Proof of Concept of Telemedicine-Assisted Abdominal Ultrasound Examinations to Improve the Quality of Patient Care in Rural Areas.

(1) Background: Unclear sonographic findings without adequate specialist expertise in abdominal ultrasound (AU) may harm patients in rural areas, due to overlooked diagnoses, unnecessary additional imaging (e.g., CT scan), and/or patient transport to referral expert centers. Appropriate telemedical sonography assistance could lead to corresponding savings. (2) Methods: The study was designed as a randomized trial. Selected study centers performed AU with the best local expertise. Patients were selected and monitored according to the indication that they required AU. The study depicted three basic scenarios. Group 1 corresponds to the telemedically assisted cohort, group 2 corresponds to the non-telemedically assisted cohort, and group 3 corresponds to a telemedically supported cohort for teaching purposes. The target case number of all three groups was 400 patients (20 calculated dropouts included). (3) Discussion: This study might help to clarify whether telemedicine-assisted ultrasound by a qualified expert is non-inferior to presence sonography concerning technical success and whether one of the interventions is superior in terms of efficacy and safety in one or more secondary endpoints. Randomization was provided, as every patient who needed an AU was included and then randomized to one of the groups. The third group consisted of a lower number of patients who were selected from group 1 or 2 for teaching purposes in case of rare diseases or findings. (4) Conclusions: The study investigates whether there are benefits of telemedical ultrasound for patients, medical staff, and the health care system.

[Impact of the COVID-19 pandemic on the diagnosis and treatment of patients with head and neck cancer in Brandenburg and Berlin]. / Einfluss der COVID-19-Pandemie auf die Diagnostik und Therapie bei Patienten mit Kopf-Hals-Tumoren in Brandenburg und Berlin.

BACKGROUND: The impact of the COVID-19 pandemic on potential limitations to the diagnosis and treatment of patients with head and neck tumours has not yet been adequately investigated. There are contradictory data on this subject. Data from larger patient collectives do not exist for Germany so far. OBJECTIVE: The aim of the survey was to clarify in a large cohort whether the COVID-19 pandemic had an influence on the diagnosis and treatment of patients with head and neck tumours. METHODS: A retrospective data analysis of the reporting data of the Clinical and Epidemiological Cancer Registry of Brandenburg and Berlin (Klinisch-epidemiologischen Krebsregisters Brandenburg-Berlin, KKRBB) of 4831 cases with head and neck tumours from 2018 to 2020 was performed. The period before April 01, 2020, was evaluated as a prepandemic cohort and compared with the cases of the pandemic cohort from April 1, 2020, until December 31, 2020, in terms of patient-related baseline data, tumour location, tumour stage, tumour board and treatments administered. RESULTS: No differences were observed between the prepandemic and pandemic cohorts with regard to patient-related baseline data, tumour localisation and tumour stage. Likewise, no temporal delay in diagnosis, tumour board and treatment was evident during the pandemic period. On the contrary, the time interval between diagnosis and start of therapy was shortened by an average of 2.7 days in the pandemic phase. Tumours with T4 stage were more frequently treated surgically during the pandemic compared to the period before (20.8% vs. 29.6%), whereas primary radio(chemo)therapy decreased during the pandemic (53.3% vs. 40.4%). For all other tumour stages and entities, there were no differences in treatment. CONCLUSION: Contrary to initial speculation that the COVID-19 pandemic may have led to a decrease in tumour cases, larger tumour stages at initial presentation and a delay in diagnosis and treatment, the cohort studied for Brandenburg and Berlin showed neither a delay in tumour treatment nor an increase in tumour size and stage at initial presentation. The treatments performed, however, were subject to a change in favour of surgery and it remains to be seen whether this trend will be maintained in the long term.

Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset.

Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease. In this study, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and controls were genotyped for five immune gene SNPs in tyrosine phosphatase non-receptor type 22 (PTPN22, rs2476601), cytotoxic T-lymphocyte-associated protein 4 (CTLA4, rs3087243), tumor necrosis factor (TNF, rs1800629 and rs1799724), and interferon regulatory factor 5 (IRF5, rs3807306), which are among the most important risk variants for autoimmune diseases. Analysis of 305 ME/CFS patients and 201 healthy controls showed significant associations of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles with ME/CFS. The associations were only found in ME/CFS patients, who reported an acute onset of disease with an infection (PTPN22 rs2476601: OR 1.63, CI 1.04-2.55, p = 0.016; CTLA4 rs3087243: OR 1.53, CI 1.17-2.03, p = 0.001), but not in ME/CFS patients without infection-triggered onset (PTPN22 rs2476601: OR 1.09, CI 0.56-2.14, p = 0.398; CTLA4 rs3087243: OR 0.89, CI 0.61-1.30, p = 0.268). This finding provides evidence that autoimmunity might play a role in ME/CFS with an infection-triggered onset. Both genes play a key role in regulating B and T cell activation.

GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis.

Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer's disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system.

Cellular and humoral influenza-specific immune response upon vaccination in patients with common variable immunodeficiency and unclassified antibody deficiency.

BACKGROUND: Immunization against seasonal influenza with inactivated vaccine is recommended for patients with common variable immunodeficiency (CVID). However, humoral vaccine response in CVID patients is frequently impaired and current knowledge on T cell vaccine response in CVID and other patients with antibody deficiency is poor. OBJECTIVE: In the present study, we comparatively analyzed the antibody and T cellular immune response of patients with CVID and unclassified antibody deficiency to influenza vaccination in the season 2013-2014. METHODS: Eight patients with CVID, 8 patients with unclassified antibody deficiency and 9 healthy controls were vaccinated with a single dose of non-adjuvanted seasonal influenza vaccine. Before and 3 weeks after the vaccination antibody titers against the strains A/California/7/2009, A/Texas/50/2012, and B/Massachusetts/02/2012 included in the vaccine were measured by hemagglutination inhibition testing. Additionally, vaccine-specific T cell cytokine response was determined by stimulation with the complete vaccine in vitro. RESULTS: Whereas all healthy controls responded to vaccination with serum antibody titers, only 1/8 CVID patients and 4/8 patients with unclassified antibody deficiency showed a response against at least 1 of the 3 vaccine strains. However, 7/8 of the CVID and 6/8 of the patients with unclassified antibody deficiency had similar frequencies of vaccine-induced IFN-γ, TNF-α and IL-2 producing CD40L(+) T cells as the control group. CONCLUSION: Our data suggest that most CVID and unclassified antibody deficiency patients benefit from seasonal influenza vaccination by mounting a cellular response.

Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is considered as a neuroimmunological disease but the etiology and pathophysiology is poorly understood. Patients suffer from sustained exhaustion, cognitive impairment and an increased sensitivity to pain and sensory stimuli. A subset of patients has frequent respiratory tract infections (RRTI). Dysregulation of the sympathetic nervous system and an association with genetic variations in the catechol-O-methyltransferase (COMT) and glucocorticoid receptor genes influencing sympathetic and glucocorticoid metabolism were reported in CFS. Here, we analyzed the prevalence of SNPs of COMT and glucocorticoid receptor-associated genes in CFS patients and correlated them to immunoglobulin levels and susceptibility to RRTI. METHODS: We analyzed blood cells of 74 CFS patients and 76 healthy controls for polymorphisms in COMT, FKBP5 and CRHR1 by allelic discrimination PCR. Serum immunoglobulins were determined by immunoturbidimetric technique, cortisol levels by ECLIA. RESULTS: Contrary to previous reports, we found no difference between CFS patients and healthy controls in the prevalence of SNPs for COMT, FKBP5 and CRHR1. In patients with the Met/Met variant of COMT rs4680 we observed enhanced cortisol levels providing evidence for its functional relevance. Both enhanced IgE and diminished IgG3 levels and an increased susceptibility to RRTI were observed in CFS patients with the Met/Met variant. Such an association was not observed in 68 non-CFS patients with RRTI. CONCLUSION: Our results indicate a relationship of COMT polymorphism rs4680 with immune dysregulation in CFS providing a potential link for the association between stress and infection susceptibility in CFS.

Late-Onset Disseminated Mycobacterium avium intracellulare Complex Infection (MAC), Cerebral Toxoplasmosis and Salmonella Sepsis in a German Caucasian Patient with Unusual Anti-Interferon-Gamma IgG1 Autoantibodies.

PURPOSE: Since we described for the first time a patient with IgG4 autoantibodies to IFN-γ more than 10 years ago, many patients with IFN-γ IgG4 autoantibodies have been described, mostly in Mongolian/ Asian patients with a particular HLA background and in association with disseminated nontuberculous mycobacterial infections. Very recently, the first Caucasian US patient was reported and we now present the case of a 65-year old Caucasian woman with severe disseminated Mycobacterium avium infection, cerebral toxoplasmosis and salmonella sepsis who was tested positive for IFN-γ deficiency due to unusual anti-IFN-γ IgG1 autoantibodies. METHODS: IFN-γ production after ex vivo ConA stimulation of the patient's whole blood and isolated peripheral blood mononuclear cells was assessed. Anti-human IFN-γ antibodies were measured by Ig/Ig-subclass-specific ELISA. In vitro physiologic relevance and blocking capacity of IFN-γ-stimulation by patient's serum was analysed by flow cytometric assessment of cytokine-induced phosphorylation of pSTAT1(Y701). RESULTS: Severely impaired IFN-γ production in the patient's whole blood but normal production in peripheral blood mononuclear cells in the absence of autologous serum was observed. High titre anti-IFN-γ antibodies of the IgG1 subclass could be demonstrated in the patient's serum by ELISA. Further, the addition of patient's serum to IFN-γ-stimulated immune cells showed inhibition of STAT1 phosphorylation. CONCLUSIONS: IFN-γ autoantibodies of any IgG-isotype should be considered in patients with severe opportunistic infections independent of age at onset and ethnicity.

Human bone marrow contains a subset of quiescent early memory CD8(+) T cells characterized by high CD127 expression and efflux capacity.

Even today it is still not completely understood how CD8(+) T-cell memory is maintained long term. Since bone marrow (BM) is a niche for immunological memory, we sought to identify long-lasting early memory CD8(+) T cells in this compartment. To achieve this, we looked for CD8(+) T cells that are able to efflux Rhodamine 123, a typical property of stem cells. Indeed, we identified a distinct subset of CD8(+) T cells in BM, with the capacity to efflux and high CD127 expression. These CD127(hi) effluxers are conventional CD8(+) T cells exhibiting a broad TCR-Vß repertoire and are generated in response to viral peptides in vitro. CD127(hi) effluxer CD8(+) T cells have an early memory phenotype defined by preferential TNF-α production and a Bcl-2(hi) , KLRG-1(low) profile. This population has long telomeres and shows constitutively low frequencies of Ki-67 expression ex vivo, but has a high proliferative and differentiation capacity in vitro. However, IL-15 downmodulates CD127 in CD127(hi) effluxer CD8(+) T cells in vitro. Consequently, the CD127(low) effluxer subset may comprise cells recently exposed to IL-15. Taken together, CD127(hi) effluxer CD8(+) T cells represent a novel population of early memory T cells resident in BM with properties required for long-lived memory.

CCN1: a novel inflammation-regulated biphasic immune cell migration modulator.

In this study, we performed a comprehensive analysis of the effect of CCN1 on the migration of human immune cells. The molecule CCN1, produced by fibroblasts and endothelial cells, is considered as an important matrix protein promoting tissue repair and immune cell adhesion by binding various integrins. We recently reported that CCN1 therapy is able to suppress acute inflammation in vivo. Here, we show that CCN1 binds to various immune cells including T cells, B cells, NK cells, and monocytes. The addition of CCN1 in vitro enhances both actin polymerization and transwell migration. Prolonged incubation with CCN1, however, results in the inhibition of migration of immune cells by a mechanism that involves downregulation of PI3Kγ, p38, and Akt activation. Furthermore, we observed that immune cells themselves produce constitutively CCN1 and secretion is induced by pro-inflammatory stimuli. In line with this finding, patients suffering from acute inflammation had enhanced serum levels of CCN1. These findings extend the classical concept of CCN1 as a locally produced cell matrix adhesion molecule and suggest that CCN1 plays an important role in regulating immune cell trafficking by attracting and locally immobilizing immune cells.