Association between education and quality of diabetes care in Switzerland

PURPOSE: Low socioeconomic status is associated with higher prevalence of diabetes, worse outcomes, and worse quality of care. We explored the relationship between education, as a measure of socioeconomic status, and quality of care in the Swiss context. PATIENTS AND METHODS: Data were drawn from a population-based survey of 519 adults with diabetes during fall 2011 and summer 2012 in a canton of Switzerland. We assessed patients and diabetes characteristics. Eleven indicators of quality of care were considered (six of process and five of outcomes of care). After bivariate analyses, regression analyses adjusted for age, sex, and diabetic complications were performed to assess the relationship between education and quality of care. RESULTS: Of 11 quality-of-care indicators, three were significantly associated with education: funduscopy (patients with tertiary versus primary education were more likely to get the exam: odds ratio, 1.8; 95% confidence interval [CI], 1.004-3.3) and two indicators of health-related quality of life (patients with tertiary versus primary education reported better health-related quality of life: Audit of Diabetes-Dependent Quality of Life: β=0.6 [95% CI, 0.2-0.97]; SF-12 mean physical component summary score: β=3.6 [95% CI, 0.9-6.4]). CONCLUSION: Our results suggest the presence of educational inequalities in quality of diabetes care. These findings may help health professionals focus on individuals with increased needs to decrease health inequalities

Protective Efficacy of Individual CD8+ T Cell Specificities in Chronic Viral Infection.

Specific CD8(+) T cells (CTLs) play an important role in resolving protracted infection with hepatitis B and C virus in humans and lymphocytic choriomeningitis virus (LCMV) in mice. The contribution of individual CTL specificities to chronic virus control, as well as epitope-specific patterns in timing and persistence of antiviral selection pressure, remain, however, incompletely defined. To monitor and characterize the antiviral efficacy of individual CTL specificities throughout the course of chronic infection, we coinoculated mice with a mixture of wild-type LCMV and genetically engineered CTL epitope-deficient mutant virus. A quantitative longitudinal assessment of viral competition revealed that mice continuously exerted CTL selection pressure on the persisting virus population. The timing of selection pressure characterized individual epitope specificities, and its magnitude varied considerably between individual mice. This longitudinal assessment of "antiviral efficacy" provides a novel parameter to characterize CTL responses in chronic viral infection. It demonstrates remarkable perseverance of all antiviral CTL specificities studied, thus raising hope for therapeutic vaccination in the treatment of persistent viral diseases

Fingolimod and tumor-infiltrating lymphocytes in checkpoint-inhibitor treated cancer patients.

Immune checkpoint inhibitors (ICIs) are emerging as the new standard of care for treating various metastatic cancers. It is known that effective anti-tumor immune responses are associated with a stronger presence of tumor-infiltrating lymphocytes (TILs) in solid tumor tissue. Cancer patients with relapsing-remitting multiple sclerosis (RRMS) are often under continuous treatment with fingolimod, an immune-modulating drug that inhibits lymphocyte egress from secondary lymphatic organs. Little is known about the effect of fingolimod on ICI cancer therapy, as fingolimod may limit the number of TILs. Here we present three patients with RRMS, who developed various cancers during fingolimod treatment. Histology of all tumors consistently showed low numbers of TILs. A second biopsy taken from one of the tumors, a melanoma, revealed a significant increase of TILs after stopping fingolimod and starting pembrolizumab, indicating a surge in the number and re-invigoration of T cells. Our study suggests that fingolimod limits the number of TILs in solid tumors and may, thus, inhibit anti-cancer immune responses

Unguis incarnatus – konservative oder operative Therapie?

Unguis incarnatus, an ingrown toenail, is a common condition in primary care, which is encountered by various medical professions. Inconsistent conservative treatment and nonindicated surgical treatment often result in complications and recurrence of the disease. Patients must be thoroughly informed about the complexity of the nail organ. This is a prerequisite to prevent trivialization of the disease and to achieve appropriate patient compliance for treatment. In this article a practical diagnostic and treatment algorithm for unguis incarnatus is presented. In mild cases of acute unguis incarnatus a consistent conservative treatment is the first-line strategy showing promising results. In cases of moderate to severe forms of acute unguis incarnatus, surgical procedures that preserve the nail matrix should be applied. For cases of chronic unguis incarnatus without an acute infection, elective partial matrixectomy can be indicated. Prior to any surgical intervention, detailed informed consent must be obtained from the patients. ZUSAMMENFASSUNG Der Unguis incarnatus ist ein häufiges Krankheitsbild, mit dem sich Patienten in der Hausarztpraxis, der dermatologischen Klinik oder der chirurgischen Notaufnahme vorstellen. Häufig führt die inkonsequente konservative Therapie oder die falsch-indizierte operative Intervention zu langwierigen und komplikationsreichen Verläufen, inklusive Rezidiven. Die Patienten sollten über die Komplexität des Nagelorgans aufgeklärt werden, um der Banalisierung der Erkrankung vorzubeugen, und eine entsprechende Compliance in der Therapie zu erreichen. In diesem Manuskript wird die sachgerechte Versorgung des Unguis incarnatus im Sinne eines praktischen Behandlungsalgorithmus dargestellt. Die konsequente konservative Therapie ist bei akutem Unguis incarnatus mit milder Ausprägung die Therapie der ersten Wahl mit guten Behandlungsergebnissen. Nagelerhaltende operative Eingriffe kommen bei moderaten/schweren akuten Formen zum Einsatz. Der chronische Unguis incarnatus, ohne floride Infektion, stellt eine elektive Operationsindikation dar. Sowohl bei den nagelerhaltenden Eingriffen als auch bei erweiterten operativen Maßnahmen ist eine chirurgische Operationsaufklärung obligat

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.

Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma

BP180-specific IgG is associated with skin adverse events, therapy response and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors

BACKGROUND: Anti-PD1/PD-L1 therapy frequently entails immune-related adverse events (irAEs) and biomarkers to predict irAEs are lacking. While checkpoint inhibitors have been found to re-invigorate T-cells, the relevance of autoantibodies remains elusive. OBJECTIVE: Our aim was to explore whether IgG autoantibodies directed against co-expressed antigens by tumor tissue and healthy skin correlate with skin irAEs and therapy outcome. METHODS: We measured skin-specific IgG via ELISA in non-small cell lung cancer (NSCLC) patients, who received anti-PD1/PD-L1 treatment between July 2015 and September 2017 at the Kantonsspital St. Gallen. Sera were sampled at baseline and during therapy after 8 weeks. RESULTS: Analysis of publicly available tumor expression data revealed that NSCLC and skin co-express BP180, BP230 and type VII collagen. Of 40 recruited patients, 16 (40%) developed a skin irAE. Only elevated anti-BP180 IgG at baseline significantly correlated with the development of skin irAEs (P=.04), therapy response (P=.01) and overall survival (P=.04). LIMITATIONS: The patients were recruited in a single tertiary care center. CONCLUSIONS: Our data suggest that the level of anti-BP180 IgG of NSCLC patients at baseline is associated with better therapy response, overall survival and a higher probability to develop skin irAEs during anti-PD1/PD-L1 treatment

Replicating viral vector platform exploits alarmin signals for potent CD8⁺ T cell-mediated tumour immunotherapy.

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTL <sup>eff</sup> ) responses. Conversely, the induction of protective tumour-specific CTL <sup>eff</sup> and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTL <sup>eff</sup> responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTL <sup>eff</sup> influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy

Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment.

The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated a Cxcl13-expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation of Il33 gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells