Determinants In HIV Counselling And Testing In Couples In North Rift Kenya

Background: Voluntary HIV counselling and testing (VCT) has been shown to be an acceptable and effective tool in the fight against HIV/AIDS. Couple HIV Counselling and Testing (CHCT) however, is a relatively new concept whose acceptance and efficacy is yet to be determined.Objective: To describe factors that motivate couples to attend VCT as a couple. Design: A cross sectional qualitative study.Setting: Moi Teaching and Referral Hospital and Moi University, School of Medicine, Eldoret, KenyaSubjects: Seventy one individuals were interviewed during KII (9) and dyad interviews (31 couples). Ten FGDs involving a total of 109 individuals were held. Results: Cultural practices, lack of CHCT awareness, stigma and fear of results deter CHCT utilisation. Location of centre where it is unlikely to be associated with HIV testing, qualified professional staff and minimal waiting times would enhance CHCT utilisation.Conclusions: CHCT as a tool in the fight against HIV/AIDS in this region of Kenya is feasible as the factors that would deter couples are not insurmountable

Stakeholders perception of HIV sero-discordant couples in western Kenya

Objective: To describe the perceptions of key stakeholders regarding the counselling needs of HI V sero-discordant couples as part of preparation for a clinical trial involving HIV sero-discordant couples. Design: Qualitative study using key informant and couple interviews. Setting: Moi Teaching and Referral Hospital (MTRH). Subjects: A purposive sample of nine key informants and 31 couple interviews totaling 71 participants. The couple interviews consisted of HI V untested, HI V concordant (positive and negative) and discordant couples. Results: Seventy one individuals participated in nine key informant and 31 couple interviews. The responses identified the following as key issues in counselling HIV discordant couples: The need for education on the meaning of HI V sero-discordancy including potential sources of infection; assistance in disclosing HIV test results to one\'s partner; discussion of the stigma surrounding formula feeding. Overall, the participants supported safer sexual practices in discordant partnerships. Conclusions: Psychosocial support of HI V sero-discordant couples should include messages about the meaning, mechanisms and implications of sero-discordancy. Culturally appropriate HI Vdisclosure and safer sex messages are also needed to support these partnerships. East African Medical Journal Vol. 85 (7) 2008: pp. 326-33

Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by motor neuron loss, resulting in muscle wasting, paralysis and eventual death. A key pathological feature of ALS is cytoplasmically mislocalized and aggregated TDP-43 protein in >95% of cases, which is considered to have prion-like properties. Historical studies have predominantly focused on genetic forms of ALS, which represent ∼10% of cases, leaving the remaining 90% of sporadic ALS relatively understudied. Additionally, the role of astrocytes in ALS and their relationship with TDP-43 pathology is also not currently well understood. We have therefore used highly enriched human induced pluripotent stem cell (iPSC)-derived motor neurons and astrocytes to model early cell type-specific features of sporadic ALS. We first demonstrate seeded aggregation of TDP-43 by exposing human iPSC-derived motor neurons to serially passaged sporadic ALS post-mortem tissue (spALS) extracts. Next, we show that human iPSC-derived motor neurons are more vulnerable to TDP-43 aggregation and toxicity compared with their astrocyte counterparts. We demonstrate that these TDP-43 aggregates can more readily propagate from motor neurons into astrocytes in co-culture paradigms. We next found that astrocytes are neuroprotective to seeded aggregation within motor neurons by reducing (mislocalized) cytoplasmic TDP-43, TDP-43 aggregation and cell toxicity. Furthermore, we detected TDP-43 oligomers in these spALS spinal cord extracts, and as such demonstrated that highly purified recombinant TDP-43 oligomers can reproduce this observed cell-type specific toxicity, providing further support to a protein oligomer-mediated toxicity hypothesis in ALS. In summary, we have developed a human, clinically relevant, and cell-type specific modelling platform that recapitulates key aspects of sporadic ALS and uncovers both an initial neuroprotective role for astrocytes and the cell type-specific toxic effect of TDP-43 oligomers

A model for extending antiretroviral care beyond the rural health centre

<p>Abstract</p> <p>Background</p> <p>A major obstacle facing many lower-income countries in establishing and maintaining HIV treatment programmes is the scarcity of trained health care providers. To address this shortage, the World Health Organization has recommend task shifting to HIV-infected peers.</p> <p>Methods</p> <p>We designed a model of HIV care that utilizes HIV-infected patients, community care coordinators (CCCs), to care for their clinically stable peers with the assistance of preprogrammed personal digital assistants (PDAs). Rather than presenting for the standard of care, monthly clinic visits, in this model, patients were seen every three months in clinics and monthly by their CCCs in the community during the interim two months. This study was conducted in Kosirai Division, western Kenya, where eight of the 24 sub-locations (defined geographic areas) within the division were randomly assigned to the intervention with the remainder used as controls.</p> <p>Prior to entering the field, CCCs underwent intensive didactic training and mentoring related to the assessment and support of HIV patients, as well as the use of PDAs. PDAs were programmed with specific questions and to issue alerts if responses fell outside of pre-established parameters. CCCs were regularly evaluated in six performance areas. An impressionistic analysis on the transcripts from the monthly group meetings that formed the basis of the continuous feedback and quality improvement programme was used to assess this model.</p> <p>Results</p> <p>All eight of the assigned CCCs successfully passed their training and mentoring, entered the field and remained active for the two years of the study. On evaluation of the CCCs, 89% of their summary scores were documented as superior during Year 1 and 94% as superior during Year 2. Six themes emerged from the impressionistic analysis in Year 1: confidentiality and "community" disclosure; roles and responsibilities; logistics; clinical care partnership; antiretroviral adherence; and PDA issues. At the end of the trial, of those patients not lost to follow up, 64% (56 of 87) in the intervention and 52% (58 of 103) in the control group were willing to continue in the programme (p = 0.26).</p> <p>Conclusion</p> <p>We found that an antiretroviral treatment delivery model that shifted patient monitoring and antiretroviral dispensing tasks into the community by HIV-infected patients was both acceptable and feasible.</p> <p>Trial registration</p> <p>ClinicalTrials.gov ID NCT00371540</p

Short-Term Rationing of Combination Antiretroviral Therapy: Impact on Morbidity, Mortality, and Loss to Follow-Up in a Large HIV Treatment Program in Western Kenya

Background. There was a 6-month shortage of antiretrovirals (cART) in Kenya. Methods. We assessed morbidity, mortality, and loss to follow-up (LTFU) in this retrospective analysis of adults who were enrolled during the six-month period with restricted cART (cap) or the six months prior (pre-cap) and eligible for cART at enrollment by the pre-cap standard. Cox models were used to adjust for potential confounders. Results. 9009 adults were eligible for analysis: 4,714 pre-cap and 4,295 during the cap. Median number of days from enrollment to cART initiation was 42 pre-cap and 56 for the cap (P < 0.001). After adjustment, individuals in the cap were at higher risk of mortality (HR = 1.21; 95% CI : 1.06–1.39) and LTFU (HR = 1.12; 95% CI : 1.04–1.22). There was no difference between the groups in their risk of developing a new AIDS-defining illness (HR = 0.92 95% CI 0.82–1.03). Conclusions. Rationing of cART, even for a relatively short period of six months, led to clinically adverse outcomes

Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis

OBJECTIVE: To evaluate the combined blood expression of neuromuscular and inflammatory biomarkers as predictors of disease progression and prognosis in amyotrophic lateral sclerosis (ALS). METHODS: Logistic regression adjusted for markers of the systemic inflammatory state and principal component analysis were carried out on plasma levels of creatine kinase (CK), ferritin, and 11 cytokines measured in 95 patients with ALS and 88 healthy controls. Levels of circulating biomarkers were used to study survival by Cox regression analysis and correlated with disease progression and neurofilament light chain (NfL) levels available from a previous study. Cytokines expression was also tested in blood samples longitudinally collected for up to 4 years from 59 patients with ALS. RESULTS: Significantly higher levels of CK, ferritin, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β, IL-2, IL-8, IL-12p70, IL-4, IL-5, IL-10, and IL-13 and lower levels of interferon (IFN)-γ were found in plasma samples from patients with ALS compared to controls. IL-6, TNF-α, and IFN-γ were the most highly regulated markers when all explanatory variables were jointly analyzed. High ferritin and IL-2 levels were predictors of poor survival. IL-5 levels were positively correlated with CK, as was TNF-α with NfL. IL-6 was strongly associated with CRP levels and was the only marker showing increasing expression towards end-stage disease in the longitudinal analysis. CONCLUSIONS: Neuromuscular pathology in ALS involves the systemic regulation of inflammatory markers mostly active on T-cell immune responses. Disease stratification based on the prognostic value of circulating inflammatory markers could improve clinical trials design in ALS

A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK.

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis

Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

OBJECTIVE: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders. METHODS: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype. RESULTS: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3). CONCLUSIONS: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials

Profilin1 E117G is a moderate risk factor for amyotrophic lateral sclerosis

This is a post-peer-review, pre-copyedit version of an article published in Neurogenetics. The final authenticated version is available online at: J Neurol Neurosurg Psychiatry 2014;85:506–508. doi:10.1136/jnnp-2013-306761Background Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders that share significant clinical, pathological and genetic overlap and are considered to represent different ends of a common disease spectrum. Mutations in Profilin1 have recently been described as a rare cause of familial ALS. The PFN1 E117G missense variant has been described in familial and sporadic cases, and also found in controls, casting doubt on its pathogenicity. Interpretation of such variants represents a significant clinical-genetics challenge. Objective and results Here, we combine a screen of a new cohort of 383 ALS patients with multiple-sequence datasets to refine estimates of the ALS and FTD risk associated with PFN1 E117G. Together, our cohorts add up to 5118 ALS and FTD cases and 13 089 controls. We estimate a frequency of E117G of 0.11% in controls and 0.25% in cases. Estimated odds after population stratification is 2.44 (95% CI 1.048 to ∞, Mantel-Haenszel test p=0.036). Conclusions Our results show an association between E117G and ALS, with a moderate effect size.PF is funded by MRC/MNDA Lady Edith Wolfson Fellowship. EMCF is funded by the UK Motor Neuron Disease Association. PF and EMCF are funded by the UK Medical Research Council and the Thierry Latran Foundation

Dry and Humid Periods Reconstructed from Tree Rings in the Former Territory of Sogdiana (Central Asia) and Their Socio-economic Consequences over the Last Millennium

One of the richest societies along the Silk Road developed in Sogdiana, located in present-day Tajikistan, Uzbekistan, and Kyrgyzstan. This urban civilisation reached its greatest prosperity during the golden age of the Silk Road (sixth to ninth century ce). Rapid political and economic changes, accelerated by climatic variations, were observed during last millennium in this region. The newly developed tree-ring-based reconstruction of precipitation for the pastmillennium revealed a series of dry and wet stages. During the Medieval Climate Anomaly (MCA), two dry periods occurred (900–1000 and 1200–1250), interrupted by a phase of wetter conditions. Distinct dry periods occurred around 1510–1650, 1750–1850, and 1920–1970, respectively. The juniper tree-ring record of moisture changes revealed that major dry and pluvial episodes were consistent with those indicated by hydroclimatic proxy data from adjacent areas. These climate fluctuations have had longand short term consequences for human history in the territory of former Sogdiana