of these findings will require further analyses., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

Background: The current results of the "German Health Interview and Examination Survey for Children and Adolescents" (KiGGS Wave 2, 2014-2017) indicate that the prevalence of overweight and obesity among children and adolescents in Germany has hardly changed during this period., Objectives: What are the current prevalences for the other categories of the BMI distribution (severe underweight, underweight, and extreme obesity) and what changes have occurred between the KiGGS baseline survey (2003-2006) and KiGGS Wave 2 with regard to the BMI categories and the distribution of BMI values?, Materials and Methods: KiGGS Wave 2 analyses are based on data from 1762 boys and 1799 girls aged 3 to 17 years with valid measurements of height and weight. The KiGGS baseline survey provides information on 7531 boys and 7215 girls for trend evaluations., Results: For underweight prevalence as well as for the prevalence of extreme obesity no change over time can be observed. The BMI percentiles also show only minor differences between the two survey periods with a marginal shift of the upper BMI percentiles downwards before puberty and a slight increase after puberty. There is no clear shift in the BMI distribution towards lower BMI values., Discussion: There are now many activities at the national, regional, and local level that focus on prevention and intervention to reduce overweight and obesity. The marginal shifts in the upper BMI percentiles in the upper BMI percentiles before puberty observed here suggest that some success may have been achieved in obesity prevention among children in Germany.

Background: The German Health Interview and Examination Survey for Children and Adolescents (KiGGS) is an important data source for assessing the occurrence of underweight, overweight and obesity in children and adolescents in Germany. However, to assess trends over time, it must be considered that methodological changes in the calculation of prevalences have been necessary and that the reference system has been revised., Objective: Are the effects of the methodological changes in weighting factors and reference systems so important that they significantly influence the available prevalence estimates and statements on trends over time?, Materials and Methods: The data are based on valid measurements of body height and weight from the KiGGS baseline survey (2003-2006, 7531 boys and 7215 girls) and from KiGGS Wave 2 (2014-2017, 1762 boys and 1799 girls). The participants were aged between 3 and 17 years. Prevalences (%, 95% CI) of underweight, overweight and obesity for the KiGGS baseline survey were calculated depending on the reference system and different weighting factors used., Results: The statements on the temporal trend in the prevalence of underweight, overweight, and obesity remain valid even when methodological changes are taken into account. Only among 16- and especially 17-year-old girls, can a noticeable difference due to the altered reference system be noted., Discussion: With regard to the trend examined here, the methodological changes can be neglected, as long as no small subgroups are analysed. However, this conclusion cannot be generalised; the effects of methodological changes must be re-examined for each study question.

Regular physical activity and good motor performance are the basis for healthy physical development in childhood and are considered a protective factor for various health risks. However, children and adolescents in Germany are not physically active enough because sedentary activities have increased. One consequence is the decline in motor capacity, the totality of structures and functions that are responsible for the performance of motor actions.In the second follow-up survey of the study on the health of children and adolescents in Germany (KiGGS Wave 2, 2014-2017), the motor performance (LF) of 4‑ to 10-year-old children was examined with three motor tests: one-leg stand (EIN), stand and reach (RB), and jumping sideways (SHH). The purpose of this paper is to present the results of the tests and to compare them with data from the KiGGS baseline survey (2003-2006). It also analyzes how motor performance differs in terms of different characteristics such as sociodemographic factors, obesity, and physical activity.Compared to the KiGGS baseline survey, the 4‑ to 10-year-olds' motor performance in KiGGS Wave 2 has slightly improved in EIN, but RB and SHH are stagnating at low level. The test results indicate that middle and high social status, club sport activity, and "no overweight" are associated with above-average motor performance.Health policy, sports organizations, schools, and kindergartens should work together more closely so that all children have the same chance of good motor performance.

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase ( Pf KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both Pf KRS1 and C. parvum KRS ( Cp KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED 90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between Pf KRS1 and Cp KRS. This series of compounds inhibit Cp KRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for Pf KRS1 and Cp KRS vs. (human) Hs KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis., Competing Interests: Conflict of interest statement: A patent relating to this work has been filed (PCT/GB2017/051809). F.-J.G. and L.M.S. are employees of GlaxoSmithKline and own shares of the company. M.B.J.-D. and I.A.-B. have shares in The Art of Discovery. Editor D.E.G. is a recent coauthor with two authors of this paper. He published a research article with M.A. in 2015. With E.A.W. he published two research articles in 2016, one research article in 2018, and coauthored a research article forthcoming in 2019. D.E.G. is a coinvestigator with E.A.W. on a 2012–2019 grant., (Copyright © 2019 the Author(s). Published by PNAS.)

In Germany, the reference system according to Kromeyer-Hauschild is usually used to define underweight, overweight and obesity in children and adolescents. International classification systems to describe prevalence are the reference systems of the World Health Organization (WHO) and the International Obesity Task Force (IOTF). This article reports underweight, overweight and obesity prevalences among children and adolescents according to WHO and IOTF criteria using data from the second wave of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Wave 2, 2014-2017). According to the WHO reference system, the prevalence of underweight among 5- to 17-year-olds is 1.6%, the prevalence of overweight is 26.3% (including obesity) and the prevalence of obesity is 8.8%. According to IOTF, the prevalence of underweight among 3- to 17-year-olds is 10.0%. The prevalence of overweight (including obesity) is 19.3% and the prevalence of obesity is 4.7%. From a public health point of view, underweight as an indicator of malnutrition plays a rather minor role in Germany. The prevalence of overweight according to WHO is three quarters higher and one quarter higher according to IOTF than the national reference. When comparing the international reference systems, the WHO prevalence is one third higher than IOTF prevalence. According to national and international reference systems, no further increase in the prevalence of overweight and obesity is observed, but the prevalence remain at a high level., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

During bone healing, tissue formation processes are governed by mechanical strain. Sost/sclerostin, a key Wnt signaling inhibitor and mechano-sensitive pathway, is downregulated in response to mechanical loading. Sclerostin neutralizing antibody (SclAb) increases bone formation. Nevertheless, it remains unclear whether sclerostin inhibition can rescue bone healing in situations of mechanical instability, which otherwise delay healing. We investigated SclAb's influence on tissue formation in a mouse femoral osteotomy, stabilized with rigid or semirigid external fixation. The different fixations allowed different magnitudes of interfragmentary movement during weight bearing, thereby influencing healing outcome. SclAb or vehicle (veh) was administeredand bone healing was assessed at multiple time points up to day 21 postoperatively by in vivo micro-computed tomography, histomorphometry, biomechanical testing, immunohistochemistry, and gene expression. Our results show that SclAb treatment caused a greater bone volume than veh. However, SclAb could not overcome the characteristic delayed healing of semirigid fixation. Indeed, semirigid fixation resulted in delayed healing with a prolonged endochondral ossification phase characterized by increased cartilage, lower bone volume fraction, and less bony bridging across the osteotomy gap than rigid fixation. In a control setting, SclAb negatively affected later stages of healing under rigid fixation, evidenced by the high degree of endosteal bridging at 21 days in the rigid-SclAb group compared with rigid-veh, indicating delayed fracture callus remodeling and bone marrow reconstitution. Under rigid fixation, Sost and sclerostin expression at the gene and protein level, respectively, were increased in SclAb compared with veh-treated bones, suggesting a negative feedback mechanism. Our results suggest that SclAb could be used to enhance overall bone mass but should be carefully considered in bone healing. SclAb may help to increase bone formation early in the healing process but not during advanced stages of fracture callus remodeling and not to overcome delayed healing in semirigid fixation. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

For some time, there have been indications that the prevalence of overweight and obesity among children and adolescents in Germany has stabilised at a high level. The second wave of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Wave 2, 2014-2017) once again provides nationwide measurements on height and weight of children and adolescents aged 3 to 17 years. The results are confirming this trend. The prevalence of overweight is 15.4% and 5.9% for obesity. There are no differences between girls and boys. Overweight and obesity prevalence increases with age. Children and adolescents with low socioeconomic status (SES) are more likely to be overweight and obese than those with high SES. Compared to the KiGGS baseline study (2003-2006), there was no further increase in overweight and obesity prevalence overall and in all age groups., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

Glycosylation is an important posttranslational protein modification in all eukaryotes. Besides glycosylphosphatidylinositol (GPI) anchors and N-glycosylation, O-fucosylation has been recently reported in key sporozoite proteins of the malaria parasite. Previous analyses showed the presence of GDP-fucose (GDP-Fuc), the precursor for all fucosylation reactions, in the blood stages of Plasmodium falciparum. The GDP-Fuc de novo pathway, which requires the action of GDP-mannose 4,6-dehydratase (GMD) and GDP-L-fucose synthase (FS), is conserved in the parasite genome, but the importance of fucose metabolism for the parasite is unknown. To functionally characterize the pathway we generated a PfGMD mutant and analyzed its phenotype. Although the labelling by the fucose-binding Ulex europaeus agglutinin I (UEA-I) was completely abrogated, GDP-Fuc was still detected in the mutant. This unexpected result suggests the presence of an alternative mechanism for maintaining GDP-Fuc in the parasite. Furthermore, PfGMD null mutant exhibited normal growth and invasion rates, revealing that the GDP-Fuc de novo metabolic pathway is not essential for the development in culture of the malaria parasite during the asexual blood stages. Nonetheless, the function of this metabolic route and the GDP-Fuc pool that is generated during this stage may be important for gametocytogenesis and sporogonic development in the mosquito.