• Vaccinations and Infections Are Associated With Unrelated Antibody Titers: An Analysis From the German Birth Cohort Study LISA.

      Caputo, Mahrrouz; Raupach-Rosin, Heike; Karch, André; Borte, Michael; Lehmann, Irina; Liebert, Uwe Gerd; Standl, Marie; Heinrich, Joachim; Mikolajczyk, Rafael T; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Frontiers, 2019-01-01)
      The evidence for non-specific effects (NSE) of vaccinations on all-cause morbidity and mortality among children is growing. However, our understanding of the underlying mechanisms is still limited. One hypothesis is that NSE are mediated by antibody titers. We used data of 2,123 children from the population-based birth cohort study LISA conducted in Germany to explore whether routine childhood vaccinations and the individual infection history in the first 2 years of life are associated with unrelated antibody titers. We selected 19 exposures (infections and vaccinations) and investigated their association with levels of 12 IgG antibody titers at the age of 2 years. Based on univariable analyses (ANOVA), we identified 21 crude associations between exposures and titers (p < 0.05), while 11 (95%-CI: 6, 17) spurious associations were expected due to multiple testing. In exploratory multivariable analyses, we observed associations between seven investigated IgG titers and 10 exposures; either administered vaccines [e.g., higher anti-hRSV IgG titer in BCG-vaccinated children (regression-coefficient in standard-deviation-units: 0.38; 95%-CI: 0.12, 0.65)] or infections [e.g., higher anti-measles IgG titer in children with reported chickenpox (0.44; 95%-CI: 0.08, 0.80)]. Our results indicate the existence of associations between immunogenic exposures and unrelated antibody titers. Further studies investigating the underlying immunological mechanisms are required.
    • Guidelines and recommendations for ensuring Good Epidemiological Practice (GEP): a guideline developed by the German Society for Epidemiology.

      Hoffmann, Wolfgang; Latza, Ute; Baumeister, Sebastian E; Brünger, Martin; Buttmann-Schweiger, Nina; Hardt, Juliane; Hoffmann, Verena; Karch, André; Richter, Adrian; Schmidt, Carsten Oliver; et al. (Springer, 2019-03-01)
      Objective To revise the German guidelines and recommendations for ensuring Good Epidemiological Practice (GEP) that were developed in 1999 by the German Society for Epidemiology (DGEpi), evaluated and revised in 2004, supplemented in 2008, and updated in 2014. Methods The executive board of the DGEpi tasked the third revision of the GEP. The revision was arrived as a result of a consensus-building process by a working group of the DGEpi in collaboration with other working groups of the DGEpi and with the German Association for Medical Informatics, Biometry and Epidemiology, the German Society of Social Medicine and Prevention (DGSMP), the German Region of the International Biometric Society (IBS-DR), the German Technology, Methods and Infrastructure for Networked Medical Research (TMF), and the German Network for Health Services Research (DNVF). The GEP also refers to related German Good Practice documents (e.g. Health Reporting, Cartographical Practice in the Healthcare System, Secondary Data Analysis). Results The working group modified the 11 guidelines (after revision: 1 ethics, 2 research question, 3 study protocol and manual of operations, 4 data protection, 5 sample banks, 6 quality assurance, 7 data storage and documentation, 8 analysis of epidemiological data, 9 contractual framework, 10 interpretation and scientific publication, 11 communication and public health) and modified and supplemented the related recommendations. All participating scientific professional associations adopted the revised GEP. Conclusions The revised GEP are addressed to everyone involved in the planning, preparation, execution, analysis, and evaluation of epidemiological research, as well as research institutes and funding bodies.
    • Labour characteristics of women achieving successful vaginal birth after caesarean section in three European countries.

      Gross, Mechthild M; Clarke, Mike; Begley, Cecily; Daly, Deirdre; Healy, Patricia; Nicoletti, Jane; Devane, Declan; Morano, Sandra; Krause, Gérard; Karch, André; et al. (Elsevier, 2019-07-01)
      Objective: Knowledge about labour characteristics of women achieving successful vaginal birth after caesarean section (VBAC) might be used to improve labour and birth management. This study examined sociodemographic and labour process-related factors regarding a) differences between countries, b) the comparison of successful VBAC with unplanned caesarean section, and c) predictors for the success of planned VBAC in three European countries. Design: We analysed observational data collected within the OptiBIRTH trial, a clusterrandomised controlled trial. Setting: Fifteen study sites in Ireland, Italy and Germany, five in each country. Participants: 790 participants going into labour for planned VBAC. Measurements: Descriptive statistics and random-effects logistic regression models were applied. Findings: The pooled successful VBAC-rate was 74.6%. Italy had the highest proportion of women receiving none of the four intrapartum interventions amniotomy (ARM), oxytocin, epidural or opioids (42.5% vs Ireland: 26.8% and Germany: 25.3%, p<0.001). Earlier performance of ARM was associated with successful VBAC (3.50 hrs vs 6.08 hrs, p=0.004). A positive predictor for successful vaginal birth was a previous vaginal birth (OR=3.73, 95% CI [2.17, 6.44], p<0.001). The effect of ARM increased with longer labour duration (OR for interaction term=1.06, 95% CI [1.004, 1.12], p=0.035). Higher infant birthweight (OR per kg=0.34, 95% CI [0.23, 0.50], p<0.001), ARM (reference spontaneous rupture of membranes (SROM), OR=0.20, 95% CI [0.11, 0.37], p<0.001) and a longer labour duration (OR per hour=0.93, 95% CI [0.90, 0.97], p<0.001) decreased the odds of a vaginal birth. Key conclusion: Women with a previous vaginal birth, an infant with a lower birth weight, SROM and a shorter labour duration were most likely to have a successful vaginal birth. If SROM did not occur, an earlier ARM increased the odds of a vaginal birth. Implication for practice: Labour progress should be accelerated by fostering endogenous uterine contractions. With slow labour progress and intact membranes, ARM might increase the chance of a vaginal birth
    • Early Detection of Infection Chains & Outbreaks: Use Case Infection Control.

      Sargeant, A; von Landesberger, T; Baier, C; Bange, F; Dalpke, A; Eckmanns, T; Glöckner, S; Kaase, M; Krause, G; Marschollek, M; et al. (IOS Press, 2019-01-01)
      Within the HiGHmed Project there are three medical use cases. The use cases include the scopes cardiology, oncology and infection. They serve to specify the requirements for the development and implementation of a local and federated platform, with the result that data from medical care and research should be retrievable, reusable and interchangeable. The Use Case Infection Control aims to establish an early detection of transmission events as well as clusters and outbreaks of various pathogens. Therefore the use case wants to establish the smart infection control system (SmICS).
    • Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.

      James, Spencer Lewis; Karch, Andre; GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators (Elsevier Lancet, 2019-01-01)
      BackgroundTraumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury.Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our resultsfor disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility.FindingsIn 2016, there were 27·08 million (95% uncertainty interval [UI] 24·30–30·30 million) new cases of TBI and 0·93 million (0·78–1·16 million) new cases of SCI, with age-standardised incidence rates of 369 (331–412) per 100000 population for TBI and 13 (11–16) per 100000 for SCI. In 2016, the number of prevalent cases of TBI was 55·50 million (53·40–57·62 million) and of SCI was 27·04 million (24·98–30·15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8·4% (95% UI 7·7 to 9·2), whereas that of SCI did not change significantly (–0·2% [–2·1 to 2·7]). Age-standardised incidence rates increased by 3·6% (1·8 to 5·5) for TBI,but did not change significantly for SCI (–3·6% [–7·4 to 4·0]). TBI caused 8·1 million (95% UI 6·0–10·4 million) YLDs and SCI caused 9·5 million (6·7–12·4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82–141) per 100000 for TBI and 130 (90–170) per 100000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions.Interpretation TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily byfalls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth,which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments.
    • Knowledge on Antibiotic Use, Self-Reported Adherence to Antibiotic Intake, and Knowledge on Multi-Drug Resistant Pathogens - Results of a Population-Based Survey in Lower Saxony, Germany.

      Raupach-Rosin, Heike; Rübsamen, Nicole; Schütte, Gesa; Raschpichler, Gabriele; Chaw, Pa Saidou; Mikolajczyk, Rafael T; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Frontiers, 2019-01-01)
      Introduction: Assessment of public awareness on antibiotic use and resistance can identify key issues for campaigns addressing these problems. Our aim was to assess the knowledge, attitudes, and practice (KAP) related to antibiotic use and multi-drug resistant (MDR) pathogens in a general population in Germany. Methods: We conducted a KAP survey on antibiotics and on MDR pathogens using an online panel recruited from the general population, which was established using stratified random sampling from the population registry in four districts in Lower Saxony, Germany. Results: In the 12 months preceding the survey, 32.3% of the participants had received at least one prescription for antibiotics, 95.7% reported to follow the recommendations of prescribers, and 10.3% reported to stop taking antibiotics as soon as they feel better. Up to 94.9% of the participants had heard of MDR pathogens, 42.7% reported to know somebody who had been tested positive for it, 0.8% had an infection with it, and 37.2% were worried of contracting it. In case of contact with a carrier of MDR pathogens, over 90% would increase hand hygiene and 0.8% would avoid the carrier completely. Participants considered health care workers (75.1%) and everybody in society (87.8%) to be responsible for combating the spread of MDR pathogens. Conclusion: There is a high reported exposure to antibiotics and awareness of the problem of MDR pathogens. Despite personal worries, most of the participants indicated a reasonable, non-stigmatizing behavior toward carriers of MDR pathogens, and that every individual was responsible to avoid their spread.
    • Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.

      Stanaway, Jeffrey D.; Karch, Andre; Murray, Christopher J. L.; GBD 2017 Risk Factor Collaborators; HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (Elsevier: Lancet, 2018-11-10)
      Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk–outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk–outcome pairs, and new data on risk exposure levels and risk–outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk–outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings In 2017, 34·1 million (95% uncertainty interval [UI] 33·3–35·0) deaths and 1·21 billion (1·14–1·28) DALYs were attributable to GBD risk factors. Globally, 61·0% (59·6–62·4) of deaths and 48·3% (46·3–50·2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10·4 million (9·39–11·5) deaths and 218 million (198–237) DALYs, followed by smoking (7·10 million [6·83–7·37] deaths and 182 million [173–193] DALYs), high fasting plasma glucose (6·53 million [5·23–8·23] deaths and 171 million [144–201] DALYs), high body-mass index (BMI; 4·72 million [2·99–6·70] deaths and 148 million [98·6–202] DALYs), and short gestation for birthweight (1·43 million [1·36–1·51] deaths and 139 million [131–147] DALYs). In total, risk-attributable DALYs declined by 4·9% (3·3–6·5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23·5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18·6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning.
    • Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: a systematic analysis from the Global Burden of Disease Study 2016.

      Fullman, Nancy; GBD 2016 Healthcare Access and Quality Collaborators; Karch, Andre; HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (Elsevier: Lancet, 2018-06-02)
      BACKGROUND: A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. METHODS: Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. FINDINGS: In 2016, HAQ Index performance spanned from a high of 97·1 (95% UI 95·8-98·1) in Iceland, followed by 96·6 (94·9-97·9) in Norway and 96·1 (94·5-97·3) in the Netherlands, to values as low as 18·6 (13·1-24·4) in the Central African Republic, 19·0 (14·3-23·7) in Somalia, and 23·4 (20·2-26·8) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91·5 (89·1-93·6) in Beijing to 48·0 (43·4-53·2) in Tibet (a 43·5-point difference), while India saw a 30·8-point disparity, from 64·8 (59·6-68·8) in Goa to 34·0 (30·3-38·1) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4·8-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20·9-point to 17·0-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17·2-point to 20·4-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. INTERPRETATION: GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle-SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view-and subsequent provision-of quality health care for all populations.
    • Global, regional, and national burden of meningitis, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.

      Zunt, Joseph Raymund; GBD 2016 Meningitis Collaborators; Karch, Andre; HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (Elsevier, 2018-12-01)
      SummaryBackground Acute meningitis has a high case-fatality rate and survivors can have severe lifelong disability. We aimed to provide a comprehensive assessment of the levels and trends of global meningitis burden that could help to guide introduction, continuation, and ongoing development of vaccines and treatment programmes.Methods The Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2016 study estimated meningitis burden due to one of four types of cause: pneumococcal, meningococcal, Haemophilusinfluenzae type b, and a residual category of other causes. Cause-specific mortality estimates were generated via cause of death ensemble modelling of vital registration and verbal autopsy data that were subject to standardised data processing algorithms. Deaths were multiplied by the GBD standard life expectancy at age of death to estimate years of life lost, the mortality component of disability-adjusted life-years (DALYs). A systematic analysis of relevant publications and hospital and claims data was used to estimate meningitis incidence via a Bayesian meta-regression tool.Meningitis deaths and cases were split between causes with meta-regressions of aetiological proportions of mortality and incidence, respectively. Probabilities of long-term impairment by cause of meningitiswere applied to survivors and used to estimate years of life lived with disability (YLDs). We assessed the relationship between burden metrics and Socio-demographic Index (SDI), a composite measure of development based on fertility, income, and education.Findings Global meningitis deaths decreased by 21·0% from 1990 to 2016, from 403012 (95% uncertainty interval [UI] 319426–458514) to 318400 (265218–408705). Incident cases globally increased from 2·50 million (95% UI 2·19–2·91) in 1990 to 2·82 million (2·46–3·31) in 2016. Meningitis mortality and incidence were closely related toSDI. The highest mortality rates and incidence rates were found in the peri-Sahelian countries that comprise the African meningitis belt, with six of the ten countries with the largest number of cases and deaths being located within this region. Haemophilus influenzaetype b was the most common cause of incident meningitisin 1990, at 780070 cases (95% UI 613585–978219) globally, but decreased the most (–49·1%)to become the least commoncause in 2016, with 397297 cases (291076–533662). Meningococcus was the leading cause of meningitis mortality in 1990 (192833 deaths [95% UI153358–221503] globally), whereas other meningitis was the leading cause for both deaths (136423 [112682–178022]) and incident cases (1·25 million [1·06–1·49]) in 2016. Pneumococcus caused the largest number of YLDs (634458 [444787–839749]) in 2016, owing to its more severe long-term effects on survivors. Globally in 2016, 1·48 million (1·04—1·96) YLDs were due to meningitis compared with 21·87 million (18·20—28·28) DALYs, indicating that the contribution of mortality to meningitis burden is far greater than the contribution of disabling outcomes.Interpretation Meningitis burden remains high and progress lags substantially behind that of other vaccine-preventable diseases. Particular attention should be given to developing vaccines with broader coverage against the causes of meningitis, making these vaccines affordable in the most affected countries, improving vaccine uptake, improving access to low-cost diagnostics and therapeutics, and improving support for disabled survivors. Substantial uncertainty remains around pathogenic causes and risk factors for meningitis. Ongoing, active cause-specific surveillance of meningitis is crucial to continue and to improve monitoring of meningitis burdens and trends throughout the world.
    • Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.

      Global Burden of Disease Study; Karch, Andre; James, Spencer Lewis; HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany. (Elsevier, 2018-11-10)
      BACKGROUND: Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardised estimates of mortality. We present single-calendar year and single-year of age estimates of fertility and population by sex with standardised and replicable methods. METHODS: We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10-54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10-14 years and 50-54 years was estimated from data on fertility in women aged 15-19 years and 45-49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories. FINDINGS: From 1950 to 2017, TFRs decreased by 49·4% (95% uncertainty interval [UI] 46·4-52·0). The TFR decreased from 4·7 livebirths (4·5-4·9) to 2·4 livebirths (2·2-2·5), and the ASFR of mothers aged 10-19 years decreased from 37 livebirths (34-40) to 22 livebirths (19-24) per 1000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83·8 million people per year since 1985. The global population increased by 197·2% (193·3-200·8) since 1950, from 2·6 billion (2·5-2·6) to 7·6 billion (7·4-7·9) people in 2017; much of this increase was in the proportion of the global population in south Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2·0%; this rate then remained nearly constant until 1970 and then decreased to 1·1% in 2017. Population growth rates in the southeast Asia, east Asia, and Oceania GBD super-region decreased from 2·5% in 1963 to 0·7% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2·7%. The global average age increased from 26·6 years in 1950 to 32·1 years in 2017, and the proportion of the population that is of working age (age 15-64 years) increased from 59·9% to 65·3%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1·0 livebirths (95% UI 0·9-1·2) in Cyprus to a high of 7·1 livebirths (6·8-7·4) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0·08 livebirths (0·07-0·09) in South Korea to 2·4 livebirths (2·2-2·6) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0·3 livebirths (0·3-0·4) in Puerto Rico to a high of 3·1 livebirths (3·0-3·2) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in central, eastern, and western Europe, whereas population growth rates of more than 2·0% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger. INTERPRETATION: Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress.
    • Development and validation of a diagnostic model for early differentiation of sepsis and non-infectious SIRS in critically ill children - a data-driven approach using machine-learning algorithms.

      Lamping, Florian; Jack, Thomas; Rübsamen, Nicole; Sasse, Michael; Beerbaum, Philipp; Mikolajczyk, Rafael T; Boehne, Martin; Karch, André; HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany. (BioMedCentral, 2018-03-15)
      BACKGROUND: Since early antimicrobial therapy is mandatory in septic patients, immediate diagnosis and distinction from non-infectious SIRS is essential but hampered by the similarity of symptoms between both entities. We aimed to develop a diagnostic model for differentiation of sepsis and non-infectious SIRS in critically ill children based on routinely available parameters (baseline characteristics, clinical/laboratory parameters, technical/medical support). METHODS: This is a secondary analysis of a randomized controlled trial conducted at a German tertiary-care pediatric intensive care unit (PICU). Two hundred thirty-eight cases of non-infectious SIRS and 58 cases of sepsis (as defined by IPSCC criteria) were included. We applied a Random Forest approach to identify the best set of predictors out of 44 variables measured at the day of onset of the disease. The developed diagnostic model was validated in a temporal split-sample approach. RESULTS: A model including four clinical (length of PICU stay until onset of non-infectious SIRS/sepsis, central line, core temperature, number of non-infectious SIRS/sepsis episodes prior to diagnosis) and four laboratory parameters (interleukin-6, platelet count, procalcitonin, CRP) was identified in the training dataset. Validation in the test dataset revealed an AUC of 0.78 (95% CI: 0.70-0.87). Our model was superior to previously proposed biomarkers such as CRP, interleukin-6, procalcitonin or a combination of CRP and procalcitonin (maximum AUC = 0.63; 95% CI: 0.52-0.74). When aiming at a complete identification of sepsis cases (100%; 95% CI: 87-100%), 28% (95% CI: 20-38%) of non-infectious SIRS cases were assorted correctly. CONCLUSIONS: Our approach allows early recognition of sepsis with an accuracy superior to previously described biomarkers, and could potentially reduce antibiotic use by 30% in non-infectious SIRS cases. External validation studies are necessary to confirm the generalizability of our approach across populations and treatment practices.
    • Design and characterization of dietary assessment in the German National Cohort.

      Knüppel, Sven; Clemens, Matthias; Conrad, Johanna; Gastell, Sylvia; Michels, Karin B; Leitzmann, Michael; Krist, Lilian; Pischon, Tobias; Krause, Gerard; Ahrens, Wolfgang; et al. (Springer Nature, 2019-01-15)
      BACKGROUND/OBJECTIVES: The aim of the study was to describe a novel dietary assessment strategy based on two instruments complemented by information from an external population applied to estimate usual food intake in the large-scale multicenter German National Cohort (GNC). As proof of concept, we applied the assessment strategy to data from a pretest study (2012-2013) to assess the feasibility of the novel assessment strategy. SUBJECTS/METHODS: First, the consumption probability for each individual was modeled using three 24 h food lists (24h-FLs) and frequencies from one food frequency questionnaire (FFQ). Second, daily consumed food amounts were estimated from the representative German National Nutrition Survey II (NVS II) taking the characteristics of the participants into account. Usual food intake was estimated using the product of consumption probability and amounts. RESULTS: We estimated usual intake of 41 food groups in 318 men and 377 women. The participation proportion was 100, 84.4, and 68.5% for the first, second, and third 24h-FL, respectively. We observed no associations between the probability of participating and lifestyle factors. The estimated distributions of usual food intakes were plausible and total energy was estimated to be 2707 kcal/day for men and 2103 kcal/day for women. The estimated consumption frequencies did not differ substantially between men and women with only few exceptions. The differences in energy intake between men and women were mostly due to differences in estimated daily amounts. CONCLUSIONS: The combination of repeated 24h-FLs, a FFQ, and consumption-day amounts from a reference population represents a user-friendly dietary assessment approach having generated plausible, but not yet validated, food intake values in the pretest study
    • Ebola Outbreak Containment: Real-Time Task and Resource Coordination With SORMAS

      Perscheid, Cindy; Benzler, Justus; Hermann, Claus; Janke, Michael; Moyer, David; Laedtke, Todd; Adeoye, Olawunmi; Denecke, Kerstin; Beermann, Sandra; Schwarz, Norbert; et al. (Frontiers Media S.A., 2018-04-10)
      Background: Since the beginning of the Ebola outbreak in West Africa in 2014, more than 11,000 people died. For outbreaks of infectious diseases like this, the rapid implementation of control measures is a crucial factor for containment. In West African countries, outbreak surveillance is a paper-based process with significant delays in forwarding outbreak information, which affects the ability to react adequately to situational changes. Our objective therefore was to develop a tool that improves data collection, situation assessment, and coordination of response measures in outbreak surveillance processes for a better containment. Methods: We have developed the Surveillance and Outbreak Response Management System (SORMAS) based on findings from Nigeria's 2014 Ebola outbreak. We conducted a thorough requirements engineering and defined personas and processes. We also defined a data schema with specific variables to measure in outbreak situations. We designed our system to be a cloud application that consists of interfaces for both mobile devices and desktop computers to support all stakeholders in the process. In the field, health workers collect data on the outbreak situation via mobile applications and directly transmit it to control centers. At the control centers, health workers access SORMAS via desktop computers, receive instant updates on critical situations, react immediately on emergencies, and coordinate the implementation of control measures with SORMAS. Results: We have tested SORMAS in multiple workshops and a field study in July 2015. Results from workshops confirmed derived requirements and implemented features, but also led to further iterations on the systems regarding usability. Results from the field study are currently under assessment. General feedback showed high enthusiasm about the system and stressed its benefits for an effective outbreak containment of infectious diseases. Conclusions: SORMAS is a software tool to support health workers in efficiently handling outbreak situations of infectious diseases, such as Ebola. Our tool enables a bi-directional exchange of situational data between individual stakeholders in outbreak containment. This allows instant and seamless collection of data from the field and its instantaneous analysis in operational centers. By that, SORMAS accelerates the implementation of control measures, which is crucial for a successful outbreak containment.
    • Immune Status in Children Before Liver Transplantation-A Cross-Sectional Analysis Within the ChilsSFree Multicentre Cohort Study.

      Möhring, Tamara; Karch, André; Falk, Christine S; Laue, Tobias; d'Antiga, Lorenzo; Debray, Dominique; Hierro, Loreto; Kelly, Deirdre; McLin, Valerie; McKiernan, Patrick; et al. (Frontiers, 2019-01-01)
      Background: Both, markers of cellular immunity and serum cytokines have been proposed as potential biomarkers for graft rejection after liver transplantation. However, no good prognostic model is available for the prediction of acute cellular rejection. The impact of underlying disease and demographic factors on immune status before pediatric liver transplantation (pLTx) is still poorly understood. We investigated expression of immune markers before pLTx, in order to better understand the pre-transplant immune status. Improved knowledge of the impact of pre-transplant variables may enhance our understanding of immunological changes post pLTx in the future. Methods: This is a cross-sectional analysis of data from the ChilSFree study, a European multicentre cohort study investigating the longitudinal patterns of immune response before and after pLTx. Immune cell counts and soluble immune markers were measured in 155 children 1–30 days before pLTx by TruCount analysis and BioPlex assays. Results were logarithmised due to skewed distributions and then compared according to age, sex, and diagnosis using t-tests, ANOVAs, and Tukey post-hoc tests. The association between immune markers at time of pLTx and patients' age was assessed using a fractional polynomial approach. Multivariable regression models were used to assess the relative contribution of each factor. Results: Sex had no effect on immune status. We found strong evidence for age-specific differences in the immune status. The majority of immune markers decreased in a log-linear way with increasing age. T and B cells showed a sharp increase within the first months of life followed by a log-linear decline in older age groups. Several immune markers were strongly associated with underlying diagnoses. The effects of age and underlying disease remained virtually unchanged when adjusting for each other in multivariable models. Discussion: We show for the first time that age and diagnosis are major independent determinants of cellular and soluble immune marker levels in children with end-stage liver disease. These results need to be considered for future research on predictive immune monitoring after pLTx.
    • Herpes zoster incidence in Germany - an indirect validation study for self-reported disease data from pretest studies of the population-based German National Cohort.

      Caputo, Mahrrouz; Horn, Johannes; Karch, André; Akmatov, Manas K; Becher, Heiko; Braun, Bettina; Brenner, Hermann; Castell, Stefanie; Fischer, Beate; Giani, Guido; et al. (2019-01-30)
      Until now, herpes zoster (HZ)-related disease burden in Germany has been estimated based on health insurance data and clinical findings. However, the validity of self-reported HZ is unclear. This study investigated the validity of self-reported herpes zoster (HZ) and its complication postherpetic neuralgia (PHN) using data from the pretest studies of the German National Cohort (GNC) in comparison with estimates based on health insurance data. Data of 4751 participants aged between 20 and 69 years from two pretest studies of the GNC carried out in 2011 and 2012 were used. Based on self-reports of physician-diagnosed HZ and PHN, age- and sex-specific HZ incidence rates and PHN proportions were estimated. For comparison, estimates based on statutory health insurance data from the German population were considered. Eleven percent (95%-CI, 10.4 to 12.3, n = 539) of the participants reported at least one HZ episode in their lifetime. Our estimated age-specific HZ incidence rates were lower than previous estimates based on statutory health insurance data. The PHN proportion in participants older than 50 years was 5.9% (1.9 to 13.9%), which was in line with estimates based on health insurance data. As age- and sex-specific patterns were comparable with that in health insurance data, self-reported diagnosis of HZ seems to be a valid instrument for overall disease trends. Possible reasons for observed differences in incidence rates are recall bias in self-reported data or overestimation in health insurance data.
    • Bacterial community structure and effects of picornavirus infection on the anterior nares microbiome in early childhood.

      Caputo, Mahrrouz; Zoch-Lesniak, Beate; Karch, André; Vital, Marius; Meyer, Frederic; Klawonn, Frank; Baillot, Armin; Pieper, Dietmar H; Mikolajczyk, Rafael T; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (BMC, 2019-01-07)
      Little is known regarding the nasal microbiome in early childhood and the impact of respiratory infection on the infants' nasal microbial composition. Here we investigated the temporal dynamics and diversity of the bacterial composition in the anterior nares in children attending daycare centers. For our investigation, we considered 76 parental-taken nasal swabs of 26 children (aged 13 to 36 months) collected over a study period of 3 months. Overall, there was no significant age-specific effect or seasonal shift in the nasal bacterial community structure. In a sub-sample of 14 healthy children the relative abundance of individual taxa as well as the overall diversity did not reveal relevant changes, indicating a stable community structure over the entire study period. Moreover, the nasal bacterial profiles clustered subject-specific with Bray-Curtis similarities being elevated in intra-subject calculations compared to between-subject calculations. The remaining subset of 12 children provided samples taken during picornavirus infection (PVI) and either before or after a PVI. We detected an association between the relative abundance of members of the genus Streptococcus and PV when comparing both (i) samples taken during PVI with samples out of 14 healthy children and (ii) samples taken during PVI with samples taken after PVI within the same individual. In addition, the diversity was higher during PVI than after infection. Our findings suggest that a personalized structure of the nasal bacterial community is established already in early childhood and could be detected over a timeframe of 3 months. Studies following infants over a longer time with frequent swab sampling would allow investigating whether certain parameter of the bacterial community, such as the temporal variability, could be related to viral infection.
    • DEVELOPMENT OF A QUANTITATIVE SCORING METHOD FOR STROBE CHECKLIST

      Limaye, Dnyanesh; Limaye, Vaidehi; Pitani, Ravi Shankar; Fortwengel, Gerhard; Sydymanov, Arlan; Otzipka, Christian; Ziesenis, Patrick; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
    • Side effects and efficacy of renal sparing immunosuppression in pediatric liver transplantation-A single center matched cohort study.

      Leiskau, Christoph; Rajanayagam, Jeremy; Pfister, Eva-Doreen; Goldschmidt, Imeke; Junge, Norman; Karch, André; Lerch, Christian; Richter, Nicolas; Lehner, Frank; Schrem, Harald; et al. (Blackwell Publishing Inc., 2018-01-01)
      Immunosuppressive combination therapy with MMF can reduce CNI associated nephrotoxicity. We investigated effectiveness and safety of de novo MMF-tacrolimus based immunosuppression after pLTx. Patients after pLTx receiving immunosuppression with MMF/tacrolimus (MMF/TAC) were compared to retrospectively selected age- and diagnosis-matched patients with tacrolimus monotherapy (TAC) and cyclosporine/prednisolone therapy (CSA) (19 patients each, n = 57). Effectiveness, renal function and side effects were analyzed for 1 year after pLTx. Tacrolimus reduction in combination therapy (0.7 μg/L over the year) was lower than aspired (2 μg/L). Acute BPAR occurred equally in MMF/TAC and TAC groups (31.6% each), being slightly higher in CSA group (42.1%; OR = 1.5; 95% CI = 0.42-5.44; P = .5). GFR deteriorated comparably in all 3 groups (P < .01 each) without significant differences between the groups. Septicemia was detected significantly more often in MMF/TAC (73.6%) than in TAC (31.6%) (OR 4.17; 1.07-16.27; P = .04). EBV reactivation occurred more often in CSA patients (84.2%) than in MMF/TAC (47.4%; OR 5.16; 0.98-27.19; P = .05) and TAC patients (52.6%; OR 8.16; 1.48-44.89; P = .02) the same was true for other viral infections (47.4% (CSA) vs 15.8% (TAC); OR 4.21; 0.95-18.55; P = .05). Our study does not provide additional evidence for a benefit of initial use of MMF/TAC over TAC regarding renal function, but raises concerns regarding a potentially increased risk of serious infections under MMF/TAC compared to TAC monotherapy at equivalent renal outcome; our study is, however, limited by the minor CNI reduction in combination therapy.
    • Assessing the Concepts and Designs of 58 Mobile Apps for the Management of the 2014-2015 West Africa Ebola Outbreak: Systematic Review.

      Tom-Aba, Daniel; Nguku, Patrick Mboya; Arinze, Chinedu Chukwujekwu; Krause, Gerard; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2018-10-29)
      The use of mobile phone information technology (IT) in the health sector has received much attention especially during the 2014-2015 Ebola virus disease (EVD) outbreak. mHealth can be attributed to a major improvement in EVD control, but there lacks an overview of what kinds of tools were available and used based on the functionalities they offer. We aimed to conduct a systematic review of mHealth tools in the context of the recent EVD outbreak to identify the most promising approaches and guide further mHealth developments for infectious disease control. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched for all reports on mHealth tools developed in the context of the 2014-2015 EVD outbreak published between January 1, 2014 and December 31, 2015 on Google Scholar, MEDLINE, CAB Abstracts (Global Health), POPLINE, and Web of Science in any language using the search strategy: ("outbreak" OR "epidemic") AND ("mobile phone" OR "smartphone" OR "smart phone" OR "mobile phone" OR "tablet" OR "mHealth") AND ("Ebola" OR "EVD" OR "VHF" OR "Ebola virus disease" OR "viral hemorrhagic fever") AND ("2014" OR "2015"). The relevant publications were selected by 2 independent reviewers who applied a standardized data extraction form on the tools' functionalities. We identified 1220 publications through the search strategy, of which 6.31% (77/1220) were original publications reporting on 58 specific mHealth tools in the context of the EVD outbreak. Of these, 62% (34/55) offered functionalities for surveillance, 22% (10/45) for case management, 18% (7/38) for contact tracing, and 6% (3/51) for laboratory data management. Only 3 tools, namely Community Care, Sense Ebola Followup, and Surveillance and Outbreak Response Management and Analysis System supported all four of these functionalities.