Immune targets for therapeutic development in depression: towards precision medicine.

Over the past two decades, compelling evidence has emerged indicating that immune mechanisms can contribute to the pathogenesis of major depressive disorder (MDD) and that drugs with primary immune targets can improve depressive symptoms. Patients with MDD are heterogeneous with respect to symptoms, treatment responses and biological correlates. Defining a narrower patient group based on biology could increase the treatment response rates in certain subgroups: a major advance in clinical psychiatry. For example, patients with MDD and elevated pro-inflammatory biomarkers are less likely to respond to conventional antidepressant drugs, but novel immune-based therapeutics could potentially address their unmet clinical needs. This article outlines a framework for developing drugs targeting a novel patient subtype within MDD and reviews the current state of neuroimmune drug development for mood disorders. We discuss evidence for a causal role of immune mechanisms in the pathogenesis of depression, together with targets under investigation in randomized controlled trials, biomarker evidence elucidating the link to neural mechanisms, biological and phenotypic patient selection strategies, and the unmet clinical need among patients with MDD.Johnson and Johnso

Assessing health and well-being among older people in rural South Africa

Background: The population in developing countries is ageing, which is likely to increase the burden of noncommunicable diseases and disability. Objective: To describe factors associated with self-reported health, disability and quality of life (QoL) of older people in the rural northeast of South Africa. Design: Cross-sectional survey of 6,206 individuals aged 50 and over. We used multivariate analysis to examine relationships between demographic variables and measures of self-reported health (Health Status), functional ability (WHODASi) and quality of life (WHOQoL). Results: About 4,085 of 6,206 people eligible (65.8%) completed the interview. Women (Odds Ratio (OR) 1.30, 95% CI 1.09, 1.55), older age (OR2.59, 95% CI 1.97, 3.40), lower education (OR1.62, 95% CI 1.31,2.00), single status (OR1.18, 95% CI 1.01, 1.37) and not working at present (OR1.29, 95% CI 1.06, 1.59) were associated with a low health status. Women were also more likely to report a higher level of disability (OR1.38, 95% CI 1.14, 1.66), as were older people (OR2.92, 95% CI 2.25, 3.78), those with no education (OR1.57, 95% CI 1.26, 1.97), with single status (OR1.25, 95% CI 1.06, 1.46) and not working at present (OR1.33, 95% CI 1.06, 1.66). Older age (OR1.35, 95% CI 1.06, 1.74), no education (OR1.39, 95% CI 1.11, 1.73), single status (OR1.28, 95% CI 1.10, 1.49), a low household asset score (OR1.52, 95% CI 1.19, 1.94) and not working at present (OR1.32; 95% CI 1.07, 1.64) were all associated with lower quality of life. Conclusions: This study presents the first population-based data from South Africa on health status, functional ability and quality of life among older people. Health and social services will need to be restructured to provide effective care for older people living in rural South Africa with impaired functionality and other health problems

Eccrine porocarcinoma of the head: An important differential diagnosis in the elderly patient

Background: Eccrine porocarcinoma is a rare malignant tumor of the sweat gland, characterized by a broad spectrum of clinicopathologic presentations. Surprisingly, unlike its benign counterpart eccrine poroma, eccrine porocarcinoma is seldom found in areas with a high density of eccrine sweat glands, like the palms or soles. Instead, eccrine porocarcinoma frequently occurs on the lower extremities, trunk and abdomen, but also on the head, resembling various other skin tumors, as illustrated in the patients described herein. Observations: We report 5 cases of eccrine porocarcinoma of the head. All patients were initially diagnosed as having epidermal or melanocytic skin tumors. Only after histopathologic examination were they classified as eccrine porocarcinoma, showing features of epithelial tumors with abortive ductal differentiation. Characteristic clinical, histopathologic and immunohistochemical findings of eccrine porocarcinomas are illustrated. Conclusion: Eccrine porocarcinomas are potentially fatal adnexal malignancies, in which extensive metastatic dissemination may occur. Porocarcinomas are commonly overlooked, or misinterpreted as squamous or basal cell carcinomas as well as other common malignant and even benign skin tumors. Knowledge of the clinical pattern and histologic findings, therefore, is crucial for an early therapeutic intervention, which can reduce the risk of tumor recurrence and serious complications. Copyright (c) 2008 S. Karger AG, Basel

Parameter estimation in spatially extended systems: The Karhunen-Loeve and Galerkin multiple shooting approach

Parameter estimation for spatiotemporal dynamics for coupled map lattices and continuous time domain systems is shown using a combination of multiple shooting, Karhunen-Loeve decomposition and Galerkin's projection methodologies. The resulting advantages in estimating parameters have been studied and discussed for chaotic and turbulent dynamics using small amounts of data from subsystems, availability of only scalar and noisy time series data, effects of space-time parameter variations, and in the presence of multiple time-scales.Comment: 11 pages, 5 figures, 4 Tables Corresponding Author - V. Ravi Kumar, e-mail address: [email protected]

Microextensive Chaos of a Spatially Extended System

By analyzing chaotic states of the one-dimensional Kuramoto-Sivashinsky equation for system sizes L in the range 79 <= L <= 93, we show that the Lyapunov fractal dimension D scales microextensively, increasing linearly with L even for increments Delta{L} that are small compared to the average cell size of 9 and to various correlation lengths. This suggests that a spatially homogeneous chaotic system does not have to increase its size by some characteristic amount to increase its dynamical complexity, nor is the increase in dimension related to the increase in the number of linearly unstable modes.Comment: 5 pages including 4 figures. Submitted to PR

Tools for Assessing the Protective Efficacy of TB Vaccines in Humans: in vitro Mycobacterial Growth Inhibition Predicts Outcome of in vivo Mycobacterial Infection.

Tuberculosis (TB) remains a leading global cause of morbidity and mortality and an effective new vaccine is urgently needed. A major barrier to the rational development of novel TB vaccines is the lack of a validated immune correlate or biomarker of protection. Mycobacterial Growth Inhibition Assays (MGIAs) provide an unbiased measure of ability to control mycobacterial growth in vitro, and may represent a functional correlate of protection. However, the biological relevance of any potential correlate can only be assessed by determining the association with in vivo protection from either a controlled mycobacterial infection or natural development of TB disease. Our data demonstrate that the direct MGIA using peripheral blood mononuclear cells (PBMC) is measuring a biologically relevant response that correlates with protection from in vivo human BCG infection across two independent cohorts. This is the first report of an MGIA correlating with in vivo protection in the species-of-interest, humans, and furthermore on a per-individual as well as per-group basis. Control of mycobacterial growth in the MGIA is associated with a range of immune parameters measured post-BCG infection in vivo including the IFN-γ ELISpot response, frequency of PPD-specific IFN-γ or TNF-α producing CD4+ T cells and frequency of specific sub-populations of polyfunctional CD4+ T cells. Distinct transcriptomic profiles are associated with good vs. poor mycobacterial control in the MGIA, with good controllers showing enrichment for gene sets associated with antigen processing/presentation and the IL-23 pathway, and poor controllers showing enrichment for hypoxia-related pathways. This study represents an important step toward biologically validating the direct PBMC MGIA for use in TB vaccine development and furthermore demonstrates the utility of this assay in determining relevant immune mechanisms and pathways of protection

Protocol on a multicentre statistical and economic modelling study of risk-based stratified and personalised screening for diabetes and its complications in India (SMART India)

INTRODUCTION: The aim of this study is to develop practical and affordable models to (a) diagnose people with diabetes and prediabetes and (b) identify those at risk of diabetes complications so that these models can be applied to the population in low-income and middle-income countries (LMIC) where laboratory tests are unaffordable. METHODS AND ANALYSIS: This statistical and economic modelling study will be done on at least 48 000 prospectively recruited participants aged 40 years or above through community screening across 20 predefined regions in India. Each participant will be tested for capillary random blood glucose (RBG) and complete a detailed health-related questionnaire. People with known diabetes and all participants with predefined levels of RBG will undergo further tests, including point-of-care (POC) glycated haemoglobin (HbA1c), POC lipid profile and POC urine test for microalbuminuria, retinal photography using non-mydriatic hand-held retinal camera, visual acuity assessment in both eyes and complete quality of life questionnaires. The primary aim of the study is to develop a model and assess its diagnostic performance to predict HbA1c diagnosed diabetes from simple tests that can be applied in resource-limited settings; secondary outcomes include RBG cut-off for definition of prediabetes, diagnostic accuracy of cost-effective risk stratification models for diabetic retinopathy and models for identifying those at risk of complications of diabetes. Diagnostic accuracy inter-tests agreement, statistical and economic modelling will be performed, accounting for clustering effects. ETHICS AND DISSEMINATION: The Indian Council of Medical Research/Health Ministry Screening Committee (HMSC/2018–0494 dated 17 December 2018 and institutional ethics committees of all the participating institutions approved the study. Results will be published in peer-reviewed journals and will be presented at national and international conferences. TRIAL REGISTRATION: ISRCTN57962668 V1.0 24/09/2018

A practical tool for assessing ecosystem services enhancement and degradation associated with invasive alien species

Current approaches for assessing the effects of invasive alien species (IAS) are biased toward the negative effects of these species, resulting in an incomplete picture of their real effects. This can result in an inefficient IAS management. We address this issue by describing the INvasive Species Effects Assessment Tool (INSEAT) that enables expert elicitation for rapidly assessing the ecological consequences of IAS using the ecosystem services (ES) framework. INSEAT scores the ecosystem service “gains and losses” using a scale that accounted for the magnitude and the reversibility of its effects. We tested INSEAT on 18 IAS in Great Britain. Here, we highlighted four case studies: Harmonia axyridis (Harlequin ladybird), Astacus leptodactylus (Turkish crayfish), Pacifastacus leniusculus (Signal crayfish) and Impatiens glandulifera (Himalayan balsam). The results demonstrated that a collation of different experts’ opinions using INSEAT could yield valuable information on the invasive aliens’ ecological and social effects. The users can identify certain IAS as ES providers and the trade-offs between the ES provision and loss associated with them. This practical tool can be useful for evidence-based policy and management decisions that consider the potential role of invasive species in delivering human well-being.</p