Technical and management coaching for government institutions: Lessons learned and health systems transformations across 8 countries in sub-Saharan Africa and India.

Traditional engagement with local governments often relies on financial and human resources from international or local partners, leading to direct implementation by organizations, which can hinder sustainability. While some organizations include sustainability indicators, few focus on transferring technical and financial ownership to governments. The Challenge Initiative (TCI) uses a phased coaching model-lead, assist, observe, and monitor-to build local government capacity for scaling family planning (FP) and adolescent and youth sexual and reproductive health (AYSRH) programs.

Developing a system response to health and homelessness: The important role of health leaders.

This article examines the role of health leaders in the early stages of a community response to address health and homelessness in London, Ontario. Specifically, we explore how leaders from large healthcare-providing organizations have influenced the dynamics of the entire community response. We argue that the high level of engagement from health leaders has been a key ingredient in the early successes of the new approach in London, in part because it validated the reframing of homelessness as a healthcare issue-importantly, changing perceptions about who shares the responsibility to address it.

The nutrition-related adverse events associated with immune checkpoint inhibitor treatment for patients with non-small cell lung cancer: A systematic review.

Aims: Immune checkpoint inhibitor therapy used for lung cancer has significantly changed response and survival rates, however, the impact on patients' nutritional status remains largely unexplored. This review aims to identify common adverse events that increase nutrition risk induced in non-small cell lung cancer patients treated with immune checkpoint inhibitor therapy and assess impact on nutritional status.

Methods: PubMed, Medline and CINAHL were systematically searched in September 2023 for randomised controlled trials comparing immune checkpoint inhibitor treatment of non-small cell lung cancer to a control group.

Engaging Community Health Workers to Enhance Modern Contraceptive Uptake Among Young First-Time Parents in Five Cities of Uttar Pradesh.

Introduction: Young newly married women and first-time parents (FTPs), particularly those living in slum settlements, have a high unmet need for modern contraceptive methods to limit and space births. We describe an intervention in which adolescents and youth sexual and reproductive health (AYSRH) services tailored to FTPs were incorporated into the government's existing family planning (FP) program in 5 cities of Uttar Pradesh. We examined the effect of this intervention on modern contraceptive use among FTPs aged 15-24 years.

Relationship between global leadership initiative on malnutrition (GLIM) defined malnutrition and survival, length of stay and post-operative complications in people with cancer: A systematic review.

Background & Aims: The predictive validity of the GLIM criteria for survival, length of hospital stay (LOHS) and post-operative complications among people with cancer have not been systematically reviewed. This systematic review aims to determine whether GLIM malnutrition is predictive of these outcomes, and whether the predictive validity is affected by how phenotypic and etiologic criteria are assessed.

Methods: Cohort studies published after 2018 were systematically reviewed according to PRISMA guidelines from Embase, Medline Complete and CINAHL Complete.

RAISE: A Management and Organizational Sustainability Tool for Local Governments to Systematically Self-Evaluate the Effectiveness of Their Programs.

Context: Many donor-driven public health programs are now seeking evidence for sustainability prior to investment, creating the need for tools to better appraise these capabilities. Assessing the sustainability of programs and interventions at the local level remains a community-wide challenge.

Program: This article presents a new self-assessment tool, the Reflection and Action to Improve Self-reliance and Effectiveness (RAISE) Tool ("the Tool"), modeled after The Challenge Initiative's (TCI) Sustainability Pillars.

Scaling Access to Contraception for Youth in Urban Slums: The Challenge Initiative's Systems-Based Multi-Pronged Strategy for Youth-Friendly Cities.

Introduction: More than half of all adolescents globally live in Asia, with India having the largest adolescent population in the world at 253 million. In sub-Saharan Africa, adolescents make up the greatest proportion of the population, with 23% of the population aged 10-19. And these numbers are predicted to grow rapidly-particularly in urban areas as rural youth migrate to cities for economic opportunities.

Deficiency of the innate immune adaptor STING promotes autoreactive T cell expansion in NOD mice.

Aims/hypothesis: Stimulator of IFN genes (STING) is a central hub for cytosolic nucleic acid sensing and its activation results in upregulation of type I IFN production in innate immune cells. A type I IFN gene signature seen before the onset of type 1 diabetes has been suggested as a driver of disease initiation both in humans and in the NOD mouse model. A possible source of type I IFN is through activation of the STING pathway.

IL-21 regulates SOCS1 expression in autoreactive CD8 T cells but is not required for acquisition of CTL activity in the islets of non-obese diabetic mice.

In type 1 diabetes, maturation of activated autoreactive CD8 T cells to fully armed effector cytotoxic T lymphocytes (CTL) occurs within the islet. At present the signals required for the maturation process are poorly defined. Cytokines could potentially provide the necessary "third signal" required to generate fully mature CTL capable of killing insulin-producing β-cells.

Granzyme A Deficiency Breaks Immune Tolerance and Promotes Autoimmune Diabetes Through a Type I Interferon-Dependent Pathway.

Granzyme A is a protease implicated in the degradation of intracellular DNA. Nucleotide complexes are known triggers of systemic autoimmunity, but a role in organ-specific autoimmune disease has not been demonstrated. To investigate whether such a mechanism could be an endogenous trigger for autoimmunity, we examined the impact of granzyme A deficiency in the NOD mouse model of autoimmune diabetes.

Cognate antigen engagement on parenchymal cells stimulates CD8 T cell proliferation in situ.

T-cell responses are initiated upon cognate presentation by professional antigen presenting cells in lymphoid tissue. T cells then migrate to inflamed tissues, but further T-cell stimulation in these parenchymal target sites is not well understood. Here we show that T-cell expansion within inflamed tissues is a distinct phase that is neither a classical primary nor classical secondary response.

Repurposed JAK1/JAK2 Inhibitor Reverses Established Autoimmune Insulitis in NOD Mice.

Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics used to treat other diseases to treat type 1 diabetes, especially when there is evidence for overlapping mechanisms. Janus kinase (JAK) 1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis.

Perinatal tolerance to proinsulin is sufficient to prevent autoimmune diabetes.

High-affinity self-reactive thymocytes are purged in the thymus, and residual self-reactive T cells, which are detectable in healthy subjects, are controlled by peripheral tolerance mechanisms. Breakdown in these mechanisms results in autoimmune disease, but antigen-specific therapy to augment natural mechanisms can prevent this. We aimed to determine when antigen-specific therapy is most effective.

Rotavirus acceleration of type 1 diabetes in non-obese diabetic mice depends on type I interferon signalling.

Rotavirus infection is associated with childhood progression to type 1 diabetes. Infection by monkey rotavirus RRV accelerates diabetes onset in non-obese diabetic (NOD) mice, which relates to regional lymph node infection and a T helper 1-specific immune response. When stimulated ex vivo with RRV, plasmacytoid dendritic cells (pDCs) from naïve NOD mice secrete type I interferon, which induces the activation of bystander lymphocytes, including islet-autoreactive T cells.

Perforin facilitates beta cell killing and regulates autoreactive CD8+ T-cell responses to antigen in mouse models of type 1 diabetes.

In type 1 diabetes, cytotoxic CD8(+) T lymphocytes (CTLs) directly interact with pancreatic beta cells through major histocompatibility complex class I. An immune synapse facilitates delivery of cytotoxic granules, comprised mainly of granzymes and perforin. Perforin deficiency protects the majority of non-obese diabetic (NOD) mice from autoimmune diabetes.

Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release.

The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis. Pharmacological inhibition of AMPK is regarded as a therapeutic strategy in some disease settings including obesity and cancer; however, the broadly used direct AMPK inhibitor compound C suffers from poor selectivity. We have discovered a dihydroxyquinoline drug (MT47-100) with novel AMPK regulatory properties, being simultaneously a direct activator and inhibitor of AMPK complexes containing the β1 or β2 isoform, respectively.

BIM Deficiency Protects NOD Mice From Diabetes by Diverting Thymocytes to Regulatory T Cells.

Because regulatory T-cell (Treg) development can be induced by the same agonist self-antigens that induce negative selection, perturbation of apoptosis will affect both negative selection and Treg development. But how the processes of thymocyte deletion versus Treg differentiation bifurcate and their relative importance for tolerance have not been studied in spontaneous organ-specific autoimmune disease. We addressed these questions by removing a critical mediator of thymocyte deletion, BIM, in the NOD mouse model of autoimmune diabetes.

Deficiency in type I interferon signaling prevents the early interferon-induced gene signature in pancreatic islets but not type 1 diabetes in NOD mice.

Type I interferons (IFNs) have been implicated in the initiation of islet autoimmunity and development of type 1 diabetes. To directly test their involvement, we generated NOD mice deficient in type I IFN receptors (NOD.IFNAR1(-/-)).

Effector-memory T cells develop in islets and report islet pathology in type 1 diabetes.

CD8(+) T cells are critical in human type 1 diabetes and in the NOD mouse. In this study, we elucidated the natural history of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific CD8(+) T cells in NOD diabetes using MHC-tetramer technology. IGRP206-214-specific T cells in the peripheral lymphoid tissue increased with age, and their numbers correlated with insulitis progression.

Proinflammatory cytokines contribute to development and function of regulatory T cells in type 1 diabetes.

Type 1 diabetes is caused by immune-mediated loss of pancreatic beta cells. It has been proposed that inflammatory cytokines play a role in killing beta cells. Expression of interleukin (IL)-1 and tumor necrosis factor (TNF-α) has been detected in islets from patients with type 1 diabetes, and these cytokines can induce beta cell death in vitro.

Granzyme B is dispensable in the development of diabetes in non-obese diabetic mice.

Pancreatic beta cell destruction in type 1 diabetes is mediated by cytotoxic CD8(+) T lymphoctyes (CTL). Granzyme B is an effector molecule used by CTL to kill target cells. We previously showed that granzyme B-deficient allogeneic CTL inefficiently killed pancreatic islets in vitro.

Intra-islet proliferation of cytotoxic T lymphocytes contributes to insulitis progression.

Infiltration of pancreatic islets by immune cells, termed insulitis, increases progressively once it begins and leads to clinical type 1 diabetes. But even after diagnosis some islets remain unaffected and infiltration is patchy rather than uniform. Traffic of autoreactive T cells into the pancreas is likely to contribute to insulitis progression but it could also depend on T-cell proliferation within islets.

How do alternative ways of responding influence 3- and 4-year-olds' performance on tests of executive function and theory of mind?

A total of 69 preschool children were tested on measures of false belief understanding (the Unexpected Transfer task), inhibitory control (the Grass/Snow task), and strategic reasoning (the Windows task). For each task, children indicated their response either by pointing with their index finger or by using a nonstandard response mode (pointing with a rotating arrow). The means of responding had no effect on children's performance on the Grass/Snow task or on the Unexpected Transfer task, although children performed better on the Unexpected Transfer task when the key object in the story was removed.

Pathogenic mechanisms in type 1 diabetes: the islet is both target and driver of disease.

Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells.

Complete diabetes protection despite delayed thymic tolerance in NOD8.3 TCR transgenic mice due to antigen-induced extrathymic deletion of T cells.

Prevention of autoimmunity requires the elimination of self-reactive T cells during their development in the thymus and maturation in the periphery. Transgenic NOD mice that overexpress islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP) in antigen-presenting cells (NOD-IGRP mice) have no IGRP-specific T cells. To study the relative contribution of central and peripheral tolerance mechanisms to deletion of antigen-specific T cells, we crossed NOD-IGRP mice to highly diabetogenic IGRP206-214 T-cell receptor transgenic mice (NOD8.