Glutamate Receptors in Neuroinflammatory Demyelinating Disease

Multiple sclerosis (MS) is a chronic demyelinating disease of the human central nervous system (CNS). The condition predominantly affects young adults and is characterised by immunological and inflammatory changes in the periphery and CNS that contribute to neurovascular disruption, haemopoietic cell invasion of target tissues, and demyelination of nerve fibres which culminate in neurological deficits that relapse and remit or are progressive. The main features of MS can be reproduced in the inducible animal counterpart, experimental autoimmune encephalomyelitis (EAE). The search for new MS treatments invariably employs EAE to determine drug activity and provide a rationale for exploring clinical efficacy. The preclinical development of compounds for MS has generally followed a conventional, immunotherapeutic route. However, over the past decade, a group of compounds that suppress EAE but have no apparent immunomodulatory activity have emerged. These drugs interact with the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-isoxazolepropionic acid (AMPA)/kainate family of glutamate receptors reported to control neurovascular permeability, inflammatory mediator synthesis, and resident glial cell functions including CNS myelination. The review considers the importance of the glutamate receptors in EAE and MS pathogenesis. The use of receptor antagonists to control EAE is also discussed together with the possibility of therapeutic application in demyelinating disease

Invited Review Article Glutamate Receptors in Neuroinflammatory Demyelinating Disease

Multiple sclerosis (MS) is a chronic demyelinating disease of the human central nervous system (CNS). The condition predominantly affects young adults and is characterised by immunological and inflammatory changes in the periphery and CNS that contribute to neurovascular disruption, haemopoietic cell invasion of target tissues, and demyelination of nerve fibres which culminate in neurological deficits that relapse and remit or are progressive. The main features of MS can be reproduced in the inducible animal counterpart, experimental autoimmune encephalomyelitis (EAE). The search for new MS treatments invariably employs EAE to determine drug activity and provide a rationale for exploring clinical efficacy. The preclinical development of compounds for MS has generally followed a conventional, immunotherapeutic route. However, over the past decade, a group of compounds that suppress EAE but have no apparent immunomodulatory activity have emerged. These drugs interact with the Nmethyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-isoxazolepropionic acid (AMPA)/kainate family of glutamate receptors reported to control neurovascular permeability, inflammatory mediator synthesis, and resident glial cell functions including CNS myelination. The review considers the importance of the glutamate receptors in EAE and MS pathogenesis. The use of receptor antagonists to control EAE is also discussed together with the possibility of therapeutic application in demyelinating disease

Paradoxical and powerful: Volunteers’ experiences of befriending people with dementia

This qualitative UK study explored the lived experiences of volunteer befrienders to people with dementia, using interpretative phenomenological analysis. Individual semi-structured interviews were conducted with nine befrienders aged between 25 and 66 years. The relationship that developed between befriender and befriendee was at the heart of befrienders’ experiences. It comprised numerous paradoxical processes that generated issues of power, equality and boundaries, characterising befriending as a complex and unique phenomenon. Befriending was expressed as a deeply personal and human experience, often with emotional power and profound meaning. Befrienders’ personal learning included seeing past dementia stereotypes, challenging their own assumptions and boundaries, and reflecting on love, life and humanness. Dissemination of these findings could help to challenge the stigma around dementia, and enhance recruitment and support of dementia befrienders. Future research should consider befriendee experiences of the relationship, additional measures of befriending effectiveness, and exploration of befriender attrition and support. </jats:p

Feasibility and Effectiveness of a Peer Referral Incentive Intervention to Promote Male Circumcision Uptake in Zambia

Medical male circumcision is a promising HIV prevention tool in countries with generalized HIV epidemics, but demand creation interventions are needed to support scale-up. We piloted a peer referral intervention in which circumcision clients were offered incentives for referring their peers for circumcision

Integrating HIV treatment with primary care outpatient services: opportunities and challenges from a scaled-up model in Zambia

Background: Integration of HIV treatment with other primary care services has been argued to potentially improve effectiveness, efficiency and equity. However, outside the field of reproductive health, there is limited empirical evidence regarding the scope or depth of integrated HIV programmes or their relative benefits. Moreover,the body of work describing operational models of integrated service-delivery in context remains thin. Between 2008 and 2011, the Lusaka District Health Management Team piloted and scaled-up a model of integrated HIV and general outpatient department (OPD) services in 12 primary health care clinics. This paper examines the effect of the integrated model on the organization of clinic services, and explores service providers' perceptions of the integrated model. Methods: We used a mixed methods approach incorporating facility surveys and key informant interviews with clinic managers and district officials. On-site facility surveys were carried out in 12 integrated facilities to collect data on the scope of integrated services, and 15 semi-structured interviews were carried out with 12 clinic managers and three district officials to explore strengths and weaknesses of the model. Quantitative and qualitative data were triangulated to inform overall analysis. Findings: Implementation of the integrated model substantially changed the organization of service delivery across a range of clinic systems. Organizational and managerial advantages were identified, including more efficient use of staff time and clinic space, improved teamwork and accountability, and more equitable delivery of care to HIV and non-HIV patients. However, integration did not solve ongoing human resource shortages or inadequate infrastructure, which limited the efficacy of the model and were perceived to undermine service delivery. Conclusion: While resource and allocative efficiencies are associated with this model of integration, a more important finding was the model's demonstrated potential for strengthening organizational culture and staff relationships, in turn facilitating more collaborative and motivated service delivery in chronically under-resourced primary healthcare clinics

Prevention of mother-to-child HIV transmission within the continuum of maternal, newborn, and child health services

To reach virtual elimination of pediatric HIV, programs for the prevention of mother-to-child HIV transmission (PMTCT) must expand coverage and achieve long-term retention of mothers and infants. While PMTCT have been traditionally aligned with maternal, newborn, and child health (MNCH) services, novel approaches are needed to address the increasing demands of evolving global PMTCT policies

Association between hepatitis B co-infection and elevated liver stiffness among HIV-infected adults in Lusaka, Zambia

In sub-Saharan Africa, liver disease epidemiology among HIV-infected individuals is not well described, in part due to limited access to diagnostic tests for liver fibrosis

Cervical cancer screening outcomes in Zambia, 2010-19: a cohort study.

BACKGROUND Globally, cervical cancer is the fourth leading cause of cancer-related death among women. Poor uptake of screening services contributes to the high mortality. We aimed to examine screening frequency, predictors of screening results, and patterns of sensitisation strategies by age group in a large, programmatic cohort. METHODS We did a cohort study including 11 government health facilities in Lusaka, Zambia, in which we reviewed routine programmatic data collected through the Cervical Cancer Prevention Program in Zambia (CCPPZ). Participants who underwent cervical cancer screening in one of the participating study sites were considered for study inclusion if they had a screening result. Follow-up was accomplished per national guidelines. We did descriptive analyses and mixed-effects logistic regression for cervical cancer screening results allowing random effects at the individual and clinic level. FINDINGS Between Jan 1, 2010, and July 31, 2019, we included 183 165 women with 204 225 results for visual inspection with acetic acid and digital cervicography (VIAC) in the analysis. Of all those screened, 21 326 (10·4%) were VIAC-positive, of whom 16 244 (76·2%) received treatment. Of 204 225 screenings, 92 838 (45·5%) were in women who were HIV-negative, 76 607 (37·5%) were in women who were HIV-positive, and 34 780 (17·0%) had an unknown HIV status. Screening frequency increased 65·7% between 2010 and 2019 with most appointments being first-time screenings (n=158 940 [77·8%]). Women with HIV were more likely to test VIAC-positive than women who were HIV-negative (adjusted odds ratio 3·60, 95% CI 2·14-6·08). Younger women (≤29 years) with HIV had the highest predictive probability (18·6%, 95% CI 14·2-22·9) of screening positive. INTERPRETATION CCPPZ has effectively increased women's engagement in screening since its inception in 2006. Customised sensitisation strategies relevant to different age groups could increase uptake and adherence to screening. The high proportion of screen positivity in women younger than 20 years with HIV requires further consideration. Our data are not able to discern if women with HIV have earlier disease onset or whether this difference reflects misclassification of disease in an age group with a higher sexually transmitted infection prevalence. These data inform scale-up efforts required to achieve WHO elimination targets. FUNDING US President's Emergency Plan for AIDS Relief

Pediatric HIV–HBV Coinfection in Lusaka, Zambia: Prevalence and Short-Term Treatment Outcomes: Table 1.

Hepatitis B virus (HBV) is endemic in Africa, where it may occur as an HIV coinfection. Data remain limited on HIV–HBV epidemiology in Africa, particularly in children. Using programmatic data from pediatric HIV clinics in Lusaka, Zambia during 2011–2014, we analyzed the prevalence of chronic HBV coinfection (defined as a single positive hepatitis B surface antigen [HBsAg] test) and its impact on immune recovery and liver enzyme elevation (LEE) during the first year of antiretroviral therapy. Among 411 children and adolescents, 10.4% (95% confidence interval, 7.6–14.1) had HIV–HBV. Coinfected patients were more likely to have World Health Organization stage 3/4, LEE and CD4 <14% at care entry (all p < 0.05). During treatment, CD4 increases and LEE incidence were similar by HBsAg status. HBsAg positivity decreased (11.8% vs. 6.6%; p = 0.24) following HBV vaccine introduction. These findings support screening pediatric HIV patients in Africa for HBV coinfection. Dedicated cohorts are needed to assess long-term outcomes of coinfection

Immunologic Risk Factors for Early Mortality After Starting Antiretroviral Therapy in HIV-Infected Zambian Children

To explore immunologic risk factors for death within 90 days of highly active antiretroviral therapy (HAART) initiation, CD4+ and CD8+ T cell subsets were measured by flow cytometry and characterized by logistic regression in 149 Zambian children between 9 months and 10 years of age enrolled in a prospective, observational study of the impact of HAART on measles immunity. Of 21 children who died during follow-up, 17 (81%) had known dates of death and 16 (76%) died within 90 days of initiating HAART. Young age and low weight-for-age z-scores were associated with increased risks of mortality within 90 days of starting HAART, whereas CD4+ T cell percentage was not associated with mortality. After adjusting for these factors, each 10% increase in CD8+ effector T cells increased the odds of overall mortality [OR=1.43 (95% CI: 1.08, 1.90)] and was marginally associated with early mortality [OR=1.29 (95% CI: 0.97, 1.72)]. Conversely, each 10% increase in CD4+ central memory T cells decreased the odds of overall [OR=0.06 (95% CI: 0.01, 0.59)] and early mortality [OR=0.09 (95% CI: 0.01, 0.97)]. Logistic regression prediction models demonstrated areas under the receiver-operator characteristic curves of ≥85% for early and overall mortality, with bootstrapped sensitivities of 82–85% upon validation, supporting the predictive accuracy of the models. CD4+ and CD8+ T cell subsets may be more accurate predictors of early mortality than CD4+ T cell percentages and could be used to identify children who would benefit from more frequent clinical monitoring after initiating HAART