Plasma immune signatures can predict rejection-free survival in the first year after pediatric liver transplantation.

BACKGROUND & AIMS: After pediatric liver transplantation (pLT), children undergo life-long immunosuppression since reliable biomarkers for the assessment of rejection probability are scarce. In the multicenter (n = 7) prospective clinical cohort "ChilSFree" study, we aimed to characterize longitudinal dynamics of soluble and cellular immune mediators during the first year after pLT and identify early biomarkers associated with outcome. METHODS: Using a Luminex-based multiplex technique paired with flow cytometry, we characterized longitudinal dynamics of soluble immune mediators (SIMs, n = 50) and immune cells in the blood of 244 patients at eight visits over 1 year: before, and 7/14/21/28 days and 3/6/12 months after pLT. RESULTS: The unsupervised clustering of patients based on SIM profiles revealed six unique SIM signatures associated with clinical outcome. From three signatures linked to improved outcome, one was associated with 1-year-long rejection-free survival and stable graft function and was characterized by low levels of pro-inflammatory SIMs (CXCL8/9/10/12, CCL7, SCGF-ß, sICAM-1), and high levels of regenerative (SCF, TNF-ß) and pro-apoptotic (TRAIL) SIMs (all, p <0.001, fold change >100). Of note, this SIM signature appeared 2 weeks after pLT and remained stable over the entire year, pointing towards its potential as a novel early biomarker for minimizing or weaning immunosuppression. In the blood of these patients, a higher frequency of CD56bright natural killer cells (p <0.01), a known hallmark also associated with operationally tolerant pLT patients, was detected. The concordance of the model for prediction of rejection based on identified SIM signatures was 0.715, and 0.795, in combination with living-related transplantation as a covariate, respectively. CONCLUSIONS: SIM blood signatures may enable the non-invasive and early assessment of rejection risks in the first year after pLT, paving the way for improved clinical management. IMPACT AND IMPLICATIONS: ChilSFree represents the largest pediatric liver transplant (pLT) cohort with paired longitudinal data on soluble immune mediators (SIMs) and immune phenotyping in the first year after pLT. SIM signatures allow for the selection of rejection-free patients 2 weeks after pLT independently of patient diagnosis, sex, or age. The SIM signatures may enable the non-invasive and early assessment of rejection risks, paving the way for minimization or withdrawal of immunosuppression after pLT.

Presentation, patterns of care, and outcomes of patients with prostate cancer in sub-Saharan Africa: A population-based registry study.

BACKGROUND: Although prostate cancer (PCa) is the most commonly diagnosed cancer in men of sub-Saharan Africa (SSA), little is known about its management and survival. The objective of the current study was to describe the presentation, patterns of diagnosis, treatment, and survival of patients with PCa in 10 countries of SSA. METHODS: In this observational registry study with data collection from 2010 to 2018, the authors drew a random sample of 738 patients with PCa who were registered in 11 population-based cancer registries. They described proportions of patients receiving recommended care and presented survival estimates. Multivariable Cox regression was used to calculate hazard ratios comparing the survival of patients with and without cancer-directed therapies (CDTs). RESULTS: The study included 693 patients, and tumor characteristics and treatment information were available for 365 patients, 37.3% of whom had metastatic disease. Only 11.2% had a complete diagnostic workup for risk stratification. Among the nonmetastatic patients, 17.5% received curative-intent therapy, and 27.5% received no CDT. Among the metastatic patients, 59.6% received androgen deprivation therapy. The 3- and 5-year age-standardized relative survival for 491 patients with survival time information was 58.8% (95% confidence interval [CI], 48.5%-67.7%) and 56.9% (95% CI, 39.8%-70.9%), respectively. In a multivariable analysis, survival was considerably poorer among patients without CDT versus those with therapy. CONCLUSIONS: This study shows that a large proportion of patients with PCa in SSA are not staged or are insufficiently staged and undertreated, and this results in unfavorable survival. These findings reemphasize the need for improving diagnostic workup and access to care in SSA in order to mitigate the heavy burden of the disease in the region.

Relevance of intra-hospital patient movements for the spread of healthcare-associated infections within hospitals - a mathematical modeling study.

The aim of this study is to analyze patient movement patterns between hospital departments to derive the underlying intra-hospital movement network, and to assess if movement patterns differ between patients at high or low risk of colonization. For that purpose, we analyzed patient electronic medical record data from five hospitals to extract information on risk stratification and patient intra-hospital movements. Movement patterns were visualized as networks, and network centrality measures were calculated. Next, using an agent-based model where agents represent patients and intra-hospital patient movements were explicitly modeled, we simulated the spread of multidrug resistant enterobacteriacae (MDR-E) inside a hospital. Risk stratification of patients according to certain ICD-10 codes revealed that length of stay, patient age, and mean number of movements per admission were higher in the high-risk groups. Movement networks in all hospitals displayed a high variability among departments concerning their network centrality and connectedness with a few highly connected departments and many weakly connected peripheral departments. Simulating the spread of a pathogen in one hospital network showed positive correlation between department prevalence and network centrality measures. This study highlights the importance of intra-hospital patient movements and their possible impact on pathogen spread. Targeting interventions to departments of higher (weighted) degree may help to control the spread of MDR-E. Moreover, when the colonization status of patients coming from different departments is unknown, a ranking system based on department centralities may be used to design more effective interventions that mitigate pathogen spread.

Worsened Financial Situation During the COVID-19 Pandemic Was Associated With Depressive Symptomatology Among University Students in Germany: Results of the COVID-19 International Student Well-Being Study.

Background: Previous findings suggest that university students are at an elevated risk to experience financial hardship and to suffer from depressive symptoms. This vulnerability may have substantially increased during the coronavirus disease 19 (COVID-19) pandemic which might have affected students' socio-economic situation but possibly also their mental well-being. We examined whether the financial situation changed during the COVID-19 pandemic among German university students, and whether changes were associated with mental well-being. Methods: We conducted a cross-sectional online survey in May and July 2020 at five German universities. Participants were asked, if they had sufficient financial resources to cover monthly expenses before and during the pandemic. The answer options were dichotomized into worsened and no change/better financial situation compared to before the COVID-19 pandemic. Depressive symptoms were assessed using the CES-D 8 scale. For examining associations between sociodemographic, study-related, and financial factors and "worsened financial situation," we ran a generalized linear mixed model. To assess associations between depressive symptoms and worsened financial situation, we performed a linear mixed model. Results: We included 7,199 participants in the analyses (69% female, 30% male, 1% diverse, mean age: 24 years, standard deviation: 4.7). Overall, 25% of the participants reported to have a worsened financial situation at the time of the survey than in the time before COVID-19. Factors associated with a worsened financial situation were migration background, parents not being academics, not being able to borrow money, and payment of tuition fee by student and loan [odds ratios (OR) ranging from 1.20 to 2.35]. Factors associated with lower odds were: being single, living with others, studying a health-related field, being enrolled in a doctoral/Ph.D. or state exam program, and publicly funded tuition/tuition paid with a scholarship (OR ranging from 0.42 to 0.80). A worsened financial situation was associated with 1.02 points more on the CES-D 8 scale (95% CI: 0.80-1.24). Conclusion: Our results suggest that the pandemic put a number of students under financial strain with detrimental consequences for their mental well-being. Renewed attention must be paid to this vulnerable group to prevent the potentially damaging effects on their mental health.

Modelling pathogen spread in a healthcare network: Indirect patient movements.

Inter-hospital patient transfers (direct transfers) between healthcare facilities have been shown to contribute to the spread of pathogens in a healthcare network. However, the impact of indirect transfers (patients re-admitted from the community to the same or different hospital) is not well studied. This work aims to study the contribution of indirect transfers to the spread of pathogens in a healthcare network. To address this aim, a hybrid network-deterministic model to simulate the spread of multiresistant pathogens in a healthcare system was developed for the region of Lower Saxony (Germany). The model accounts for both, direct and indirect transfers of patients. Intra-hospital pathogen transmission is governed by a SIS model expressed by a system of ordinary differential equations. Our results show that the proposed model reproduces the basic properties of healthcare-associated pathogen spread. They also show the importance of indirect transfers: restricting the pathogen spread to direct transfers only leads to 4.2% system wide prevalence. However, adding indirect transfers leads to an increase in the overall prevalence by a factor of 4 (18%). In addition, we demonstrated that the final prevalence in the individual healthcare facilities depends on average length of stay in a way described by a non-linear concave function. Moreover, we demonstrate that the network parameters of the model may be derived from administrative admission/discharge records. In particular, they are sufficient to obtain inter-hospital transfer probabilities, and to express the patients' transfers as a Markov process. Using the proposed model, we show that indirect transfers of patients are equally or even more important as direct transfers for the spread of pathogens in a healthcare network.

Risk estimation for air travel-induced malaria transmission in central Europe - A mathematical modelling study.

BACKGROUND: Aim of our study was to identify conditions under which malaria transmission caused by imported infectious mosquitoes or travellers could occur at large central European airports, and if such transmission could be sustained by indigenous mosquitoes. METHODS: We developed a deterministic and a stochastic compartmental Susceptible-Exposed-Infectious-Recovered-Susceptible (humans)/Susceptible-Exposed-Infectious (mosquitoes) model with two mosquito (imported Anopheles gambiae, indigenous A. plumbeus) and three human (travellers, airport personnel exposed/not exposed to imported A. gambiae) populations. We assessed various scenarios to identify combinations of model parameters leading to ongoing malaria transmission at the airport. RESULTS: The number of infected airport personnel was low (five infected employees/six months) under assumptions reflecting possible future climatic conditions, current passenger mobility and no desinsection of airports/aircraft. Almost all infections among airport personnel were directly due to bites by imported A. gambiae. Indigenous mosquitoes would need to have comparable transmission parameters to A. gambiae to sustain disease transmission. Incoming infectious passengers play only a minor role in malaria transmission. Use of aircraft/airport desinsection led to no transmission events in the model. CONCLUSION: Our study shows that sustainable air travel-induced malaria transmission in central Europe is unlikely under current conditions or conditions which might become realistic in the next century.

Lung Cancer Attributed Mortality Among 316,336 Early Stage Breast Cancer Cases Treated by Radiotherapy and/or Chemotherapy, 2000-2015: Evidence From the SEER Database.

OBJECTIVE: To estimate the risk of death from lung cancer in patients treated for breast cancer (BC) in relation to the general population. METHODS: BC data, covering 2000 to 2015, were extracted from the Surveillance, Epidemiology and End Results-18 (SEER-18) cancer registry database. A comparison of lung cancer attributed mortality between BC patients and the general population was performed using standardized mortality ratios (SMRs) and SMRs conditional on survival length (cSMRs). Prognostic factors of lung cancer mortality were identified using flexible parametric modelling. Our model adjusts the effect of downstream (histopathological BC tumor grade and hormone receptor status) and upstream (age at diagnosis, ethnicity, and marital status) factors. RESULTS: The median follow-up was 6.4 years (interquartile range, 3.0-10.3 years). BC cases who received only radiotherapy (cSMR = 0.93; 95%CI: 0.77-1.13), only chemotherapy (cSMR = 0.91; 0.62-1.33), and radio-and chemotherapy (cSMR = 1.04; 0.77-1.39) had no evidence of increased lung cancer mortality relative to the general population. The adjusted model identified that lung cancer mortality was higher for women who were older at diagnosis compared to those <50 years (ranging from HR50-59 = 3.41 [95%CI: 2.72-4.28] to HR70-79 = 10.53 [95%CI: 8.44-13.13]) and for cases with negative estrogen and progesterone receptors (HR =1.38; 95% CI: 1.21-1.57). Compared to married cases, widowed, divorced, single or others had a 76%, 45%, and 25% higher hazard of lung cancer mortality, respectively. Lung cancer mortality was lower for American Indian/Alaska Native and Asian/Pacific Islander ethnicities (HR = 0.51; 95% CI: 0.40-0.64) compared to BC cases with white ethnic background. CONCLUSIONS: There is no evidence for a higher lung cancer mortality in BC patients when compared to the general population.

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

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.

Implementation of preventive measures against tick-borne infections in a non-endemic area for tick-borne encephalitis-Results from a population-based survey in Lower Saxony, Germany.

Lyme borreliosis (LB) and tick-borne encephalitis (TBE) are the most common tick-borne diseases in Germany. While for LB only non-specific prevention strategies exist, TBE can be additionally prevented by vaccination. It is unclear to which extent non-specific prevention strategies are applied by individuals living in non-endemic areas for TBE in Germany, and whether TBE vaccination status affects their implementation. Participants of the HaBIDS panel (Hygiene and Behavior Infectious Diseases Study) from four counties of Lower Saxony were invited to fill out a questionnaire on their TBE vaccination status, their LB diagnoses as well as their knowledge, attitudes, and practice related to prevention measures for tick-borne diseases. Based on self-reported data we estimated cumulative lifetime incidence (CUM) and incidence of LB as well as TBE vaccination coverage. One year later, participants received a supplementary questionnaire focusing on reasons for vaccination against TBE and compliance with the vaccination schedule. 1,573 (74.2% of those invited) panel members aged 18-69 years participated in this study. Of these, 22.8% reported to have ever been vaccinated against TBE. The estimated CUM of LB was 5.1% (95%-CI: 4.1%-6.4%), and the incidence was 1.09 per 1,000 person years (95%-CI: 0.87-1.36). 98% of participants knew that LB is transmitted by the bite of an infected tick, but about 50% didn't know that TBE vaccination does not protect against LB. Even though about 80% of study participants were convinced that recommended non-specific prevention strategies were indeed protective, a much lower proportion implemented them. TBE-vaccinated participants were better informed about tick-borne diseases compared to non-vaccinated participants, whereby being vaccinated did not negatively affect implementation of non-specific prevention strategies. Based on data from the supplementary questionnaire, traveling to endemic areas (75.3%) was the main reason for TBE vaccination; 33.0% of those vaccinated had a complete vaccination schedule with three doses. Our study in a TBE non-endemic area revealed deficits in knowledge about which pathogens are covered by TBE vaccination, and a lack in the implementation of non-specific prevention measures. TBE vaccination was not associated with a reduced uptake of non-specific prevention measures.

Immune Status in Children Before Liver Transplantation-A Cross-Sectional Analysis Within the ChilsSFree Multicentre Cohort Study.

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.

Bacterial community structure and effects of picornavirus infection on the anterior nares microbiome in early childhood.

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.

Epidemiologic estimates of hepatitis E virus infection in European countries.

OBJECTIVES: Reliable epidemiologic estimates of Hepatitis E Virus (HEV) infection and evidence on factors determining country-differences are sparse. We systematically assessed and extracted research data on three HEV infection markers and identified factors influencing HEV-positivity to generated adjusted EU/EEA country-specific estimates by a meta-analysis. METHODS: Reports on HEV published 2005-2015 for EU/EEA countries were obtained from PubMed, Embase, Scopus, and Cochrane databases. Utilizing data on anti-HEV IgG, IgM and HEV-RNA we estimated HEV sero-prevalence, recent and acute HEV infections. Respective magnitude of factors influencing HEV-positivity was characterized using deviance. Country-specific estimates were generated by multivariable logistic regression. RESULTS: Of 4980 records, 165 covering 18 EU/EEA countries met inclusion criteria. The majority of collected data were published for Germany, France, United Kingdom, The Netherlands, and Spain. Most influential factor for anti-HEV IgG was the assay used (42% of total deviance); IgM and HEV-RNA were predominately determined by studied population (34%, 74%). Adjusted country-specific estimates for anti-HEV IgG ranged from 1.82%-17.06%, IgM 0.14%-6.54%, and HEV-RNA 0.00%-0.10%. No general geographical pattern of HEV-positivity was visible. CONCLUSIONS: Our analysis revealed a high heterogeneity regarding data availability and HEV-seropositivity across EU/EEA countries. Determinants of HEV-estimates including assay are to be considered when interpreting HEV-epidemiology and its burden.

Predictive Factors for Survival in Children Receiving Liver Transplants for Wilson's Disease: A Cohort Study Using European Liver Transplant Registry Data.

Liver transplantation (LT) is a rescue therapy for life-threatening complications of Wilson's disease (WD). However, data on the outcome of WD patients after LT are scarce. The aim of our study was to analyze a large pediatric WD cohort with the aim of investigating the longterm outcome of pediatric WD patients after LT and to identify predictive factors for patient and transplant survival. This is a retrospective cohort study using data of all children (<18 years) transplanted for WD enrolled in the European Liver Transplant Registry from January 1968 until December 2013. In total, 338 patients (57.6% female) transplanted at 80 different European centers (1-26 patients per center) were included in this study. The median age at transplantation was 14.0 years (interquartile range [IQR], 11.2-16.1 years); patients were followed up for a median of 5.4 years (IQR, 1.0-10.9 years) after LT. Overall patient survival rates were high with 87% (1-year survival), 84% (5-year survival), and 81% (10-year survival); survival rates increased considerably with the calendar year (P < 0.001). Early age at LT, living donation, and histidine tryptophan ketoglutarate preservation liquid were identified as risk factors for poor patient survival in the multivariate analysis. LT is an excellent treatment option for pediatric patients with WD and associated end-stage liver disease. Longterm outcome in these patients is similar to other pediatric causes for LT. Overall patient and graft survival rates improved considerably over the last decades. To improve future research in the field, the vast variability of allocation strategies should be harmonized and a generally accepted definition or discrimination of acute versus chronic WD needs to be found.

Changes in risk perceptions during the 2014 Ebola virus disease epidemic: results of two consecutive surveys among the general population in Lower Saxony, Germany.

BACKGROUND: The Ebola virus disease (EVD) outbreak 2014 received extensive news media coverage, which faded out before the outbreak ended. News media coverage impacts risk perception; it is, however, unclear if the components of risk perception (affective and cognitive responses) change differently over time. METHODS: In an online panel, we asked participants (n = 1376) about EVD risk perceptions at the epidemic's peak (November 2014) and after news media coverage faded out (August 2015). We investigated worry (affective response), perceived likelihood of infection, perceived personal impact, and coping efficacy (dimensions of cognitive response), and knowledge about transmission. Differences between the surveys with respect to manifestations of affective and cognitive dimensions were tested using the Wilcoxon signed-rank test. The association between individual change in knowledge and worries about EVD in the first survey was investigated using linear regression. RESULTS: In November 2014, the survey was filled in by 974 participants. Ten months later, 662 of them were still members of the online panel and were invited to the follow-up survey. Among the 620 respondents, affective response decreased between the surveys. Knowledge about EVD also decreased; however, participants worried about EVD in 2014 had increased knowledge in 2015. Perceived likelihood of infection decreased over time, while perceived personal impact and coping efficacy did not. CONCLUSIONS: Risk communication appealing to cognitive reactions by informing clearly on the risk of infection in unaffected countries may decrease inappropriate behaviors.

Poor knowledge of vaccination recommendations and negative attitudes towards vaccinations are independently associated with poor vaccination uptake among adults - Findings of a population-based panel study in Lower Saxony, Germany.

OBJECTIVES: The aims of this study were to (a) assess knowledge of official vaccination recommendations and attitudes towards vaccinations among adults and (b) examine their association with vaccination uptake among adults. METHODS: This study was part of the HaBIDS study (Hygiene and Behaviour Infectious Diseases Survey), which is an online panel established in March 2014 in Lower Saxony, Germany with males and females aged between 15 and 69 years (n = 2379). Every few months, participants completed questionnaires on different aspects of infectious diseases. In September 2014, knowledge of vaccination recommendations, attitudes towards vaccinations and information on uptake of vaccinations in the last 10 years (practice) were collected using a knowledge-attitude-practice (KAP) questionnaire. Multiple correspondence analysis was applied to identify underlying structures in each KAP domain and fractional polynomial regression analysis to examine the associations of knowledge and attitudes with vaccination uptake. RESULTS: Of the 2379 panel members, 1698 (71%) completed the KAP questionnaire on vaccinations. The majority of participants (80%) knew that the vaccine against diphtheria and tetanus should be administered every 10 years. Regarding other recommendations, the proportion of correct answers varied between 35% and 60%. 82% of participants agreed that adult vaccinations should be mandatory for selected groups such as health care workers and 40% stated that vaccinations should be mandatory for all adults. For the different vaccines, the odds of being unvaccinated were 1.5- to 5-times higher among participants with poor knowledge of vaccination recommendations compared to participants with good knowledge. Participants with negative attitudes towards vaccinations were also more likely to be unvaccinated. CONCLUSIONS: Efforts should be undertaken to improve knowledge of official vaccination recommendations in the general population and reduce common misconceptions about vaccinations. This information can be provided during general practitioner visits or through media campaigns.

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.

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. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT00209768; registration date: September 21, 2005.

Influence of demographic changes on the impact of vaccination against varicella and herpes zoster in Germany - a mathematical modelling study.

BACKGROUND: Epidemiological studies suggest that reduced exposure to varicella might lead to an increased risk for herpes zoster (HZ). Reduction of exposure to varicella is a consequence of varicella vaccination but also of demographic changes. We analyzed how the combination of vaccination programs and demographic dynamics will affect the epidemiology of varicella and HZ in Germany over the next 50 years. METHODS: We used a deterministic dynamic compartmental model to assess the impact of different varicella and HZ vaccination strategies on varicella and HZ epidemiology in three demographic scenarios, namely the projected population for Germany, the projected population additionally accounting for increased immigration as observed in 2015/2016, and a stationary population. RESULTS: Projected demographic changes alone result in an increase of annual HZ cases by 18.3% and a decrease of varicella cases by 45.7% between 1990 and 2060. Independently of the demographic scenario, varicella vaccination reduces the cumulative number of varicella cases until 2060 by approximately 70%, but also increases HZ cases by 10%. Unlike the currently licensed live attenuated HZ vaccine, the new subunit vaccine candidate might completely counteract this effect. Relative vaccine effects were consistent across all demographic scenarios. CONCLUSION: Demographic dynamics will be a major determinant of HZ epidemiology in the next 50 years. While stationary population models are appropriate for assessing vaccination impact, models incorporating realistic population structures allow a direct comparison to surveillance data and can thus provide additional input for immunization decision-making and resource planning.

Transluminal angioplasty and stenting versus conservative treatment in patients with symptomatic basilar artery stenosis : Perspective for future clinical trials.

PURPOSE: Two recent randomized controlled trials (RCT) consistently showed superiority of aggressive medical treatment versus percutaneous transluminal angioplasty and stenting (PTAS) in patients with intracranial artery stenosis. Patients with symptomatic basilar stenosis have a higher long-term risk of recurrent stroke compared to patients with anterior circulation stenosis but no study has specifically focused on the role of PTAS in this subgroup. The aim of our study was to investigate the subgroup of patients with symptomatic basilar artery stenosis to find evidence for the feasibility of a future clinical trial. METHODS: Patients with ischemic stroke caused by a symptomatic basilar stenosis and admitted to five German tertiary care hospitals were included in this multicenter effectiveness study. Primary outcome was a composite endpoint of stroke recurrence, clinically relevant restenosis, progression and death. Shared frailty Cox regression models were used to compare outcome rates between groups. RESULTS: Of the 139 patients included in the study 79 (57 %) underwent PTAS and 60 (43 %) conservative treatment alone. The median follow-up period was 300 (IQR 18-738) days. Risks of the primary composite outcome (hazard ratio HR 0.49, 95 % confidence interval CI 0.25-0.97, p = 0.039) and of the key secondary outcomes recurrent stroke (HR 0.42, 95 % CI 0.19-0.95, p = 0.037) and clinically relevant restenosis/progression (HR 0.12, 95 % CI 0.03-0.59, p = 0.009) were lower in patients with PTAS compared to conservative treatment. There was no difference in all-cause mortality between groups (HR 0.98, 95 % CI 0.19-5.09, p = 0.979). CONCLUSION: In this retrospective study we could not reproduce the findings from large RCTs on intracranial stenting. Our data could be considered as a basis for a prospective study on patient selection for PTAS in the basilar artery.

Perceptions of Zika virus risk in Germany in 2016.

Background: Risks associated with Zika virus (ZIKV) transmission in the Americas have been discussed widely in the media as several European athletes declined to participate in the 2016 Summer Olympic Games. Since risk perceptions of individuals in unaffected areas are unknown, we assessed the risk perceptions of ZIKV and related behaviour in Lower Saxony, Germany, with a specific focus on pregnant women and their partners. Methods: In May 2016, we surveyed 1,037 participants aged 15-69 years of an online panel (addressing hygiene and preventive behaviour regarding infections) in Lower Saxony with respect to their risk perceptions related to ZIKV. We additionally included 26 expectant parents who were recruited at antenatal preparation courses in Braunschweig and Hannover between May and July 2016. Results: Six hundred fifty-five (69.1%) of the panel participants had ever heard about ZIKV. About 8% of the study participants reported to be concerned about ZIKV. Pregnant women had the highest odds of reporting concern about ZIKV (OR: 6.24; 95% CI: 2.94-13.26, reference: non-pregnant women). The vast majority of participants (79%) would travel to the Olympics if they won a free trip; this proportion was lower in currently pregnant women (46%). Risk perceptions towards ZIKV were considerably lower than those towards Ebola during the 2014 epidemic. Conclusion: This study showed that fear of contracting ZIKV is not a major deterrent for travelling to high-risk areas. Pregnant women are appropriately concerned about the risk of ZIKV. Studies modelling the further spread of ZIKV need to account for these results.

The Risk of Hospitalizations with Injury Diagnoses in a Matched Cohort of Children and Adolescents with and without Attention Deficit/Hyperactivity Disorder in Germany: A Database Study.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder in children and adolescents worldwide, and children with ADHD have elevated risk of injuries. Our aim was to assess the risk of hospitalizations with injury diagnoses and their various subtypes in children and adolescents with newly diagnosed ADHD compared to those without ADHD, as well as to study sex effects on this risk in the setting of the German health care system. METHODS: The German Pharmacoepidemiological Research Database, in which 20 million insured from four statutory health insurances in Germany are included, was used to set up a matched cohort study of 3- to 17-year-old children and adolescents with and without ADHD. We calculated age-specific incidence rates and used Cox regression to obtain hazard ratios (HRs) for hospitalizations with injury diagnoses. We used the injury mortality diagnosis matrix for classification of injuries. RESULTS: The matched cohort comprised a total of 75,300 children. The age-specific incidence rates for hospitalization with injury diagnosis for males with ADHD displayed a u-shaped form with highest incidences in the in the age groups 3-6 years [26.2 per 1,000 person-years; 95% confidence interval (CI) 20.5-33.0] and 18-21 years (28.6; 22.4-36.0). Girls with ADHD were less affected in younger age-groups, but the incidence rate for 18-21 year olds was similar to boys with ADHD (26.4; 17.4-38.4). The adjusted HR for children with ADHD was 1.40 (95% CI 1.30-1.49) compared to non-affected children. With respect to nature of injury, ADHD was associated with hospitalization with injury diagnoses of the internal organs, open wounds, and contusions but not with other injuries. With respect to body regions, children with ADHD were more prone to hospitalizations with injuries of the abdomen, traumatic brain injuries, other head injuries, and system-wide injuries such as poisoning and intoxication. No significant associations were seen for the other body regions. Differences between sexes were only seen for system-wide injuries. CONCLUSION: Children and adolescents with ADHD are at an increased risk for hospitalizations with diagnoses of injuries compared to non-affected children. Despite differences in health-care systems, the risk increase is at a similar level in Germany as in other countries.