COVID-19 case findings and contact tracing in South German nursing homes.

BACKGROUND: The air borne SARS-CoV-2 poses a high threat to the elderly and people with underlying diseases. COVID-19 spread quickly in South German nursing homes and for this reason called for preventive measures by the German government. The aim of this paper is to showcase the testing strategies implemented by the Public Health Department Reutlingen to control the spread of COVID-19 in local nursing homes and to report the results thereof. METHODS: This study reports COVID-19 outbreaks in nursing homes in Reutlingen County and how they were dealt with through extensive testing, contact tracing, isolation and hygiene inspections. The testing strategy consisted of three phases: In phase 1 only suspected cases, in phase 2 all staff and residents, and in phase 3 all suspected cases and their contacts were tested. RESULTS: Nearly all residents (98%) and staff members (92%) of all nursing homes in Reutlingen County were tested for SARS-COV-2. 25 of 37 nursing homes had COVID-19 cases, 5 had 30-81 cases/home. 62% of the 395 nursing homes cases were residents, but less than half of them exhibited symptoms (41%). The cases uncovered in nursing homes represented 26% of all 1529 cases in Reutlingen County during the time of this study. CONCLUSIONS: Many COVID-19 cases were discovered through extensive testing, allowing for early interventions. The results shed light on the COVID-19 situation in nursing homes and allowed for individually designed preventive measures. The results also lead to a change in the German legislation. The outbreak management methods of the Public Health Department Reutlingen may also be applicable in other countries.

Epidemiological analysis of 3,219 COVID-19 outbreaks in the state of Baden-Wuerttemberg, Germany.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emerged as an unprecedented global crisis challenging health systems. This paper aims to assess and characterise SARS-CoV-2 outbreaks in the state of Baden-Wuerttemberg to identify groups at greatest risk, to establish early measures to curb transmission. We analysed all mandatory notified (i.e. laboratory-confirmed) coronavirus disease (COVID-19) outbreaks with more than two cases in Baden-Wuerttemberg from calendar weeks 18-49 (from 27 April to 6 December 2020). We used the following classification for settings: asylum and refugee accommodation, care homes, care facilities, day care child centres, hobby-related, hospitality, hospitals, households, other, residence halls, schools, supported housing, training schools, transportation, treatment facilities and workplace (occupational). We used R program version 3.6.3 for analysis. In our analysis, 3219 outbreaks with 22 238 individuals were included. About 48% were in household and hobby-related settings. Care homes accounted for 9.5% of outbreaks and 21.6% of cases. The median age across all settings was 43 (interquartile range (IQR) 24-63). The median age of cases in care homes was 81 (IQR 56-88). Of all reported cases in care homes, 72.1% were women. Over 30% (466/1511) of hospitalisations were among cases in care homes compared to 17.7% (268/1511) in households. Overall, 70% (500/715) of all deceased persons in outbreaks in the study period were in care homes compared to 4.2% in household settings (30/715). We observed an exponential increase in the number of notified outbreaks starting around the 41st week with N = 291 outbreaks reported in week 49. The median number of cases in outbreaks in care homes and care facilities after the 40th week was 14 (IQR 5-29) and 11 (IQR 5-20), respectively, compared to 3 (IQR 3-5) in households. We observed an increase in hospitalisations, and mortality associated with COVID-19 outbreaks in care homes after the 40th week. We found the care home demographic to be at greatest risk after the 40th week, based on the exponential increase in outbreaks, the number of cases, hospitalisations and mortality trends. Our analysis highlights the necessity of targeted, setting-specific approaches to control transmission in this vulnerable population. Regular screening of staff members and visitors' using rapid antigen point-of-care-tests could be a game-changer in curbing transmission in this setting.

The COVID-19 pandemic preparedness simulation tool: CovidSIM.

BACKGROUND: Efficient control and management in the ongoing COVID-19 pandemic needs to carefully balance economical and realizable interventions. Simulation models can play a cardinal role in forecasting possible scenarios to sustain decision support. METHODS: We present a sophisticated extension of a classical SEIR model. The simulation tool CovidSIM Version 1.0 is an openly accessible web interface to interactively conduct simulations of this model. The simulation tool is used to assess the effects of various interventions, assuming parameters that reflect the situation in Austria as an example. RESULTS: Strict contact reduction including isolation of infected persons in quarantine wards and at home can substantially delay the peak of the epidemic. Home isolation of infected individuals effectively reduces the height of the peak. Contact reduction by social distancing, e.g., by curfews, sanitary behavior, etc. are also effective in delaying the epidemic peak. CONCLUSIONS: Contact-reducing mechanisms are efficient to delay the peak of the epidemic. They might also be effective in decreasing the peak number of infections depending on seasonal fluctuations in the transmissibility of the disease.

[Surgical techniques in the treatment of basal cell carcinoma-a prospective investigation]. / Chirurgische Techniken in der Therapie des Basalzellkarzinoms ­ eine prospektive Untersuchung.

BACKGROUND: Basal cell carcinomas are the most frequent epithelial skin tumors and a frequent indication for dermatological interventions. Despite the establishment of drug treatment options, surgery is still the treatment of choice. Various options are available ranging from curettage to complex dermatosurgical procedures. In addition to the main aspect of low local recurrence rates, esthetic factors and the number of procedures are also important for the choice of treatment. METHODS: In this study 347 patients with 398 basal cell carcinomas (nodular type, diameter up to 10 mm) were prospectively examined. The patients were randomized into two treatment arms: in one group the tumor was treated by ring curettage and in the other group the tumor was excised. Patients who underwent 3D histologically controlled surgery due to basal cell carcinoma during the same investigation period served as controls. RESULTS: The highest local recurrence rate was observed after curettage (14.0%), whereas the group with 3D histology had the lowest recurrence rate (0.9%, p < 0.001). In the 3D group, more re-excisions were required to achieve complete tumor clearance compared to the group who underwent excisions with serial section histology. Patients rated the esthetic outcome best after curettage. The median follow-up was 3.9 years. CONCLUSION: The choice of surgical treatment for small nodular basal cell carcinomas depends on individual circumstances. Excisions controlled by 3D histology with wound closure after complete tumor clearance showed the lowest recurrence rate in our study; however, curettage is also a possible surgical treatment option with minimal effort and an acceptable recurrence rate, which can lead to good esthetic results.

IL-4 abrogates T(H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells.

Interleukin 4 (IL-4) can suppress delayed-type hypersensitivity reactions (DTHRs), including organ-specific autoimmune diseases in mice and humans. Despite the broadly documented antiinflammatory effect of IL-4, the underlying mode of action remains incompletely understood, as IL-4 also promotes IL-12 production by dendritic cells (DCs) and IFN-γ-producing T(H)1 cells in vivo. Studying the impact of IL-4 on the polarization of human and mouse DCs, we found that IL-4 exerts opposing effects on the production of either IL-12 or IL-23. While promoting IL-12-producing capacity of DCs, IL-4 completely abrogates IL-23. Bone marrow chimeras proved that IL-4-mediated suppression of DTHRs relies on the signal transducer and activator of transcription 6 (STAT6)-dependent abrogation of IL-23 in antigen-presenting cells. Moreover, IL-4 therapy attenuated DTHRs by STAT6- and activating transcription factor 3 (ATF3)-dependent suppression of the IL-23/T(H)17 responses despite simultaneous enhancement of IL-12/TH1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/T(H)17 responses without blocking IL-12/T(H)1, selective IL-4-mediated IL-23/T(H)17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12-dependent T(H)1 responses.

Direct and indirect effects of influenza vaccination.

BACKGROUND: After vaccination, vaccinees acquire some protection against infection and/or disease. Vaccination, therefore, reduces the number of infections in the population. Due to this herd protection, not everybody needs to be vaccinated to prevent infections from spreading. METHODS: We quantify direct and indirect effects of influenza vaccination examining the standard Susceptible-Infected-Recovered (SIR) and Susceptible-Infected-Recovered-Susceptible (SIRS) model as well as simulation results of a sophisticated simulation tool which allows for seasonal transmission of four influenza strains in a population with realistic demography and age-dependent contact patterns. RESULTS: As shown analytically for the simple SIR and SIRS transmission models, indirect vaccination effects are bigger than direct ones if the effective reproduction number of disease transmission is close to the critical value of 1. Simulation results for 20-60% vaccination with live influenza vaccine of 2-17 year old children in Germany, averaged over 10 years (2017-26), confirm this result: four to seven times as many influenza cases are prevented among non-vaccinated individuals as among vaccinees. For complications like death due to influenza which occur much more frequently in the unvaccinated elderly than in the vaccination target group of children, indirect benefits can surpass direct ones by a factor of 20 or even more than 30. CONCLUSIONS: The true effect of vaccination can be much bigger than what would be expected by only looking at vaccination coverage and vaccine efficacy.

Local measles vaccination gaps in Germany and the role of vaccination providers.

BACKGROUND: Measles elimination in Europe is an urgent public health goal, yet despite the efforts of its member states, vaccination gaps and outbreaks occur. This study explores local vaccination heterogeneity in kindergartens and municipalities of a German county. METHODS: Data on children from mandatory school enrolment examinations in 2014/15 in Reutlingen county were used. Children with unknown vaccination status were either removed from the analysis (best case) or assumed to be unvaccinated (worst case). Vaccination data were translated into expected outbreak probabilities. Physicians and kindergartens with statistically outstanding numbers of under-vaccinated children were identified. RESULTS: A total of 170 (7.1%) of 2388 children did not provide a vaccination certificate; 88.3% (worst case) or 95.1% (best case) were vaccinated at least once against measles. Based on the worst case vaccination coverage, <10% of municipalities and <20% of kindergartens were sufficiently vaccinated to be protected against outbreaks. Excluding children without a vaccination certificate (best case) leads to over-optimistic views: the overall outbreak probability in case of a measles introduction lies between 39.5% (best case) and 73.0% (worst case). Four paediatricians were identified who accounted for 41 of 109 unvaccinated children and for 47 of 138 incomplete vaccinations; GPs showed significantly higher rates of missing vaccination certificates and unvaccinated or under-vaccinated children than paediatricians. CONCLUSIONS: Missing vaccination certificates pose a severe problem regarding the interpretability of vaccination data. Although the coverage for at least one measles vaccination is higher in the studied county than in most South German counties and higher than the European average, many severe and potentially dangerous vaccination gaps occur locally. If other federal German states and EU countries show similar vaccination variability, measles elimination may not succeed in Europe.

Influence of social contact patterns and demographic factors on influenza simulation results.

BACKGROUND: The demographic composition and the frequency and nature of social contacts may affect the spread of influenza virus in a population, resulting in distinct age-dependent immunity patterns. As demography and social contact rates differ strongly between European countries, this may impact infection incidence and vaccine effectiveness and thus limit the extent to which conclusions derived from observations in one country can be generalized to others. In the current study, we aimed to decipher the impact of social contact patterns and demographic factors on simulation results and, thus, to determine to what extent vaccination results can be generalized. METHODS: We simulated the transmission of four influenza strains (A(H1N1), A(H3N2), B/Victoria, B/Yamagata) in Belgium, Finland, Germany, GB, Italy, Luxembourg, Netherlands and Poland, using the simulation tool 4Flu. Individuals were connected in a dynamically evolving age-dependent contact network based on the POLYMOD study. RESULTS: When averaged over 20 years, simulation results without vaccination ranged from annually 20,984 (Germany) to 31,322 infections (Italy) per 100,000 individuals. QIV annually prevented 1758 (Poland) to 7720 infections (Germany) per 100,000. Variability of prevented cases remained high when the country-specific vaccination was replaced by unified coverage, but was reduced considerably if the same demography was used for all countries, or even more so when the same contact matrix was used. CONCLUSIONS: Contact matrix and demography strongly influence the age-dependent incidence of influenza and the success of vaccination. Projecting simulation results from one country to another can, therefore, lead to erroneous results.

[Public Health initiative for improved vaccination for asylum seekers]. / ÖGD-Initiative zur Verbesserung der Durchimpfung bei Asylsuchenden.

The number of asylum seekers in Germany has increased dramatically in 2015. Their medical care includes the officially recommended vaccinations; yet, no detailed information on this is yet available in Germany. In light of the rising number of asylum seekers, we have developed a concept to facilitate their vaccination. This concept includes the coordination of different partners, the supply of vaccines and other materials through the local health office, and the cooperation with the local physicians' association. To evaluate and accelerate progress, we compared the number of vaccinations conducted by physicians independently of the vaccination concept with those conducted within the new concept. For the period of investigation, 2,256 new asylum seekers were temporarily accommodated in the facilities. The vaccination concept was applied in only some of the facilities. Twenty-eight percent of all asylum seekers (642) were vaccinated at least once; 89 % of the vaccinees (571) were vaccinated within the newly developed concept. In the facilities that were not included in this concept, only 6 % of the refugees were vaccinated, whereas in the facilities that were included up to 58 % were vaccinated. Even though the new concept has started successfully, further innovations are required to reach sufficient vaccination coverage among asylum seekers. In view of the large number of new asylum seekers expected, the adjustment and expansion of the new concept requires professional planning and coordination. Furthermore, additional resources are required.

In vivo optical imaging of matrix metalloproteinase activity detects acute and chronic contact hypersensitivity reactions and enables monitoring of the antiinflammatory effects of N-acetylcysteine.

The aim of this study was to determine whether the severity of contact hypersensitivity reactions (CHSRs) can be observed by noninvasive in vivo optical imaging of matrix metalloproteinase (MMP) activity and whether this is an appropriate tool for monitoring an antiinflammatory effect. Acute and chronic CHSRs were elicited by application of a 1% trinitrochlorobenzene (TNCB) solution for up to five times on the right ear of TNCB-sensitized mice. N-Acetylcysteine (NAC)-treated and sham-treated mice were monitored by measuring ear swelling and optical imaging of MMP activity. In addition, we performed hematoxylin-eosin staining and CD31 immunohistochemistry for histopathologic analysis of the antiinflammatory effects of NAC. The ear thickness and the MMP activity increased in line with the increasing severity of the CHSR. MMP activity was enhanced 2.5- to 2.7-fold during acute CHSR and 3.1- to 4.1-fold during chronic CHSR. NAC suppressed ear swelling and MMP signal intensity in mice with acute and chronic CHSR. During chronic CHSR, the vessel density was significantly reduced in ear sections derived from NAC-treated compared to sham-treated mice. In vivo optical imaging of MMP activity measures acute and chronic CHSR and is useful to monitor antiinflammatory effects.

4Flu - an individual based simulation tool to study the effects of quadrivalent vaccination on seasonal influenza in Germany.

BACKGROUND: Influenza vaccines contain Influenza A and B antigens and are adjusted annually to match the characteristics of circulating viruses. In Germany, Influenza B viruses belonged to the B/Yamagata lineage, but since 2001, the antigenically distinct B/Victoria lineage has been co-circulating. Trivalent influenza vaccines (TIV) contain antigens of the two A subtypes A(H3N2) and A(H1N1), yet of only one B lineage, resulting in frequent vaccine mismatches. Since 2012, the WHO has been recommending vaccine strains from both B lineages, paving the way for quadrivalent influenza vaccines (QIV). METHODS: Using an individual-based simulation tool, we simulate the concomitant transmission of four influenza strains, and compare the effects of TIV and QIV on the infection incidence. Individuals are connected in a dynamically evolving age-dependent contact network based on the POLYMOD matrix; their age-distribution reproduces German demographic data and predictions. The model considers maternal protection, boosting of existing immunity, loss of immunity, and cross-immunizing events between the B lineages. Calibration to the observed annual infection incidence of 10.6% among young adults yielded a basic reproduction number of 1.575. Vaccinations are performed annually in October and November, whereby coverage depends on the vaccinees' age, their risk status and previous vaccination status. New drift variants are introduced at random time points, leading to a sudden loss of protective immunity for part of the population and occasionally to reduced vaccine efficacy. Simulations run for 50 years, the first 30 of which are used for initialization. During the final 20 years, individuals receive TIV or QIV, using a mirrored simulation approach. RESULTS: Using QIV, the mean annual infection incidence can be reduced from 8,943,000 to 8,548,000, i.e. by 395,000 infections, preventing 11.2% of all Influenza B infections which still occur with TIV (95% CI: 10.7-11.8%). Using a lower B lineage cross protection than the baseline 60%, the number of Influenza B infections increases and the number additionally prevented by QIV can be 5.5 times as high. CONCLUSIONS: Vaccination with TIV substantially reduces the Influenza incidence compared to no vaccination. Depending on the assumed degree of B lineage cross protection, QIV further reduces Influenza B incidence by 11-33%.

The epidemiological impact of childhood influenza vaccination using live-attenuated influenza vaccine (LAIV) in Germany: predictions of a simulation study.

BACKGROUND: Routine annual influenza vaccination is primarily recommended for all persons aged 60 and above and for people with underlying chronic conditions in Germany. Other countries have already adopted additional childhood influenza immunisation programmes. The objective of this study is to determine the potential epidemiological impact of implementing paediatric influenza vaccination using intranasally administered live-attenuated influenza vaccine (LAIV) in Germany. METHODS: A deterministic age-structured model is used to simulate the population-level impact of different vaccination strategies on the transmission dynamics of seasonal influenza in Germany. In our base-case analysis, we estimate the effects of adding a LAIV-based immunisation programme targeting children 2 to 17 years of age to the existing influenza vaccination policy. The data used in the model is based on published evidence complemented by expert opinion. RESULTS: In our model, additional vaccination of children 2 to 17 years of age with LAIV leads to the prevention of 23.9 million influenza infections and nearly 16 million symptomatic influenza cases within 10 years. This reduction in burden of disease is not restricted to children. About one third of all adult cases can indirectly be prevented by LAIV immunisation of children. CONCLUSIONS: Our results demonstrate that vaccinating children 2-17 years of age is likely associated with a significant reduction in the burden of paediatric influenza. Furthermore, annual routine childhood vaccination against seasonal influenza is expected to decrease the incidence of influenza among adults and older people due to indirect effects of herd protection. In summary, our model provides data supporting the introduction of a paediatric influenza immunisation programme in Germany.

Fetal mortality at and beyond term in singleton pregnancies in Baden-Wuerttemberg/Germany 2004-2009.

OBJECTIVE: To evaluate the risk of intrauterine fetal death (IUFD) in low-risk pregnancies at and beyond term under conditions of fetal monitoring practiced in Baden-Wuerttemberg/Germany (BW). METHODS: We performed a retrospective analysis of 472,843 low-risk singleton pregnancies in BW, using data from the local National Medical Birth registry. The setting of fetal monitoring was uniform during the analyzed time period (2004-2009). We calculated the IUFD rate per 1,000 ongoing pregnancies for each gestational week and compared our results to other published studies using the same calculation scheme. RESULTS: Our study demonstrates a markedly lower risk of IUFD between 37+0/7 and 42+6/7 weeks of pregnancy when compared with data from Scotland, England, and Sweden collected between 1985 and 1996. When our data were compared to a recently published study from California reporting on deliveries between 1997 and 2006, the risk for IUFD was only significantly lower from 41 weeks onward. The distribution of weekly delivery rates shows a trend to earlier deliveries in weeks 37+0/7 to 39+6/7 for the actual cohorts from California and BW. CONCLUSION: In our study, the risk for IUFD in pregnancies going beyond term is remarkably lower than found in studies published about other countries. Our results do not support current guidelines which recommend a routine induction of labor in low risk pregnancies at 41+0/7 weeks of pregnancy.

Long-term in vivo imaging of ß-amyloid plaque appearance and growth in a mouse model of cerebral ß-amyloidosis.

Extracellular deposition of the amyloid-ß peptide (Aß) in the brain parenchyma is a hallmark lesion of Alzheimer's disease (AD) and a predictive marker for the progression of preclinical to symptomatic AD. Here, we used multiphoton in vivo imaging to study Aß plaque formation in the brains of 3- to 4-month-old APPPS1 transgenic mice over a period of 6 months. A novel head fixation system provided robust and efficient long-term tracking of single plaques over time. Results revealed an estimated rate of 35 newly formed plaques per cubic millimeter of neocortical volume per week at 4-5 months of age. At later time points (i.e., in the presence of increasing cerebral ß-amyloidosis), the number of newly formed plaques decreased. On average, both newly formed and existing plaques grew at a similar growth rate of 0.3 µm (radius) per week. A solid knowledge of the dynamics of cerebral ß-amyloidosis in mouse models provides a powerful tool to monitor preclinical Aß targeting therapeutic strategies and eases the interpretation of diagnostic amyloid imaging in humans.

Finding and removing highly connected individuals using suboptimal vaccines.

BACKGROUND: Social networks are often highly skewed, meaning that the vast majority of the population has only few contacts whereas a small minority has a large number of contacts. These highly connected individuals may play an important role in case of an infectious disease outbreak. METHODS: We propose a novel strategy of finding and immunizing highly connected individuals and evaluate this strategy by computer simulations, using a stochastic, individual-and network-based simulation approach. A small random sample of the population is asked to list their acquaintances, and those who are mentioned most frequently are offered vaccination. This intervention is combined with case isolation and contact tracing. RESULTS: Asking only 10% of the population for 10 acquaintances each and vaccinating the most frequently named people strongly diminishes the magnitude of an outbreak which would otherwise have exhausted the available isolation units and gone out of control. It is extremely important to immunize all identified highly connected individuals. Omitting a few of them because of unsuccessful vaccination jeopardizes the overall success, unless non-immunized individuals are taken under surveillance. CONCLUSIONS: The strategy proposed in this paper is particularly successful because it attacks the very point from which the transmission network draws its strength: the highly connected individuals. Current preparedness and containment plans for smallpox and other infectious diseases may benefit from such knowledge.

A Computational Model of Bacterial Population Dynamics in Gastrointestinal Yersinia enterocolitica Infections in Mice.

The complex interplay of a pathogen with its virulence and fitness factors, the host's immune response, and the endogenous microbiome determine the course and outcome of gastrointestinal infection. The expansion of a pathogen within the gastrointestinal tract implies an increased risk of developing severe systemic infections, especially in dysbiotic or immunocompromised individuals. We developed a mechanistic computational model that calculates and simulates such scenarios, based on an ordinary differential equation system, to explain the bacterial population dynamics during gastrointestinal infection. For implementing the model and estimating its parameters, oral mouse infection experiments with the enteropathogen, Yersinia enterocolitica (Ye), were carried out. Our model accounts for specific pathogen characteristics and is intended to reflect scenarios where colonization resistance, mediated by the endogenous microbiome, is lacking, or where the immune response is partially impaired. Fitting our data from experimental mouse infections, we can justify our model setup and deduce cues for further model improvement. The model is freely available, in SBML format, from the BioModels Database under the accession number MODEL2002070001.

Cost-utility analysis of increasing uptake of universal seasonal quadrivalent influenza vaccine (QIV) in children aged 6 months and older in Germany.

Seasonal influenza causes many cases and related deaths in Europe annually, despite ongoing vaccination programs for older adults and people at high-risk of complications. Children have the highest risk of infection and play a key role in disease transmission. Our cost-utility analysis, based on a dynamic transmission model, estimated the impact of increasing the current vaccination coverage with inactivated quadrivalent influenza vaccine in Germany to all (healthy and high-risk) children under 5 years of age (40% uptake), or under 18 years (40% uptake), or only high-risk children under 18 years (90% uptake). Eight influenza complications were modeled, hospitalization and death rates were based on age and risk status. All three vaccination strategies provided more health benefits than the existing vaccination situation, reducing influenza cases, complications, hospitalizations and deaths across the entire population. The strategy targeting all children under 5 years was highly cost-effective (€6/quality-adjusted life-year gained, payer perspective). The other strategies were cost saving from the payer and societal perspectives. The vaccination strategy targeting all children under 18 years was estimated to provide the most health benefits (preventing on average 1.66 million cases, 179,000 complications, 14,000 hospitalizations and 3,600 deaths due to influenza annually) and the most cost savings (annually €20.5 million and €731.3 million from payer and societal perspectives, respectively). Our analysis provides policy decision-makers with evidence supporting strategies to expand childhood influenza vaccination, to directly protect children, and indirectly all other unvaccinated age groups, in order to reduce the humanistic and economic burden on healthcare systems and society.

What is the context? Every winter, millions of people in Europe become ill due to influenza (flu), and some need to be hospitalized for complications that can sometimes lead to death.While mainly older adults and people with chronic illness are at higher risk of complications from influenza, children have the highest risk of infection and of transmitting the disease.Current vaccination policies in Europe, including Germany, target older adults and high-risk populations (pregnant women, children and other age groups with chronic diseases).What is new? This analysis simulates the effects of expanding current German vaccination programs in high-risk children to include healthy children, and of increasing vaccination coverage rates, for direct protection against infection, and to reduce the disease transmission in the rest of the population.We modeled three vaccination strategies: vaccinating 40% of all (healthy and high- risk) children under 5 years old;vaccinating 40% of all (healthy and high-risk) children under 18 years old;vaccinating 90% of high-risk children under 18 years old.What is the impact? All three strategies resulted in health gains, as more influenza cases, complications and deaths were prevented in all age groups of the population compared to the current situation.The strategies targeting both healthy and high-risk children provided the greatest health benefits. In particular, a vaccination policy targeting all children under 18 years old was predicted to provide the most health benefits as well as the highest cost savings: the increased costs of vaccination were more than offset by the savings in disease management costs as a result of having fewer influenza patients.Vaccinating healthy children against influenza is expected to significantly reduce the disease burden in the total population while saving costs, due to reduced transmission of the disease.

Direct crosstalk between mast cell-TNF and TNFR1-expressing endothelia mediates local tissue inflammation.

Signaling through tumor necrosis factor receptor 1 (TNFR1) controls bacterial infections and the induction of inflammatory Th1 cell-mediated autoimmune diseases. By dissecting Th1 cell-mediated delayed-type hypersensitivity responses (DTHRs) into single steps, we localized a central defect to the missing TNFR1 expression by endothelial cells (ECs). Adoptive transfer and mast cell knockin experiments into Kit(W)/Kit(W-v), TNF(-/-), and TNFR1(-/-) mice showed that the signaling defect exclusively affects mast cell-EC interactions but not T cells or antigen-presenting cells. As a consequence, TNFR1(-/-) mice had strongly reduced mRNA and protein expression of P-selectin, E-selectin, ICAM-1, and VCAM-1 during DTHR elicitation. In consequence, intravital fluorescence microscopy revealed up to 80% reduction of leukocyte rolling and firm adhesion in TNFR1(-/-) mice. As substitution of TNF(-/-) mice with TNF-producing mast cells fully restored DTHR in these mice, signaling of mast cell-derived TNF through TNFR1-expressing ECs is essential for the recruitment of leukocytes into sites of inflammation.