XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

Thank you very much for downloading modern applied statistics with s. As you may know, people have search hundreds times for their favorite readings like this modern applied statistics with s, but end up in harmful downloads. Rather than reading a good book with a cup of coffee in the afternoon, instead they cope with some harmful virus inside their laptop. modern applied statistics with s is available in our digital library an online access to it is set as public so you can download it instantly. Our digital library saves in multiple countries, allowing you to get the most less latency time to download any of our books like this one. Kindly say, the modern applied statistics with s is universally compatible with any devices to read.

Modern Applied Statistics With S

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22759

Diagnosis, management, and treatment of hepatitis C: An update

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and a potential cause of substantial morbidity and mortality in the future. The complexity and uncertainty related to the geographic distribution of HCV infection and chronic hepatitis C, determination of its associated risk factors, and evaluation of cofactors that accelerate its progression, underscore the difficulties in global prevention and control of HCV. Because there is no vaccine and no post-exposure prophylaxis for HCV, the focus of primary prevention efforts should be safer blood supply in the developing world, safe injection practices in health care and other settings, and decreasing the number of people who initiate injection drug use.

https://courses.washington.edu/conj504/readings/alter_reading3.pdf

Global epidemiology of hepatitis C virus infection

Regulatory T (T(Reg)) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting antitumour immunity. Given that T(Reg) cells can have both beneficial and deleterious effects, there is considerable interest in determining their mechanisms of action. In this Review, we describe the basic mechanisms used by T(Reg) cells to mediate suppression and discuss whether one or many of these mechanisms are likely to be crucial for T(Reg)-cell function. In addition, we propose the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate T(Reg)-cell function.

/pdf/how-regulatory-t-cells-work-3kg9ber5qg.pdf

How regulatory T cells work.

Autoantibodies are the diagnostic hallmark of autoimmune liver diseases. Indirect immunofluorescence (IFT) is the reference method for the detection of anti-mitochondrial antibodies (AMA) and anti-liver kidney microsomal type-1 (anti-LKM1) antibodies, and inhibition ELISA (iELISA) for anti-soluble liver antigen (anti-SLA) antibodies. Given the complexity of these techniques, commercial ELISAs have emerged as a practical alternative, but without head-to-head validations. This study evaluated the agreement between three commercial ELISAs and the reference techniques and the impact of polyreactive immunoglobulin G (pIgG), a recently described phenomenon in autoimmune hepatitis, on commercial ELISAs. Inter-rater reliability was assessed using Cohen-Kappa coefficient (κ). Forty-eight, 46, and 66 samples were analyzed for AMA, anti-LKM1, and anti-SLA, respectively. For AMA, one commercial assay showed high agreement (κ = 0.91 (0.78-1.00)) with the reference method, while the other two showed weak or moderate agreement. For anti-LKM1, only one commercial assay showed high agreement (κ = 0.86 (0.71-1.0)). For anti-SLA antibodies only moderate agreement was achieved (κ up to 0.71 (0.52-0.89)). There was a trend towards higher pIgG levels in false-positives in the commercial ELISAs. Patients with high suspicion of autoimmune liver diseases should be referred to reference laboratories with the capacity of performing gold standard methods if the initial ELISA-based screening was performed. 

/pdf/evaluation-of-immunoserological-detection-of-anti-liver-3rcpaamm.pdf

Evaluation of immunoserological detection of anti-liver kidney microsomal, anti-soluble liver antigen and anti-mitochondrial antibodies

Everolimus combined with low-dose tacrolimus controls histological graft injury and liver fibrosis as sufficiently as high-dose tacrolimus combined with mycophenolate after liver transplantation

Background: Autoimmune hepatitis (AIH) can be clinically controlled by first-line immunosuppressive therapy in the majority of patients. However, a selective decrease in intrahepatic regulatory T cells (Treg) was observed with immunosuppressive therapy, which was even more pronounced in patients with incomplete responses than in patients who achieved biochemical remission. The effects of salvage therapies on the number of intrahepatic T and B cells, including Treg, are unclear. The hypothesis was that calcineurin inhibitors would further decrease intrahepatic Treg numbers, and the mammalian target of rapamycin inhibitors would increase intrahepatic Treg numbers. Methods: In this retrospective study at 2 centers, CD4+, CD8+ and CD4+FOXP3+ T cells, and CD79a+ B cells were quantified in surveillance biopsies under non–standard-of-care treatment [non-SOC: calcineurin inhibitor (n=10), second-line antimetabolites (n=9), mammalian target of rapamycin inhibitors (n=4)] compared with patients under the standard-of-care treatment (SOC). Results: Intrahepatic T-cell and B-cell counts were not significantly different between patients with biochemical remission under SOC and non-SOC. However, patients with incomplete response under non-SOC had significantly lower liver infiltration with T and B cells, whereas Treg were not reduced compared with SOC. This resulted in an even higher ratio of Treg to T and B cells in non-SOC compared with SOC when biochemical remission was not achieved. The different non-SOC regimens showed no significant difference in liver infiltration with T cells, including Treg and B cells. Conclusions: Non-SOC in AIH partially controls intrahepatic inflammation by limiting the hepatic infiltration of total T and B cells as the main drivers of inflammation without further decreasing intrahepatic Treg. A negative effect of calcineurin inhibitor and a positive effect of mammalian target of rapamycin inhibitors on the number of intrahepatic Treg was not observed.

Salvage therapies of autoimmune hepatitis limit proinflammatory immune cells while sparing regulatory T cells

Introduction: Regulatory T cells (Tregs) play an important role in the maintenance of immune homeostasis and establishment of immune tolerance. Since Tregs do not secrete endogenous IL-2, they are especially dependent external IL-2. IL-2 deficiency leads to lower Treg numbers, instability of the Treg phenotype and loss of immune regulation. After organ transplantation, patients are treated with calcineurin inhibitors (CNIs) which further limits available IL-2. Application of low dose IL-2 expands Tregs, but also activates NK and CD8+ T cells. It was recently shown that graft-specific Tregs recognizing mismatched MHC I molecules via an chimeric antigen-receptor were far more potent in tolerance induction as compared to polyclonal Tregs. Methods: We therefore aimed in amplifying transferred CAR-Treg function and stability by expression of a membrane-associated IL-2 (mbIL-2). Results: mIL-2 Treg showed increased survival, better phenotypic stability and function as compared to CAR-Tregs currently used in clinical trials. They we also more stable under inflammatory conditions. In a preclinical humanized mouse model, we demonstrated that mbIL-2 CAR-Tregs showed a better survival within the Treg niche than control CAR Tregs and were even resistant to CNI therapy with no effect on other Treg so mainly acting in cis. mIL2 CAR Treg were more effective than CAR Treg in preventing the rejection of allogenic targets in humanized mice. Conclusion: The functional and phenotypic improvements of membrane attached IL-2 on CAR-Tregs will be an important step to enhance CAR-Treg therapies currently being tested in clinical trials after kidney and liver transplantation. 

404.1: Membrane-Bound IL-2 Improves Expansion, Survival, Phenotype and Function of Car Tregs and Confers Resistance to Calcineurin-Inhibitors

Introduction: Recent successes in xenogeneic organ transplantation in humans raise hopes of overcoming the worldwide organ shortage. The availability of cells, tissues, but also solid organs of porcine origin could counteract this critical circumstance from a medical point of view and reduce the increasing gap between available donor organs and patients with end-stage organ dysfunction by xenotransplantation. In contrast, the immunological barrier must be overcome. With the development of new immunosuppressants and the generation of less immunogenic donor animals, this barrier can be reduced. However, it is unclear whether this approach will lead to long-term acceptance. Methods: Here, we describe the generation of a specific chimeric antigen receptor (CAR) that recognizes the porcine SLA*0401 molecule. Results: Modification of natural Tregs (nTregs) with the SLA CAR alters the specificity of polyspecific Tregs for antigen-specific regulators without affecting their phenotype, stability, or epigenetics. Compared to nTregs, SLA CAR-Tregs showed significantly better ability to control strong immune responses in vitro and in vivo. In the humanized mouse model (NRG mice), the use of SLA CAR-Tregs resulted in the prevention of xenogeneic target cell rejection. In the highly immunogenic skin transplantation model, adoptive SLA CAR-Treg transfer protected porcine skin from recipient-driven immune responses. In the streptozotocin-induced diabetes model in NRG mice, porcine islet cells transplanted under the kidney capsule were able to restore normoglycemia after SLA CAR-Treg transfer. Conclusion: These modified CAR-Tregs have great potential for inclusion in xenogeneic organ transplantation protocols in humans, extending graft longevity through their potent immunoregulation. 

Elmar Jaeckel

Papers

Evaluation of immunoserological detection of anti-liver kidney microsomal, anti-soluble liver antigen and anti-mitochondrial antibodies

Everolimus combined with low-dose tacrolimus controls histological graft injury and liver fibrosis as sufficiently as high-dose tacrolimus combined with mycophenolate after liver transplantation

Salvage therapies of autoimmune hepatitis limit proinflammatory immune cells while sparing regulatory T cells

404.1: Membrane-Bound IL-2 Improves Expansion, Survival, Phenotype and Function of Car Tregs and Confers Resistance to Calcineurin-Inhibitors

334.6: Porcine SLA-Specific Car Treg Enable Xenotransplantation in the Absence of Immunosuppression