An Unusual Presentation of an Enterococcus faecalis Endocarditis With Wrist and Forearm Infection: A Case Report.

In this case, an unusual presentation of Enterococcus faecalis (E.faecalis) endocarditis and clinical signs of wrist and forearm infection are reported. Before the patient was diagnosed with E.faecalis endocarditis, the patient managed to be treated with both prednisolone, various antibiotics, and colchicine on suspicion of gout, erysipelas, and deep tissue infection. Growth of E.faecalis in blood cultures raised the suspicion of endocarditis, and transesophageal echocardiography revealed vegetations on the aortic and the mitral valves with a perforation of the anterior mitral leaflet. Since the patient responded well to antibiotic treatment and there was no progression of the size of the vegetations or the perforation, it was decided by the endocarditis team to refrain from surgery. E. faecalis endocarditis can be difficult to diagnose because the patients are often elderly, and symptoms may be subtle and misleading. In the present case, the diagnostic process was based on the Danish IE guidelines, which state that E. faecalis is a typical IE bacterium. Accepting E. faecalis as a typical infective endocarditis bacterium may lead to an earlier diagnosis and treatment.

Humoral and cellular immunogenicity, effectiveness and safety of COVID-19 mRNA vaccination in patients with pediatric rheumatic diseases: A prospective cohort study.

OBJECTIVES: To evaluate immunogenicity, effectiveness and safety of COVID-19 vaccination in patients with pediatric autoimmune inflammatory rheumatic disease (pedAIIRD). METHODS: A prospective cohort study was performed at the pediatric rheumatology department of the Wilhelmina Children's Hospital in Utrecht, the Netherlands. Vaccination dates, COVID-19 cases and vaccine-related adverse events (AEs) were registered for all pedAIIRD patients during regular clinic visits from March 2021 - August 2022. SARS-CoV-2 IgG antibody levels and T-cell responses were measured from serum samples after vaccination, and clinical and drug therapy data were collected from electronic medical records. Rate of COVID-19 disease was compared between vaccinated and unvaccinated patients in a time-varying Cox regression analysis. RESULTS: A total of 157 patients were included in this study and 88 % had juvenile idiopathic arthritis (JIA). One hundred thirty-seven patients were fully vaccinated, of which 47 % used biological agents at the time of vaccination, and 20 patients were unvaccinated. Geometric mean concentrations (GMCs) of post-vaccine antibody levels against SARS-CoV-2 were above the threshold for positivity in patients who did and did not use biological agents at the time of vaccination, although biological users demonstrated significantly lower antibody levels (adjusted GMC ratio: 0.38, 95 % CI: 0.21 - 0.70). T-cell responses were adequate in all but two patients (9 %). The adjusted rate of reported COVID-19 was significantly lower for fully vaccinated patients compared to non-vaccinated patients (HR: 0.53, 95 % CI: 0.29 - 0.97). JIA disease activity scores were not significantly different after vaccination, and no serious AEs were reported. CONCLUSIONS: COVID-19 mRNA vaccines were immunogenic (both cellular and humoral), effective and safe in a large cohort of pedAIIRD patients despite their use of immunosuppressive medication.

Effects of Crossfit® and street running practice on anthropometric, lipids parameters, cardiorespiratory fitness and sleep quality.

BACKGROUND: Street running (SR) and CrossFit® (CF) have different characteristics ranging from aerobic training to high intensity. This study aimed to describe the subject's physical training, anthropometric and lipid parameters, cardiorespiratory fitness and sleep quality and duration. METHODS: Cross-sectional, study, that collected personal data, Pittsburgh Sleep Quality Index (PSQI), anthropometric assessment, cardiorespiratory fitness, and lipid profile. The subjects were separated in CF group (CFG) and SR group (SRG). RESULTS: The SRG training frequency was lower (P=0.006), had better maximum oxygen consumption (V̇O2max) levels (P<0.001). 59.3% of the SRG had excellent V̇O2max. Cardiorespiratory fitness (49.97 mL/kg/min; P=0.001) and Body Mass Index (BMI) were positively related in SR (P=0.031). An inverse correlation was found between V̇O2max and body fat percentage (BF%) (SRG: P=0.001; CFG: P=0.013). Sleep duration is strongly and inversely associated with PSQI. There was a correlation between total cholesterol (TC) and high-density lipoprotein cholesterol (P=0.020), TC and triglycerides (TGs) (P=0.029) and levels of TGs and BMI (P=0.008) in SRG. In the CFG group, there was a correlation of TC between TGs levels (P=0.025), light-density lipoprotein cholesterol (P<0.001) and BMI (P=0.050). CONCLUSIONS: The SR have a higher V̇O2max although they train less than the CF practitioners regardless of factors such as BF%, gender and age.

Prioritizing persons deprived of liberty in global guidelines for tuberculosis preventive treatment.

In this Policy Forum piece, Aditya Narayan and colleagues discuss the challenges and opportunities for tuberculosis preventive treatment in carceral settings.

The role of clopidogrel resistance-related genetic and epigenetic factors in major adverse cardiovascular events among patients with acute coronary syndrome after percutaneous coronary intervention.

Despite patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and receiving clopidogrel therapy, some patients still experience major adverse cardiovascular events (MACEs). Clopidogrel resistance, which may be regulated by genetic and epigenetic factors, may play a role in MACEs. This study aimed to determine the association between genetic (CYP2C19 and P2Y12 polymorphisms) and epigenetic (DNA methylation of CYP2C19 and P2Y12 and miRNA-26a expression) factors and their effects on MACEs among post-PCI patients. Post-PCI patients who received a standard dosage of clopidogrel at Harapan Kita Hospital between September 2018 and June 2020 were included in this study. MACEs were observed in patients within 1 year after PCI. Platelet aggregation was assessed using light transmission aggregometry (LTA). DNA methylation of CYP2C19 and P2Y12 was assessed using the bisulfite conversion method. CYP2C19 and P2Y12 polymorphisms and miRNA-26a expression were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). Among a total of 201 subjects, 49.8% were clopidogrel-resistant, and 14.9% experienced MACEs within 1 year after PCI (death was 7.5%). Hypomethylation of CYP2C19 (p = 0.037) and miRNA-26a upregulation (p = 0.020) were associated with clopidogrel resistance. CYP2C19*2/*3 polymorphisms (p = 0.047) were associated with MACEs in 1 year. This study demonstrated that hypomethylation of CYP2C19 and miRNA-26a upregulation increased the risk of clopidogrel resistance in post-PCI patients, but there was no correlation between clopidogrel resistance and MACEs. However, CYP2C19*2/*3 polymorphisms were the factors that predicted MACEs within 1 year.

A Preclinical Safety Study of Thyroid Hormone Instilled into the Lungs of Healthy Rats-an Investigational Therapy for ARDS.

Acute respiratory distress syndrome (ARDS) is a severe, life-threatening form of respiratory failure characterized by pulmonary edema, inflammation, and hypoxemia due to reduced alveolar fluid clearance (AFC). Alveolar fluid clearance is required for recovery and effective gas exchange, and higher rates of AFC are associated with reduced mortality. Thyroid hormones play multiple roles in lung function, and L-3,5,3'-triiodothyronine (T3) has multiple effects on lung alveolar type II cells. T3 enhances AFC in normal adult rat lungs when administered intramuscularly and in normal or hypoxia-injured lungs when given intratracheally. The safety of a commercially available formulation of liothyronine sodium (synthetic T3) administered intratracheally was assessed in an Investigational New Drug Application-enabling toxicology study in healthy rats. Instillation of the commercial formulation of T3 without modification rapidly caused tracheal injury and often mortality. Intratracheal instillation of T3 that was reformulated and brought to a neutral pH at the maximum feasible dose of 2.73 µg T3 in 300 µl for 5 consecutive days had no clinically relevant T3-related adverse clinical, histopathologic, or clinical pathology findings. There were no unscheduled deaths that could be attributed to the reformulated T3 or control articles, no differences in the lung weights, and no macroscopic or microscopic findings considered to be related to treatment with T3. This preclinical safety study has paved the way for a phase I/II study to determine the safety and tolerability of a T3 formulation delivered into the lungs of patients with ARDS, including coronavirus disease 2019-associated ARDS, and to measure the effect on extravascular lung water in these patients. SIGNIFICANCE STATEMENT: There is growing interest in treating lung disease with thyroid hormone [triiodothyronine (T3)] in pulmonary edema and acute respiratory distress syndrome (ARDS). However, there is not any published experience on the impact of direct administration of T3 into the lung. An essential step is to determine the safety of multiple doses of T3 administered in a relevant animal species. This study enabled Food and Drug Administration approval of a phase I/II clinical trial of T3 instillation in patients with ARDS, including coronavirus disease 2019-associated ARDS (T3-ARDS ClinicalTrials.gov Identifier NCT04115514).

Social distancing patterns in nine municipalities of Rio Grande do Sul, Brazil: the Epicovid19/RS study.

OBJECTIVE To describe social distancing practices in nine municipalities of the state of Rio Grande do Sul, Brazil, stratified by gender, age, and educational attainment. METHODS Two sequential cross-sectional studies were conducted in the municipalities of Canoas, Caxias do Sul, Ijuí, Passo Fundo, Pelotas, Porto Alegre, Santa Cruz do Sul, Santa Maria, and Uruguaiana to estimate the population prevalence of COVID-19. The study was designed to be representative of the urban population of these municipalities. A questionnaire including three questions about social distancing was also administered to the participants. Here, we present descriptive analyses of social distancing practices by subgroups and use chi-square tests for comparisons. RESULTS In terms of degree of social distancing, 25.8% of the interviewees reported being essentially isolated and 41.1% reported being quite isolated. 20.1% of respondents reported staying at home all the time, while 44.5% left only for essential activities. More than half of households reported receiving no visits from non-residents. Adults aged 20 to 59 reported the least social distancing, while more than 80% of participants aged 60 years or older reported being essentially isolated or quite isolated. Women reported more stringent distancing than men. Groups with higher educational attainment reported going out for daily activities more frequently. CONCLUSIONS The extremes of age are more protected by social distancing, but some groups remain highly exposed. This can be an important limiting factor in controlling progression of the COVID-19 pandemic.

In-depth immune cellular profiling reveals sex-specific associations with frailty.

BACKGROUND: With advancing age, the composition of leukocyte subpopulations in peripheral blood is known to change, but how this change differs between men and women and how it relates to frailty is poorly understood. Our aim in this exploratory study was to investigate whether frailty is associated with changes in immune cell subpopulations and whether this differs between men and women. Therefore, we performed in-depth immune cellular profiling by enumerating a total of 37 subpopulations of T cells, B cells, NK cells, monocytes, and neutrophils in peripheral blood of 289 elderly people between 60-87 years of age. Associations between frailty and each immune cell subpopulation were tested separately in men and women and were adjusted for age and CMV serostatus. In addition, a random forest algorithm was used to predict a participant's frailty score based on enumeration of immune cell subpopulations. RESULTS: In the association study, frailty was found to be associated with increased numbers of neutrophils in both men and in women. Frailer women, but not men, showed higher numbers of total and CD16- monocytes, and lower numbers of both CD56+ T cells and late differentiated CD4+ TemRA cells. The random forest algorithm confirmed all the findings of the association studies in men and women. In men, the predictive accuracy of the algorithm was too low (5.5%) to warrant additional conclusions on top of the ones derived from the association study. In women however, the predictive accuracy was higher (23.1%), additionally revealing that total T cell numbers and total lymphocyte numbers also contribute in predicting frailty. CONCLUSIONS: In-depth immune cellular profiling revealed consistent associations of frailty with elevated numbers of myeloid cell subpopulations in both men and women. Furthermore, additional associations were found between frailty and lower numbers of some T cell subpopulations, in women only. Thus, our study indicates sex-specific associations of immune subpopulations with frailty. We hope that our study will prompt further investigation into the sex-specific immune mechanisms associated with the development of frailty.

Unraveling the Nanoscopic Organization and Function of Central Mammalian Presynapses With Super-Resolution Microscopy.

The complex, nanoscopic scale of neuronal function, taking place at dendritic spines, axon terminals, and other minuscule structures, cannot be adequately resolved using standard, diffraction-limited imaging techniques. The last couple of decades saw a rapid evolution of imaging methods that overcome the diffraction limit imposed by Abbe's principle. These techniques, including structured illumination microscopy (SIM), stimulated emission depletion (STED), photo-activated localization microscopy (PALM), and stochastic optical reconstruction microscopy (STORM), among others, have revolutionized our understanding of synapse biology. By exploiting the stochastic nature of fluorophore light/dark states or non-linearities in the interaction of fluorophores with light, by using modified illumination strategies that limit the excitation area, these methods can achieve spatial resolutions down to just a few tens of nm or less. Here, we review how these advanced imaging techniques have contributed to unprecedented insight into the nanoscopic organization and function of mammalian neuronal presynapses, revealing new organizational principles or lending support to existing views, while raising many important new questions. We further discuss recent technical refinements and newly developed tools that will continue to expand our ability to delve deeper into how synaptic function is orchestrated at the nanoscopic level.

Social distancing patterns in nine municipalities of Rio Grande do Sul, Brazil: the Epicovid19/RS study / Padrões de distanciamento social em nove cidades gaúchas: estudo Epicovid19/RS

ABSTRACT OBJECTIVE To describe social distancing practices in nine municipalities of the state of Rio Grande do Sul, Brazil, stratified by gender, age, and educational attainment. METHODS Two sequential cross-sectional studies were conducted in the municipalities of Canoas, Caxias do Sul, Ijuí, Passo Fundo, Pelotas, Porto Alegre, Santa Cruz do Sul, Santa Maria, and Uruguaiana to estimate the population prevalence of COVID-19. The study was designed to be representative of the urban population of these municipalities. A questionnaire including three questions about social distancing was also administered to the participants. Here, we present descriptive analyses of social distancing practices by subgroups and use chi-square tests for comparisons. RESULTS In terms of degree of social distancing, 25.8% of the interviewees reported being essentially isolated and 41.1% reported being quite isolated. 20.1% of respondents reported staying at home all the time, while 44.5% left only for essential activities. More than half of households reported receiving no visits from non-residents. Adults aged 20 to 59 reported the least social distancing, while more than 80% of participants aged 60 years or older reported being essentially isolated or quite isolated. Women reported more stringent distancing than men. Groups with higher educational attainment reported going out for daily activities more frequently. CONCLUSIONS The extremes of age are more protected by social distancing, but some groups remain highly exposed. This can be an important limiting factor in controlling progression of the COVID-19 pandemic.

RESUMO OBJETIVO Descrever práticas de distanciamento social em nove municípios do Rio Grande do Sul por sexo, idade, escolaridade e cidade. MÉTODOS Foram realizados dois estudos transversais sequenciais representativos da população urbana nos municípios de Canoas, Caxias do Sul, Ijuí, Passo Fundo, Pelotas, Porto Alegre, Santa Cruz do Sul, Santa Maria e Uruguaiana com o intuito de estimar a prevalência populacional de Covid-19. Foi aplicado questionário contendo três perguntas sobre distanciamento social, cujas práticas foram submetidas a análises descritivas por subgrupos. Os dados foram comparados por testes qui-quadrado. RESULTADOS Em termos de grau de distanciamento social, 25,8% dos entrevistados relataram estar praticamente isolados e 41,1% indicam praticar bastante distanciamento. Relataram ficar em casa o tempo todo 20,1% dos entrevistados, e 44,5% informam que saem apenas para atividades essenciais. Mais da metade dos domicílios não recebe visitas de não moradores. O grupo que relatou menos distanciamento social foi o de adultos entre 20 e 59 anos, enquanto mais de 80% dos entrevistados com 60 anos ou mais relataram estar praticamente isolados ou fazendo bastante distanciamento. As mulheres relataram fazer mais distanciamento que os homens, e os grupos de maior escolaridade foram os que relataram sair diariamente para atividades regulares com mais frequência. CONCLUSÕES Os grupos mais jovens e mais idosos estão mais protegidos pelo distanciamento social, mas há grupos bastante expostos, o que pode ser um limitador importante no controle da progressão da epidemia de Covid-19.

Deoxyribonucleic acid damage and repair response in the chemotherapy of lung cancer: cross-sectional study.

This study evaluated 24 patients with lung cancer (CA) and 23 individuals with no smoking history or cancer in the family and without respiratory disease in childhood (CO). Peripheral blood lymphocytes was used to perform alkaline comet assay and to assess DNA damage as well as to evaluate methyl methane sulfonate (MMS) DNA repair after one hour and three hours at 37 ºC. The percentage of residual damage (RD) after three hours of MMS treatment, for each patient was assessed. The majority of patients were in the CA group, male patients, former smokers, with a history of smoking for 15 years and without associated comorbidities. Alkaline and residual damages were higher in the CA group when compared to controls (alkaline damage P = 0.015 and RD P = 0.05). After one hour of MMS treatment the DNA damage of the CA increased indicating failure to repair it, compared to the controls, and after three hours DNA repair was observed in both groups. Patients with lung cancer are mostly men, former smokers and with more than 15 years of tobacco consumption, undergoing chemotherapy, have high rates of DNA damage and deficiency in their ability to repair against induced damage when compared to controls.

Implementation of state-of-the-art (chemo)radiation for advanced cervix cancer in the Netherlands: A quality improvement program.

PURPOSE: To report on the "Dutch Quality Improvement Project" regarding external beam (EBRT) and brachytherapy (BT) contouring and treatment planning for locally advanced cervical cancer (LACC). MATERIAL AND METHODS: Two rounds of three workshops were organized. Data from two patients with LACC were made available for homework exercises. Contouring and treatment planning was asked for according to the EMBRACE-II protocol. The submissions were analysed and the results were addressed during the workshops. RESULTS: Almost all invited centres participated. EBRT contouring guidelines were followed within acceptable range, with major effort needed with regard to the ITV concept. BT contouring was of good quality, with especially small discrepancies for centres already participating in EMBRACE.EBRT treatment planning results improved between workshops with more centres being able to fulfil the planning aims. Guidance was especially necessary to improve the coverage probability planning for affected nodes.For BT planning prioritizing between target coverage and OAR sparing improved over time; the variation in dose to vaginal points remained considerable, as did variation in loading patterns and spatial dose distribution.The project was highly appreciated by all participants. CONCLUSION: Homework and workshop activities provide a suitable platform for discussion, exchange of experience and improvement of quality and conformity. Due to this project, radiotherapy for LACC can be administered with better and more comparable quality throughout the Netherlands.

Age-Dependent Pre-Vaccination Immunity Affects the Immunogenicity of Varicella Zoster Vaccination in Middle-aged Adults.

Background: Prevention of infectious diseases is of high priority in the rapidly aging population. Unfortunately, vaccine responses in the elderly are frequently diminished. Timely vaccination of middle-aged adults might improve the immune responses to vaccines, although knowledge on pathogen-specific immune responses and factors affecting these responses, in middle-aged adults is currently limited. We thus investigated the immune responses after vaccination with Zostavax consisting of live-attenuated varicella zoster virus (VZV). Methods: Blood samples were taken pre-, 14 days, 28 days, and 1 year after a primary VZV vaccination (Zostavax) at middle age (N = 53, 50-65 years of age). VZV-specific IFNγ-producing cells were measured by ELISpot, activated T-cells by flow cytometry, antibody levels and cytokine responses by fluorescent bead-based multiplex immunoassays, and whole blood cellular kinetics by TruCOUNT analysis. Results: Robust short-term enhancement of the VZV-specific IFNγ-producing cell numbers was observed post-vaccination in the middle-aged adults. Remarkably, long-term enhancement of VZV-specific IFNγ-producing cell numbers was induced only in participants with low numbers of VZV-specific pre-vaccination IFNγ-producing cells, who were significantly older. These participants also showed enhancement of VZV-specific activated CD4 T-cells, contrary to "exhausted" VZV-specific CD8 T-cells in participants with high numbers of VZV-specific pre-vaccination IFNγ-producing cells. Finally, a high CD4/CD8 T-cell ratio was associated with low numbers of pre-vaccination VZV-specific IFNγ-producing cells. Conclusion: These results suggest that adults in their early sixties, who showed a high CD4/CD8 T-cell ratio and low numbers of VZV-specific IFNγ-producing cells, benefit from VZV vaccination. This provides important knowledge on factors affecting VZV-specific immune responses in middle-aged adults as well as for strategies to strengthen immunity before reaching old age.

High frequency of aac(6')-Ib-cr gene associated with double mutations in gyrA and parC in Escherichia coli isolates from patients with urinary tract infections.

OBJECTIVES: The aims of this study were (i) to determine the frequency of plasmid-mediated resistance to fluoroquinolones (FQs) in Escherichia coli isolated from patients with urinary tract infections (UTIs) of nosocomial and community origin and (ii) to determine the relationships between the presence of extended-spectrum ß-lactamases (ESBLs), mutations in the gyrA and parC genes, and resistance to FQs. METHODS: A total of 71 E. coli isolates, including 38 ESBL-producers and 33 non-ESBL-producers, were analysed. The aac(6')-Ib gene was amplified using PCR and was subsequently digested with the BtsCI restriction enzyme to identify aac(6')-Ib-cr, a variant associated with FQ resistance. Detection of qnr genes was performed by multiplex PCR. In isolates that tested positive for these genes, the gyrA and parC genes were sequenced and the modulation factor of an efflux pump inhibitor was determined on the minimum inhibitory concentration (MIC) of norfloxacin. RESULTS: The frequencies of qnrS, qnrB and qnrA were 4.2%, 2.8% and 0%, respectively. The frequency of aac(6')-Ib-cr was 40.8% and this variant was associated with double mutations in gyrA and parC as well as resistance to FQs and ESBL production. Modulation of efflux pump activity was more frequent in resistant isolates that had a wild-type parC gene. CONCLUSION: An interplay of resistance mechanisms increased the level of resistance to FQs, and the high frequency of putative plasmid-mediated quinolone resistance genes associated with ESBL-producing isolates reduced therapeutic options to treat UTIs in the affected population.

Acute and chronic toxicity of diuron and carbofuran to the neotropical cladoceran Ceriodaphnia silvestrii.

In order to contribute to the increase of the body of knowledge on the sensitivity of tropical indigenous species to pesticides, acute and chronic toxicity tests were conducted with the neotropical cladoceran Ceriodaphnia silvestrii. Tests were carried out with the active ingredients diuron and carbofuran and one of their commercial formulations, the Diuron Nortox® 500 SC and the Furadan® 350 SC, respectively. For carbofuran, the active ingredient was more toxic than the commercial product, whereas for diuron, the commercial product appeared more toxic. In addition, hormetic effects on fertility were recorded for intermediate diuron concentrations. Acute and chronic toxicity data indicated that C. silvestrii was among the most sensitive invertebrate species for both test compounds. Based on concentrations measured in Brazilian water bodies, these compounds represent ecological risks for causing direct and indirect toxic effects on C. silvestrii and other aquatic organisms. Our results support previous claims on the advantages of using native species to better tune ecological risk assessment of chemicals in tropical ecosystems.

Extracellular vesicles as potential biomarkers of acute graft-vs-host disease.

Acute graft-vs-host disease (GVHD) is a serious complication after allografting. We carried out an exploratory study to investigate a potential correlation of surface antigens on extracellular vesicles (EVs) and acute GVHD. EVs were extracted from serum samples from 41 multiple myeloma patients who underwent allografting. EVs were characterized by flow cytometry using a panel of 13 antibodies against specific membrane proteins that were reported to be predictive of acute GVHD. We observed a correlation between three potential biomarkers expressed on EV surface and acute GVHD onset by both logistic regression analysis and Cox proportional hazard model. In our study, CD146 (MCAM-1) was correlated with an increased risk-by almost 60%-of developing GVHD, whereas CD31 and CD140-α (PECAM-1 and PDGFR-α) with a decreased risk-by almost 40 and 60%, respectively. These biomarkers also showed a significant change in signal level from baseline to the onset of acute GVHD. Our novel study encourages future investigations into the potential correlation between EVs and acute GVHD. Larger prospective multicenter studies are currently in progress.

Novel Intervention in the Aging Population: A Primary Meningococcal Vaccine Inducing Protective IgM Responses in Middle-Aged Adults.

INTRODUCTION: Vaccine responses are often reduced in the elderly, leaving part of the elderly population vulnerable to infectious diseases. Timely vaccination may offer a solution for strengthening memory immunity before reaching old age, which classifies middle-aged persons as a target age group for vaccine interventions. However, knowledge regarding the immunogenicity of primary immunizations in middle-aged adults is lacking. We determined the immunogenicity of a primary meningococcal vaccine towards which no or (very) low pre-vaccination immunity exists in middle-aged adults (NTR4636). METHODS: A vaccine containing multiple meningococcal groups (tetravalent) conjugated to tetanus toxoid (MenACWY-TT) was administered to middle-aged adults (50-65 years of age, N = 204) in a phase IV single-center and open-label study. Blood samples were taken pre-, 7 days, 28 days, and 1 year post-vaccination. Functional antibody titers were measured with the serum bactericidal assay (SBA). Meningococcal- and tetanus-specific antibody responses were determined with a fluorescent bead-based multiplex immunoassay. A bi-exponential decay model was used to estimate long-term protection. RESULTS: In the majority of the participants, the meningococcal vaccine clearly induced naïve responses to meningococci W (MenW) and meningococci Y (MenY) as compared to a booster response to meningococci C (MenC). After 28 days, 94, 99, and 97% of the participants possessed a protective SBA titer for MenC, MenW, and MenY, respectively, which was maintained in 76, 94, and 86% 1 year post-vaccination. At this 1-year time point, significantly lower SBA titers were found in participants without a pre-vaccination SBA titer. Overall, protective antibody titers were predicted to persist after 10 years in 40-60% of the participants. The SBA titers correlated well with the meningococcal-specific IgM responses, especially for MenW and MenY. Interestingly, these IgM responses were negatively correlated with age. CONCLUSION: Primary immunization with a tetravalent meningococcal vaccine was highly immunogenic in middle-aged adults, inducing protective antibody titers in the vast majority of the participants lasting for at least 1 year. The age-related decrease in highly functional IgM responses argues in favor of vaccination against de novo antigens before reaching old age and, hence, middle-aged persons are an age group of interest for future vaccine interventions to protect the aging population.

Elevated Immune Response Among Children 4 Years of Age With Pronounced Local Adverse Events After the Fifth Diphtheria, Tetanus, Acellular Pertussis Vaccination.

BACKGROUND: In the Netherlands, acellular pertussis vaccines replaced the more reactogenic whole-cell pertussis vaccines. This replacement in the primary immunization schedule of infants coincided with a significant increase in pronounced local adverse events (AEs) in 4 years old children shortly after the administration of a fifth diphtheria, tetanus, acellular pertussis and inactivated polio (DTaP-IPV) vaccine. The objective of this study was to investigate possible differences in vaccine antigen-specific immune responses between children with and without a pronounced local AE after the fifth DTaP-IPV vaccination. METHODS: Blood was sampled in 2 groups of 4-year-olds: a case group reporting pronounced local swelling and/or erythema up to extensive limb swelling at the injection site (n = 30) and a control group (n = 30). Peripheral blood mononuclear cells were stimulated with individual vaccine antigens. Plasma antigen-specific IgG, IgG subclass and total IgE concentrations and T-cell cytokine [interferon-gamma, interleukin (IL)-13, IL-17 and IL-10] production by stimulated peripheral blood mononuclear cells were determined by multiplex bead-based fluorescent multiplex immunoassays. RESULTS: In children with AEs, significantly higher total IgE and vaccine antigen-specific IgG and IgG4 responses as well as levels of the T-helper 2 (Th2) cytokine IL-13 were found after pertussis, tetanus and diphtheria stimulation compared with controls. CONCLUSIONS: Children with pronounced local reactions show higher humoral and cellular immune responses. Acellular vaccines are known to skew toward more Th2 responses. The pronounced local AEs may be associated with more Th2 skewing after the fifth DTaP-IPV vaccination, but other biologic factors may also impact the occurrence of these pronounced local reactions.

Differential effects of Cytomegalovirus carriage on the immune phenotype of middle-aged males and females.

The elderly population is more susceptible to infections as a result of an altered immune response, commonly referred to as immunosenescence. Cytomegalovirus (CMV)-infection associated changes in blood lymphocytes are known to impact this process, but the interaction with gender remains unclear. Therefore, we analysed the effects and interaction of gender and CMV on the absolute numbers of a comprehensive set of naive and memory T- and B-cell subsets in people between 50 and 65 years of age. Enumeration and characterisation of lymphocyte subsets by flow cytometry was performed on fresh whole blood samples from 255 middle-aged persons. CMV-IgG serostatus was determined by ELISA. Gender was a major factor affecting immune cell numbers. CMV infection was mainly associated with an expansion of late-differentiated T-cell subsets. CMV+ males carried lower numbers of total CD4+, CD4+ central memory (CM) and follicular helper T-cells than females and CMV- males. Moreover, CMV+ males had significantly lower numbers of regulatory T (Treg)-cells and memory B-cells than CMV+ females. We here demonstrate an interaction between the effects of CMV infection and gender on T- and B-cells in middle-aged individuals. These differential effects on adaptive immunity between males and females may have implications for vaccination strategies at middle-age.