Checkpoint Inhibitors and Therapeutic Vaccines for the Treatment of Chronic HBV Infection

Treatment of chronic hepatitis B virus (HBV) infection is highly effective in suppressing viral replication, but complete cure is rarely achieved. In recent years, substantial progress has been made in the development of immunotherapy to treat cancer. Applying these therapies to improve the management of chronic HBV infection is now being attempted, and has become an area of active research. Immunotherapy with vaccines and checkpoint inhibitors can boost T cell functions in vitro, and therefore may be used to reinvigorate the impaired HBV-specific T cell response. However, whether these approaches will suffice and restore antiviral T cell immunity to induce long-term HBV control remains an open question. Recent efforts have begun to describe the phenotype and function of HBV-specific T cells on the single epitope level. An improved understanding of differing T cell specificities and their contribution to HBV control will be instrumental for advancement of the field. In this review, we outline correlates of successful versus inadequate T cell responses to HBV, and discuss the rationale behind therapeutic vaccines and checkpoint inhibitors for the treatment of chronic HBV infection

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N=10,535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β=0.120). For the second research question, this was the case for 65% of the teams (median reported β=0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

A Many-analysts Approach to the Relation Between Religiosity and Well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N = 10, 535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β = 0.120). For the second research question, this was the case for 65% of the teams (median reported β = 0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

Complex interventions for preventing diabetic foot ulceration

BACKGROUND: Ulceration of the feet, which can lead to the amputation of feet and legs, is a major problem for people with diabetes mellitus, and can cause substantial economic burden. Single preventive strategies have not been shown to reduce the incidence of foot ulceration to a significant extent. Therefore, in clinical practice, preventive interventions directed at patients, healthcare providers and/or the structure of health care are often combined (complex interventions). OBJECTIVES: To assess the effectiveness of complex interventions in the prevention of foot ulcers in people with diabetes mellitus compared with single interventions, usual care or alternative complex interventions. A complex intervention is defined as an integrated care approach, combining two or more prevention strategies on at least two different levels of care: the patient, the healthcare provider and/or the structure of health care. SEARCH METHODS: For the second update we searched the Cochrane Wounds Group Specialised Register (searched 22 May 2015), The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 4), The Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library 2015, Issue 4), The Health Technology Assessment Database (HTA) (The Cochrane Library 2015, Issue 4), The NHS Economic Evaluation Database (NHS EED) (The Cochrane Library 2015, Issue 4), Ovid MEDLINE (1946 to 22 May 2015), Ovid MEDLINE (In-Process & Other Non-Indexed Citations 21 May, 2015), Ovid EMBASE (1974 to 21 May, 2015) and EBSCO CINAHL (1982 to 22 May, 2015). SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) which compared the effectiveness of combinations of preventive strategies, not solely patient education, for the prevention of foot ulcers in people with diabetes mellitus, with single interventions, usual care or alternative complex interventions. DATA COLLECTION AND ANALYSIS: Two review authors were assigned to independently select studies, to extract study data and to assess risk of bias of included studies, using predefined criteria. MAIN RESULTS: Only six RCTs met the criteria for inclusion. The study characteristics differed substantially in terms of healthcare settings, the nature of the interventions studied and outcome measures reported. In three studies that compared the effect of an education-centred complex intervention with usual care or written instructions, only little evidence of benefit was found. Three studies compared the effect of more intensive and comprehensive complex interventions with usual care. One study found a significant and cost-effective reduction, one of lower extremity amputations (RR 0.30, 95% CI 0.31 to 0.71). One other study found a significant reduction of both amputation and foot ulcers. The last study reported improvement of patients' self care behaviour. All six included RCTs were at high risk of bias, with hardly any of the predefined quality assessment criteria met. AUTHORS' CONCLUSIONS: There is no high-quality research evidence evaluating complex interventions for preventing diabetic foot ulceration and insufficient evidence of benefit

Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection

OBJECTIVE: Chronic HBV infection affects more than 250 million people worldwide and remains a global healthcare problem in part because we lack curative treatment. Sustained viral control requires HBV-specific T cells, but these become functionally impaired in chronic infection. Clinical evidence indicates that functional cure of HBV infection by the host immune response is feasible. Developing T cell-based therapies able to achieve functional cure will require identification of the requirements for a successful T cell response against HBV and the relative contribution of individual T cell specificities to HBV control. DESIGN: The phenotype and function of HBV-specific T cells were studied directly ex vivo using fluorochrome-labelled multimers. We studied multiple HBV-specific T cell specificities targeting different HBV proteins in individuals with either an acute self-limiting or chronic HBV infection. RESULTS: We detected strong T cell responses targeting multiple HBV viral proteins in acute self-limiting and low-frequency core and polymerase-specific T cells in chronic infection. Expression of the T cell inhibitory receptor PD-1, as well as T cell differentiation, T cell function and T cell regulation differed by stages and outcomes of infection. In addition, these features differed significantly between T cells targeting different HBV specificities. CONCLUSION: HBV-specific T cells with different target specificities are characterised by distinct phenotypical and functional profiles. These results have direct implications for the design of immunological studies in HBV infection, and are potentially relevant for informing immunotherapeutic approaches to induce functional cure

Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection

Background & Aims: With or without antiviral treatment, few individuals achieve sustained functional cure of chronic hepatitis B virus (HBV) infection. A better definition of what mediates functional cure is essential for improving immunotherapeutic strategies. We aimed to compare HBV-specific T cell responses in patients with different degrees of viral control. Methods: We obtained blood from 124 HBV-infected individuals, including those with acute self-limiting HBV infection, chronic infection, and chronic infection with functional cure. We screened for HBV-specific T cell specificities by ELISpot, assessed the function of HBV-specific T cells using intracellular cytokine staining, and characterized HBV-specific CD4 T cells using human leukocyte antigen (HLA) class II tetramer staining, all directly ex vivo. Results: ELISpot screening readily identified HBV-specific CD4 and CD8 T cell responses in acute resolving infection compared with more limited reactivity in chronic infection. Applying more sensitive assays revealed higher frequencies of functional HBV-specific CD4 T cells, but not CD8 T cells, in functional cure compared to chronic infection. Function independent analysis using HLA multimers also identified more HBV-specific CD4 T cell responses in functional cure compared to chronic infection, with the emergence of CD4 T cell memory both after acute and chronic infection. Conclusions: Functional cure is associated with higher frequencies of functional HBV-specific CD4 memory T cell responses. Thus, immunotherapeutic approaches designed to induce HBV functional cure should also aim to improve CD4 T cell responses. Lay summary: Immunotherapy is a form of treatment that relies on harnessing the power of an individual's immune system to target a specific disease or pathogen. Such approaches are being developed for patients with chronic HBV infection, in an attempt to mimic the immune response in patients who control HBV infection spontaneously, achieving a so-called functional cure. However, what exactly defines protective immune responses remains unclear. Herein, we show that functional cure is associated with robust responses by HBV-specific CD4 T cells (a type of immune cell)

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N = 10, 535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported beta = 0.120). For the second research question, this was the case for 65% of the teams (median reported beta = 0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates