Cost-effectiveness of Screen-Triage-Treat approach with Primary HPV Testing for Cervical Cancer Screening in Low- and Middle-Income Countries: Protocol for a Systematic Review

Background: Cervical cancer is a leading cause of mortality among women in low- and middle-income countries (LMICs). Early detection through screening is key to cervical cancer prevention. HPV DNA testing (community-based self-sampling and facility-based provider sampling) has recently been recommended by WHO as the primary screening in LMIC in a “screen, triage and treat” approach. A lack of economic evidence considering the intervention cost and the value of health gain leads to insufficient public funds allocated for healthcare. Objectives of this systematic review: 1) To summarize and compare the incremental resource use, implementation cost, and incremental cost-effectiveness of adopting different algorithms using HPV DNA primary tests followed by triage tests in LMICs. 2) To summarize and compare the resource use, implementation cost and cost-effectiveness of two sample collection methods (community-based self-sampling and facility-based provider-sampling) of the HPV-based primary screening as part of the screen-triage-treat approach for cervical cancer screening in LMICs. 3) To summarize and compare the resource use, implementation cost, and cost-effectiveness of different “Screen-triage-treat" methods in general population versus high-risk HIV-positive women. 4) To describe the methodological considerations applied in the economic evaluation studies (outcome, measures, analytical viewpoint, time horizon, discount rate, decision models) and assess the quality of economic evidence using standard CHEERS and Drummond checklists Method: A systematic review will be performed following Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) using literature from multiple databases including PubMed, Embase, Web of Science, CEA registry, NHS Economic Evaluation Database, Health Economic Evaluation Database (HEED), CINAHL, EconLit, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and Cochrane Library as well as grey literature from other sources. Details of search strategies, eligibility criteria and process for study screening, study selection, quality assessment, data extraction and analysis are described in the attachment

Strengthening Healthcare Capacity Through a Responsive, Country-Specific, Training Standard: The KITSO AIDS Training Program’s Sup-port of Botswana’s National Antiretroviral Therapy Rollout

In parallel with the rollout of Botswana’s national antiretroviral therapy (ART) program, the Botswana Ministry of Health established the KITSO AIDS Training Program by entering into long-term partnerships with the Botswana–Harvard AIDS Institute Partnership for HIV Research and Education and others to provide standardized, country-specific training in HIV/AIDS care. The KITSO training model has strengthened human capacity within Botswana’s health sector and been indispensable to successful ART rollout. Through core and advanced training courses and clinical mentoring, different cadres of health care workers have been trained to provide high-quality HIV/AIDS care at all ART sites in the country. Continuous and standardized clinical education will be crucial to sustain the present level of care and successfully address future treatment challenges

Phylogenetic Relatedness of Circulating HIV-1C Variants in Mochudi, Botswana

Background: Determining patterns of HIV transmission is increasingly important for the most efficient use of modern prevention interventions. HIV phylogeny can provide a better understanding of the mechanisms underlying HIV transmission networks in communities. Methods: To reconstruct the structure and dynamics of a local HIV/AIDS epidemic, the phylogenetic relatedness of HIV-1 subtype C env sequences obtained from 785 HIV-infected community residents in the northeastern sector of Mochudi, Botswana, during 2010–2013 was estimated. The genotyping coverage was estimated at 44%. Clusters were defined based on relatedness of HIV-1C env sequences and bootstrap support of splits. Results: The overall proportion of clustered HIV-1C env sequences was 19.1% (95% CI 17.5% to 20.8%). The proportion of clustered sequences from Mochudi was significantly higher than the proportion of non-Mochudi sequences that clustered, 27.0% vs. 14.7% (p = 5.8E-12; Fisher exact test). The majority of clustered Mochudi sequences (90.1%; 95% CI 85.1% to 93.6%) were found in the Mochudi-unique clusters. None of the sequences from Mochudi clustered with any of the 1,244 non-Botswana HIV-1C sequences. At least 83 distinct HIV-1C variants, or chains of HIV transmission, in Mochudi were enumerated, and their sequence signatures were reconstructed. Seven of 20 genotyped seroconverters were found in 7 distinct clusters. Conclusions: The study provides essential characteristics of the HIV transmission network in a community in Botswana, suggests the importance of high sampling coverage, and highlights the need for broad HIV genotyping to determine the spread of community-unique and community-mixed viral variants circulating in local epidemics. The proposed methodology of cluster analysis enumerates circulating HIV variants and can work well for surveillance of HIV transmission networks. HIV genotyping at the community level can help to optimize and balance HIV prevention strategies in trials and combined intervention packages

Risk Factors for Symptomatic Hyperlactatemia and Lactic Acidosis Among Combination Antiretroviral Therapy-Treated Adults in Botswana: Results from a Clinical Trial

Nucleoside analogue reverse transcriptase inhibitors are an integral component of combination antiretroviral treatment regimens. However, their ability to inhibit polymerase-γ has been associated with several mitochondrial toxicities, including potentially life-threatening lactic acidosis. A total of 650 antiretroviral-naive adults (69% female) initiated combination antiretroviral therapy (cART) and were intensively screened for toxicities including lactic acidosis as part of a 3-year clinical trial in Botswana. Patients were categorized as no lactic acidosis symptoms, minor symptoms but lactate <4.4 mmol/liter, and symptoms with lactate ≥ 4.4 mmol/liter [moderate to severe symptomatic hyperlactatemia (SH) or lactic acidosis (LA)]. Of 650 participants 111 (17.1%) developed symptoms and/or laboratory results suggestive of lactic acidosis and had a serum lactate drawn; 97 (87.4%) of these were female. There were 20 events, 13 having SH and 7 with LA; all 20 (100%) were female (p<0.001). Cox proportional hazard analysis limited to the 451 females revealed that having a higher baseline BMI was predictive for the development of SH/LA [aHR=1.17 per one-unit increase (1.08-1.25), p<0.0001]. Ordered logistic regression performed among all 650 patients revealed that having a lower baseline hemoglobin [aOR=1.28 per one-unit decrease (1.1-1.49), p=0.002] and being randomized to d4T/3TC-based cART [aOR=1.76 relative to ZDV/3TC (1.03-3.01), p=0.04] were predictive of the symptoms and/or the development of SH/LA. cART-treated women in sub-Saharan Africa, especially those having higher body mass indices, should receive additional monitoring for SH/LA. Women presently receiving d4T/3TC-based cART in such settings also warrant more intensive monitoring

Genital self-sampling for HPV-based cervical cancer screening: a qualitative study of preferences and barriers in rural Ethiopia

Background In the context of WHO’s “task shifting” project and growing global consensus on primary HPV-based cervical cancer screening, self-sampling is a promising new tool to expand screening access, uptake and coverage for women worldwide. We aimed to explore perceptions and acceptability of HPV self-sampling-based cervical cancer screening among community members and health professionals in rural northwest Ethiopia and to identify preferences and socio-cultural barriers regarding self-sampling in order to design a suitable high-coverage screening intervention for a rural African setting. Methods: Four community-based focus group discussions (FGD) were conducted in the rural district of Dabat, Northwest Ethiopia, each comprising 8 to 14 female participants, counting a total of 41 participants. The groups were homogenously composed in terms of their socio-economic status in the community. They included health centre attendees, community members, nurses and health development army leaders (HDAL). Two qualitative data collection experts conducted the interviews in the local language, using a FGD guide with several thematic areas. All participants granted written informed consent prior to the conduct of the interviews. As a concrete example of an existing self-sampling approach for cervical cancer screening we used the Evalyn® Brush. Results: Emerging themes included (i) misconceptions and low awareness about cervical cancer among community residents and primary health care providers in rural northwest Ethiopia, (ii) stigmatization and social exclusion of affected women, (iii) delay in seeking of health care due to poor access and availability of services, and lacking of a concept of early cancer prevention, (iv) need of spousal permission, (v) fear of financial burden and (vi) fear of social marginalization. The self-sampling device was regarded to be acceptable and was judged to be easy to use for most women. The existing Ethiopian health care structure could facilitate a community approach. Conclusion: Home-based self-sampling for cervical cancer screening is a socially acceptable and feasible “task shifting” method that will increase cervical cancer screening access and coverage in the Ethiopian study community. Education, awareness creation, community mobilization and family inclusion are identified as key activities to promote, implement and facilitate “task shifting” approaches like self-sampling

Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases

Dominant mutations in five tRNA synthetases cause Charcot–Marie–Tooth (CMT) neuropathy, suggesting that altered aminoacylation function underlies the disease. However, previous studies showed that loss of aminoacylation activity is not required to cause CMT. Here we present a Drosophila model for CMT with mutations in glycyl-tRNA synthetase (GARS). Expression of three CMT-mutant GARS proteins induces defects in motor performance and motor and sensory neuron morphology, and shortens lifespan. Mutant GARS proteins display normal subcellular localization but markedly reduce global protein synthesis in motor and sensory neurons, or when ubiquitously expressed in adults, as revealed by FUNCAT and BONCAT. Translational slowdown is not attributable to altered tRNA[superscript Gly] aminoacylation, and cannot be rescued by Drosophila Gars overexpression, indicating a gain-of-toxic-function mechanism. Expression of CMT-mutant tyrosyl-tRNA synthetase also impairs translation, suggesting a common pathogenic mechanism. Finally, genetic reduction of translation is sufficient to induce CMT-like phenotypes, indicating a causal contribution of translational slowdown to CMT.National Institutes of Health (U.S.) (Grant GM17151

HIV-1 Subtype C-Infected Individuals Maintaining High Viral Load as Potential Targets for the “Test-and-Treat” Approach to Reduce HIV Transmission

The first aim of the study is to assess the distribution of HIV-1 RNA levels in subtype C infection. Among 4,348 drug-naïve HIV-positive individuals participating in clinical studies in Botswana, the median baseline plasma HIV-1 RNA levels differed between the general population cohorts (4.1–4.2 log10) and cART-initiating cohorts (5.1–5.3 log10) by about one log10. The proportion of individuals with high (≥50,000 (4.7 log10) copies/ml) HIV-1 RNA levels ranged from 24%–28% in the general HIV-positive population cohorts to 65%–83% in cART-initiating cohorts. The second aim is to estimate the proportion of individuals who maintain high HIV-1 RNA levels for an extended time and the duration of this period. For this analysis, we estimate the proportion of individuals who could be identified by repeated 6- vs. 12-month-interval HIV testing, as well as the potential reduction of HIV transmission time that can be achieved by testing and ARV treating. Longitudinal analysis of 42 seroconverters revealed that 33% (95% CI: 20%–50%) of individuals maintain high HIV-1 RNA levels for at least 180 days post seroconversion (p/s) and the median duration of high viral load period was 350 (269; 428) days p/s. We found that it would be possible to identify all HIV-infected individuals with viral load ≥50,000 (4.7 log10) copies/ml using repeated six-month-interval HIV testing. Assuming individuals with high viral load initiate cART after being identified, the period of high transmissibility due to high viral load can potentially be reduced by 77% (95% CI: 71%–82%). Therefore, if HIV-infected individuals maintaining high levels of plasma HIV-1 RNA for extended period of time contribute disproportionally to HIV transmission, a modified “test-and-treat” strategy targeting such individuals by repeated HIV testing (followed by initiation of cART) might be a useful public health strategy for mitigating the HIV epidemic in some communities

Effect of Micronutrient Supplementation on Disease Progression in Asymptomatic, Antiretroviral-Naive, HIV-Infected Adults in Botswana

IMPORTANCE Micronutrient deficiencies occur early in human immunodeficiency virus (HIV) infection, and supplementation with micronutrients may be beneficial; however, its effectiveness has not been investigated early in HIV disease among adults who are antiretroviral therapy (ART) naive. OBJECTIVE To investigate whether long-term micronutrient supplementation is effective and safe in delaying disease progression when implemented early in adults infected with HIV subtype C who are ART-naive. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of supplementation with either daily multivitamins (B vitamins and vitamins C and E), seleniumalone, or multivitamins with selenium vs placebo inafactorial design for 24 months. The study was conducted in 878 patients infected with HIV subtype C with a CD4 cell count greater than 350/μL who were not receiving ART at Princess Marina Hospital in Gaborone, Botswana, between December 2004 and July 2009. INTERVENTIONS Daily oral supplements of B vitamins and vitamins C and E, selenium alone, or multivitamins plus selenium, compared with placebo. MAIN OUTCOMES AND MEASURES Reaching a CD4 cell count less than 200/μL until May 2008; after this date, reaching a CD4 cell count of 250/μL or less, consistent with the standard of care in Botswana for initiation of ART at the time of the study. RESULTS There were 878 participants enrolled and randomized into the study. All participants were ART-naive throughout the study. In intent-to-treat analysis, participants receiving the combined supplement of multivitamins plus selenium had a significantly lower risk vs placebo of reaching CD4 cell count 250/μL or less (adjusted hazard ratio [HR], 0.46; 95% CI, 0.25-0.85; P = .01; absolute event rate [AER], 4.79/100 person-years; censoring rate, 0.92; 17 events; placebo AER, 9.22/100 person-years; censoring rate, 0.85; 32 events). Multivitamins plus selenium in a single supplement, vs placebo, also reduced the risk of secondary events of combined outcomes for disease progression (CD4 cell count ≤250/μL, AIDS-defining conditions, or AIDS-related death, whichever occurred earlier [adjusted HR, 0.56; 95% CI, 0.33-0.95; P = .03; AER, 6.48/100 person-years; censoring rate, 0.90; 23 events]). There was no effect of supplementation on HIV viral load. Multivitamins alone and selenium supplementation alone were not statistically different from placebo for any end point. Reported adverse events were adjudicated as unlikely to be related to the intervention, and there were no notable differences in incidence of HIV-related and health-related events among study groups. CONCLUSIONS AND RELEVANCE In ART-naive HIV-infected adults, 24-month supplementation with a single supplement containing multivitamins and selenium was safe and significantl

Spintronics: Fundamentals and applications

Spintronics, or spin electronics, involves the study of active control and manipulation of spin degrees of freedom in solid-state systems. This article reviews the current status of this subject, including both recent advances and well-established results. The primary focus is on the basic physical principles underlying the generation of carrier spin polarization, spin dynamics, and spin-polarized transport in semiconductors and metals. Spin transport differs from charge transport in that spin is a nonconserved quantity in solids due to spin-orbit and hyperfine coupling. The authors discuss in detail spin decoherence mechanisms in metals and semiconductors. Various theories of spin injection and spin-polarized transport are applied to hybrid structures relevant to spin-based devices and fundamental studies of materials properties. Experimental work is reviewed with the emphasis on projected applications, in which external electric and magnetic fields and illumination by light will be used to control spin and charge dynamics to create new functionalities not feasible or ineffective with conventional electronics.Comment: invited review, 36 figures, 900+ references; minor stylistic changes from the published versio