Changing Face of Vaccination in Immunocompromised Hosts

Infection prevention is a key component of care and an important determinant of clinical outcomes in a diverse population of immunocompromised hosts. Vaccination remains a fundamental preventative strategy, and clear guidelines exist for the vaccination of immunocompromised individuals and close contacts. Unfortunately, adherence to such guidelines is frequently suboptimal, with consequent missed opportunities to prevent infection. Additionally, vaccination of immunocompromised individuals is known to produce responses inferior to those observed in immunocompetent hosts. Multiple factors contribute to this finding, and developing improved vaccination strategies for those at high risk of infectious complications remains a priority of care providers. Herein, we review potential factors contributing to vaccine outcomes, focusing on host immune responses, and propose a means for applying modern, innovative systems biology technology to model critical determinants of vaccination success. With influenza vaccine in solid organ transplants used as a case in point, novel means for stratifying individuals using a host "immunophenotype” are explored, and strategies for individualizing vaccine approaches tailored to safely optimize vaccine responses in those most at risk are discussed

Effect of Immunosuppression on T-Helper 2 and B-Cell Responses to Influenza Vaccination

Background. Influenza vaccine immunogenicity is suboptimal in immunocompromised patients. However, there are limited data on the interplay of T- and B- cell responses to vaccination with simultaneous immunosuppression. Methods. We collected peripheral blood mononuclear cells from transplant recipients before and 1 month after seasonal influenza vaccination. Before and after vaccination, H1N1-specific T- and B-cell activation were quantified with flow cytometry. We also developed a mathematical model using T- and B-cell markers and mycophenolate mofetil (MMF) dosage. Results. In the 47 patients analyzed, seroconversion to H1N1 antigen was demonstrated in 34%. H1N1-specific interleukin 4 (IL-4)-producing CD4+ T-cell frequencies increased significantly after vaccination in 53% of patients. Prevaccine expression of H1N1-induced HLA-DR and CD86 on B cells was high in patients who seroconverted. Seroconversion against H1N1 was strongly associated with HLA-DR expression on B cells, which was dependent on the increase between prevaccine and postvaccine H1N1-specific IL-4+CD4+ T cells (R2 = 0.35). High doses of MMF (≥2 g/d) led to lower seroconversion rates, smaller increase in H1N1-specific IL-4+CD4+ T cells, and reduced HLA-DR expression on B cells. The mathematical model incorporating a MMF-inhibited positive feedback loop between H1N1-specific IL-4+CD4+ T cells and HLA-DR expression on B cells captured seroconversion with high specificity. Conclusions. Seroconversion is associated with influenza-specific T-helper 2 and B-cell activation and seems to be modulated by MM

Structural Musculotendinous Parameters That Predict Failed Tendon Healing After Rotator Cuff Repair

BACKGROUND: Healing of the rotator cuff after repair constitutes a major clinical challenge with reported high failure rates. Identifying structural musculotendinous predictors for failed rotator cuff repair could enable improved diagnosis and management of patients with rotator cuff disease. PURPOSE: To investigate structural predictors of the musculotendinous unit for failed tendon healing after rotator cuff repair. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Included were 116 shoulders of 115 consecutive patients with supraspinatus (SSP) tear documented on magnetic resonance imaging (MRI) who were treated with an arthroscopic rotator cuff repair. Preoperative assessment included standardized clinical and imaging (MRI) examinations. Intraoperatively, biopsies of the joint capsule, the SSP tendon, and muscle were harvested for histological assessment. At 3 and 12 months postoperatively, patients were re-examined clinically and with MRI. Structural and clinical predictors of healing were evaluated using logistic and linear regression models. RESULTS: Structural failure of tendon repair, which was significantly associated with poorer clinical outcome, was associated with older age (β = 1.12; 95% CI, 1.03 to 1.26; P = .03), shorter SSP tendon length (β = 0.89; 95% CI, 0.8 to 0.98; P = .02), and increased proportion of slow myosin heavy chain (MHC)-I/fast MHC-II hybrid muscle fibers (β = 1.23; 95% CI, 1.07 to 1.42; P = .004). Primary clinical outcome (12-month postoperative Constant score) was significantly less favorable for shoulders with fatty infiltration of the infraspinatus muscle (β = -4.71; 95% CI, -9.30 to -0.12; P = .044). Conversely, a high content of fast MHC-II muscle fibers (β = 0.24; 95% CI, 0.026 to 0.44; P = .028) was associated with better clinical outcome. CONCLUSION: Both decreased tendon length and increased hybrid muscle fiber type were independent predictors for retear. Clinical outcome was compromised by tendon retearing and increased fatty infiltration of the infraspinatus muscle. A high content of fast MHC-II SSP muscle fibers was associated with a better clinical outcome

Frequency of serological non-responders and false-negative RT-PCR results in SARS-CoV-2 testing: a population-based study.

Objectives The sensitivity of molecular and serological methods for COVID-19 testing in an epidemiological setting is not well described. The aim of the study was to determine the frequency of negative RT-PCR results at first clinical presentation as well as negative serological results after a follow-up of at least 3 weeks. Methods Among all patients seen for suspected COVID-19 in Liechtenstein (n=1921), we included initially RT-PCR positive index patients (n=85) as well as initially RT-PCR negative (n=66) for follow-up with SARS-CoV-2 antibody testing. Antibodies were detected with seven different commercially available immunoassays. Frequencies of negative RT-PCR and serology results in individuals with COVID-19 were determined and compared to those observed in a validation cohort of Swiss patients (n=211). Results Among COVID-19 patients in Liechtenstein, false-negative RT-PCR at initial presentation was seen in 18% (12/66), whereas negative serology in COVID-19 patients was 4% (3/85). The validation cohort showed similar frequencies: 2/66 (3%) for negative serology, and 16/155 (10%) for false negative RT-PCR. COVID-19 patients with negative follow-up serology tended to have a longer disease duration (p=0.05) and more clinical symptoms than other patients with COVID-19 (p<0.05). The antibody titer from quantitative immunoassays was positively associated with the number of disease symptoms and disease duration (p<0.001). Conclusions RT-PCR at initial presentation in patients with suspected COVID-19 can miss infected patients. Antibody titers of SARS-CoV-2 assays are linked to the number of disease symptoms and the duration of disease. One in 25 patients with RT-PCR-positive COVID-19 does not develop antibodies detectable with frequently employed and commercially available immunoassays

Antigen Extraction and B Cell Activation Enable Identification of Rare Membrane Antigen Specific Human B Cells

Determining antigen specificity is vital for understanding B cell biology and for producing human monoclonal antibodies. We describe here a powerful method for identifying B cells that recognize membrane antigens expressed on cells. The technique depends on two characteristics of the interaction between a B cell and an antigen-expressing cell: antigen-receptor-mediated extraction of antigen from the membrane of the target cell, and B cell activation. We developed the method using influenza hemagglutinin as a model viral membrane antigen, and tested it using acetylcholine receptor (AChR) as a model membrane autoantigen. The technique involves co-culturing B cells with adherent, bioorthogonally labeled cells expressing GFP-tagged antigen, and sorting GFP-capturing, newly activated B cells. Hemagglutinin-specific B cells isolated this way from vaccinated human donors expressed elevated CD20, CD27, CD71, and CD11c, and reduced CD21, and their secreted antibodies blocked hemagglutination and neutralized viral infection. Antibodies cloned from AChR-capturing B cells derived from patients with myasthenia gravis bound specifically to the receptor on cell membrane. The approach is sensitive enough to detect antigen-specific B cells at steady state, and can be adapted for any membrane antigen

Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection.

Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8+ T cells to produce IFN-γ. Whether acetate modulates memory CD8+ T cell metabolism and function during pathogen re-encounter remains unexplored. Here we show that at sites of infection, high acetate concentrations are being reached, yet memory CD8+ T cells shut down the acetate assimilating enzymes ACSS1 and ACSS2. Acetate, being thus largely excluded from incorporation into cellular metabolic pathways, now had different effects, namely (1) directly activating glutaminase, thereby augmenting glutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggered calcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducing immunopathology. This indicates that, during different stages of the immune response, the same metabolite-acetate-induces distinct immunometabolic programs within the same cell type

Structural and thermal evolution of the eastern Aar Massif: insights from structural field work and Raman thermometry

The thermo-kinematic evolution of the eastern Aar Massif, Swiss Alps, was investigated using peak temperature data estimated from Raman spectroscopy of carbonaceous material and detailed field analyses. New and compiled temperature-time constraints along the deformed and exhumed basement-cover contact allow us to (i) establish the timing of metamorphism and deformation, (ii) track long-term horizontal and vertical orogenic movements and (iii) assess the influence of temperature and structural inheritance on the kinematic evolution. We present a new shear zone map, structural cross sections and a step-wise retrodeformation. From ca.\;26\,Ma onwards, basement-involved deformation started with the formation of relatively discrete NNW-directed thrusts. Peak metamorphic isograds are weakly deformed by these thrusts, suggesting that they initiated before or during the metamorphic peak under ongoing burial in the footwall to the basal Helvetic roof thrust. Subsequent peak- to post-metamorphic deformation was dominated by steep, mostly NNW-vergent reverse faults (ca. 22–14 Ma). Field investigations demonstrate that these shear zones were steeper than 50∘ already at inception. This produced the massif-internal structural relief and was associated with large vertical displacements (7 km shortening vs. up to 11 km exhumation). From 14 Ma onwards, the eastern Aar massif exhumed “en bloc” (i.e., without significant differential massif-internal exhumation) in the hanging wall of frontal thrusts, which is consistent with the transition to strike-slip dominated deformation observed within the massif. Our results indicate 13 km shortening and 9 km exhumation between 14 Ma and present. Inherited normal faults were not significantly reactivated. Instead, new thrusts/reverse faults developed in the basement below syn-rift basins, and can be traced into overturned fold limbs in the overlying sediment, producing tight synclines and broad anticlines along the basement-cover contact. The sediments were not detached from their crystalline substratum and formed disharmonic folds. Our results highlight decreasing rheological contrasts between (i) relatively strong basement and (ii) relatively weak cover units and inherited faults at higher temperature conditions. Both the timing of basement-involved deformation and the structural style (shear zone dip) appear to be controlled by evolving temperature conditions

Schriftliche und mündliche Textproduktion im Französischen als 1. oder 2. Fremdsprache am Ende der Primarstufe (6. Klasse)

In G. Manno, G., Egli Cuenat, M., Le Pape Racine, C., & Brühwiler, C. (Eds.). (2020). Schulischer Mehrsprachenerwerb am Übergang zwischen Primarstufe und Sekundarstufe I. Münster: Waxmann, S. 107-13

Aufbau berufsspezifischer Sprachkompetenzen in der Aus- und Weiterbildung zur Fremdsprachenlehrperson

Der vorliegende Beitrag beschreibt einen innovativen Ansatz zur Förderung berufsbezogener Sprachkompetenzen von Fremdsprachenlehrpersonen in der Schweiz. Grundlage dafür sind die berufsspezifischen Sprachkompetenzprofile für die Primarstufe und die Sekundarstufe I, welche anhand einer sprachlichen Bedarfsanalyse erarbeitet wurden. Nach einer Situierung der Thematik in der aktuellen Forschungsliteratur sowie im Schweizer Bildungskontext werden Aufbau und Entstehung der Profile erläutert und die Resultate einer Befragung von Lehrpersonen zur deren Praxisrelevanz zusammengefasst. Anschliessend werden anhand von Beispielen mögliche didaktische Umsetzungs- und Implementierungsformen der Profile skizziert.This paper describes an innovative approach to promoting language skills of foreign language teachers in Switzerland. The approach is based on the profession-related language competence profiles for foreign language teachers in primary and lower secondary education which were developed on the basis of a linguistic needs analysis. After situating the subject in both the current state of research and the Swiss educational context, the structure and the development of the profiles are briefly described and the results of a survey of teachers regarding their practical relevance are summarized. Then, possible instances of an implementation of the profiles into teacher education are outlined and illustrated by concrete examples

Schriftliche und mündliche Textproduktion im Französischen als 1. oder 2. Fremdsprache am Ende der Primarstufe (6. Klasse)

In G. Manno, G., Egli Cuenat, M., Le Pape Racine, C., & Brühwiler, C. (Eds.). (2020). Schulischer Mehrsprachenerwerb am Übergang zwischen Primarstufe und Sekundarstufe I. Münster: Waxmann, S. 107-13