Incorrectly diagnosing children as HIV-infected : experiences from a large paediatric antiretroviral therapy site in South Africa

OBJECTIVE: To assess the extent to which children may be falsely diagnosed as HIV-infected, using data from an antiretroviral therapy (ART) site in Pretoria, South Africa. METHODS: This was a retrospective patient record review of all ART-naïve children referred to Kalafong hospital’s paediatric HIV clinic between April 2004 and March 2010, with detailed review of those found to be HIV-uninfected. RESULTS: There were 1 526 patient files analysed, with a male-to-female ratio of 1.01:1 and median age at first visit of 20 months (range 26 days - 17.5 years). Nearly half (n=715; 47%) of the children were aged <18 months. Fifty-one children were found to be HIV-uninfected after repeated diagnostic tests. Incorrect laboratory results for children aged <18 months included false-positive HIV DNA PCR tests (40), detectable HIV viral loads (4) and a false-positive HIV p24Ag test (1). One child above 18 months had false-positive HIV ELISA results. An additional 4 children were inappropriately referred after being incorrectly labelled as HIV-infected and 1 child aged <18 months was referred after an inappropriate diagnostic test for age was used. In summary, 1 in every 30 (3.3%) children was discharged HIV-uninfected, and below age 18 months, 1 in 16 children (6.3%) had false-positive HIV virological tests. CONCLUSIOS: Urgency in ART initiation in HIV-infected children is life-saving, especially in infants. However, HIV tests may produce false-positive results leading to misdiagnosis of children as HIV-infected, which has serious consequences. Meticulous checking of HIVpositive status is of utmost importance before committing any child to lifelong ART.Data presented as a poster at the 5th South African AIDS Conference 7 - 10 June 2011, Durban, South Africa.http://www.sajch.org.za/index.php/SAJC

Early diagnosis is critical to ensure good outcomes in HIV-infected children : outlining barriers to care

HIV-infected children require early initiation of antiretroviral therapy (ART) to ensure good outcomes. The aim was to investigate missed opportunities in childhood HIV diagnosis leading to delayed ART initiation. Baseline data was reviewed of all children aged <15 years referred over a one-year period for ART initiation to the Kalafong Hospital HIV services in Gauteng, South Africa. Of the 250 children, one quarter (24.5%) were of school-going age, 34.5% in the preschool group, 18% between 6-12 months old and 23% below six months of age (median age=1.5 years [IQR 0.5- 4.8]). Most children (82%) presented with advanced/severe HIV disease, particularly those aged 6-12 months (95%). Malnutrition was prominent and referrals were mostly from hospital inpatient services (61%). A structured caregiver interview was conducted in a subgroup, with detailed review of medical records and HIV results. The majority (≥89%) of the 65 interviewed caregivers reported good access to routine healthcare, except for postnatal care (26%). Maternal HIV-testing was mostly done during the 2nd & 3rd pregnancy trimesters (69%). Maternal non-disclosure of HIV status was common (63%) and 83% of mothers reported a lack of psychosocial support. Routine infant HIV-testing was not done in 66%, and inadequate reporting on patient-held records (Road-to- Health Cards/Booklets) occurred frequently (74%). Children with symptomatic HIV disease were not investigated at primary healthcare in 53%, and in 68% of families the siblings were not tested. One-third of children (35%) had a previous HIV diagnosis, with 77% of caregivers aware of these prior results, while 50% acknowledged failing to attend ART-services despite referral. In conclusion, a clear strategy on paediatric HIV case finding, especially at primary healthcare, is vital. Multiple barriers need to be overcome in the HIV care pathway to reach high uptake of services, of which especially maternal reasons for not attending paediatric ART services need further exploration.http://www.tandfonline.com/loi/caic202016-08-30hb201

Loss of detectability and indeterminate results : challenges facing HIV infant diagnosis in South Africa's expanding ART programme

BACKGROUND. Early infant diagnosis with rapid access to treatment has been found to reduce HIV-associated infant mortality and morbidity considerably. In line with international standards, current South African guidelines advocate routine HIV-1 polymerase chain reaction (PCR) testing at 6 weeks of age for all HIV-exposed infants and ‘fast-track’ entry into the HIV treatment programme for those who test positive. Importantly, testing occurs within the context of increasing efforts at prevention of mother-to-child transmission (PMTCT) by means of maternal and infant antiretroviral therapy (ART). In addition, infants already initiated on combination ART (cART) may be retested with PCR assays for ‘confirmatory’ purposes, including assessment prior to adoption. The potential for cART to compromise the sensitivity of HIV-1 PCR assays has been described, although there are limited and conflicting data regarding the effect of PMTCT regimens on HIV-1 PCR diagnostic sensitivity. METHODS. We describe a case series of three infants with different ART exposures in whom HIV diagnosis, confirmation or the result of retesting for adoption purposes were uncertain. RESULTS. These cases demonstrate that ART can be associated with a loss of detectability of HIV, leading to ‘false-negative’ HIV-1 PCR results in infants on cART. Furthermore, current PMTCT practices may lead to repeatedly indeterminate results with a subsequent delay in initiation of cART. CONCLUSION. The sensitivity of HIV-1 PCR assays needs to be re-evaluated within the context of different ART exposures, and diagnostic algorithms should be reviewed accordingly.http://www.samj.org.zaam201

Factors associated with the development of drug resistance mutations in HIV-1 infected children failing protease inhibitor-based antiretroviral therapy in South Africa

OBJECTIVE Limited data are available from the developing world on antiretroviral drug resistance in HIV-1 infected children failing protease inhibitor-based antiretroviral therapy, especially in the context of a high tuberculosis burden. We describe the proportion of children with drug resistance mutations after failed protease inhibitor-based antiretroviral therapy as well as associated factors. METHODS Data from children initiated on protease inhibitor-based antiretroviral therapy with subsequent virological failure referred for genotypic drug resistance testing between 2008 and 2012 were retrospectively analysed. Frequencies of drug resistance mutations were determined and associations with these mutations identified through logistic regression analysis. RESULTS The study included 65 young children (median age 16.8 months [IQR 7.8; 23.3]) with mostly advanced clinical disease (88.5% WHO stage 3 or 4 disease), severe malnutrition (median weight-for-age Z-score -2.4 [IQR -3.7;-1.5]; median height-for-age Z-score -3.1 [IQR -4.3;- 2.4]), high baseline HIV viral load (median 6.04 log10, IQR 5.34;6.47) and frequent tuberculosis co-infection (66%) at antiretroviral therapy initiation. Major protease inhibitor mutations were found in 49% of children and associated with low weight-for-age and height-for-age (p = 0.039; p = 0.05); longer duration of protease inhibitor regimens and virological failure (p = 0.001; p = 0.005); unsuppressed HIV viral load at 12 months of antiretroviral therapy (p = 0.001); tuberculosis treatment at antiretroviral therapy initiation (p = 0.048) and use of ritonavir as single protease inhibitor (p = 0.038). On multivariate analysis, cumulative months on protease inhibitor regimens and use of ritonavir as single protease inhibitor remained significant (p = 0.008; p = 0.033). CONCLUSION Major protease inhibitor resistance mutations were common in this study of HIV-1-infected children, with the timing of tuberculosis treatment and subsequent protease inhibitor dosing strategy proving to be important associated factors. There is an urgent need for safe, effective, and practicable HIV/tuberculosis co-treatment in young children and the optimal timing of treatment, optimal dosing of antiretroviral therapy, and alternative tuberculosis treatment strategies should be urgently addressed.All files are available from the GenBank database under accession numbers KT031999-KT032063.Ms LAW Hahne for the development of the electronic database for the Kalafong clinic. Mr T Moto for the assistance with data collection. Drs G Malherbe and P Mahasha for assisting with the development of the genotyping assay and the staff at the HIV clinics for their dedicated service to patients and their assistance with data collection.Conceived and designed the experiments: TR UF. Performed the experiments: GVD. Analyzed the data: GM. Contributed reagents/materials/analysis tools: TR GM. Wrote the paper: TR UF GM GVD WT NDP TA.This research and selected researchers (TR and GVD) were partially funded by a grant from the Delegation of the European Union to South Africa: "Drug Resistance Surveillance and Treatment Monitoring Network for the Public Sector HIV Antiretroviral Treatment Programme in the Free State” - Sante 2007/147-790 - and National Research Council of South Africa, Unlocking the Future 61509.http://www.plosone.orgam201

Ecological countermeasures to prevent pathogen spillover and subsequent pandemics

Substantial global attention is focused on how to reduce the risk of future pandemics. Reducing this risk requires investment in prevention, preparedness, and response. Although preparedness and response have received significant focus, prevention, especially the prevention of zoonotic spillover, remains largely absent from global conversations. This oversight is due in part to the lack of a clear definition of prevention and lack of guidance on how to achieve it. To address this gap, we elucidate the mechanisms linking environmental change and zoonotic spillover using spillover of viruses from bats as a case study. We identify ecological interventions that can disrupt these spillover mechanisms and propose policy frameworks for their implementation. Recognizing that pandemics originate in ecological systems, we advocate for integrating ecological approaches alongside biomedical approaches in a comprehensive and balanced pandemic prevention strategy

The seeds of divergence: the economy of French North America, 1688 to 1760

Generally, Canada has been ignored in the literature on the colonial origins of divergence with most of the attention going to the United States. Late nineteenth century estimates of income per capita show that Canada was relatively poorer than the United States and that within Canada, the French and Catholic population of Quebec was considerably poorer. Was this gap long standing? Some evidence has been advanced for earlier periods, but it is quite limited and not well-suited for comparison with other societies. This thesis aims to contribute both to Canadian economic history and to comparative work on inequality across nations during the early modern period. With the use of novel prices and wages from Quebec—which was then the largest settlement in Canada and under French rule—a price index, a series of real wages and a measurement of Gross Domestic Product (GDP) are constructed. They are used to shed light both on the course of economic development until the French were defeated by the British in 1760 and on standards of living in that colony relative to the mother country, France, as well as the American colonies. The work is divided into three components. The first component relates to the construction of a price index. The absence of such an index has been a thorn in the side of Canadian historians as it has limited the ability of historians to obtain real values of wages, output and living standards. This index shows that prices did not follow any trend and remained at a stable level. However, there were episodes of wide swings—mostly due to wars and the monetary experiment of playing card money. The creation of this index lays the foundation of the next component. The second component constructs a standardized real wage series in the form of welfare ratios (a consumption basket divided by nominal wage rate multiplied by length of work year) to compare Canada with France, England and Colonial America. Two measures are derived. The first relies on a “bare bones” definition of consumption with a large share of land-intensive goods. This measure indicates that Canada was poorer than England and Colonial America and not appreciably richer than France. However, this measure overestimates the relative position of Canada to the Old World because of the strong presence of land-intensive goods. A second measure is created using a “respectable” definition of consumption in which the basket includes a larger share of manufactured goods and capital-intensive goods. This second basket better reflects differences in living standards since the abundance of land in Canada (and Colonial America) made it easy to achieve bare subsistence, but the scarcity of capital and skilled labor made the consumption of luxuries and manufactured goods (clothing, lighting, imported goods) highly expensive. With this measure, the advantage of New France over France evaporates and turns slightly negative. In comparison with Britain and Colonial America, the gap widens appreciably. This element is the most important for future research. By showing a reversal because of a shift to a different type of basket, it shows that Old World and New World comparisons are very sensitive to how we measure the cost of living. Furthermore, there are no sustained improvements in living standards over the period regardless of the measure used. Gaps in living standards observed later in the nineteenth century existed as far back as the seventeenth century. In a wider American perspective that includes the Spanish colonies, Canada fares better. The third component computes a new series for Gross Domestic Product (GDP). This is to avoid problems associated with using real wages in the form of welfare ratios which assume a constant labor supply. This assumption is hard to defend in the case of Colonial Canada as there were many signs of increasing industriousness during the eighteenth and nineteenth centuries. The GDP series suggest no long-run trend in living standards (from 1688 to circa 1765). The long peace era of 1713 to 1740 was marked by modest economic growth which offset a steady decline that had started in 1688, but by 1760 (as a result of constant warfare) living standards had sunk below their 1688 levels. These developments are accompanied by observations that suggest that other indicators of living standard declined. The flat-lining of incomes is accompanied by substantial increases in the amount of time worked, rising mortality and rising infant mortality. In addition, comparisons of incomes with the American colonies confirm the results obtained with wages— Canada was considerably poorer. At the end, a long conclusion is provides an exploratory discussion of why Canada would have diverged early on. In structural terms, it is argued that the French colony was plagued by the problem of a small population which prohibited the existence of scale effects. In combination with the fact that it was dispersed throughout the territory, the small population of New France limited the scope for specialization and economies of scale. However, this problem was in part created, and in part aggravated, by institutional factors like seigneurial tenure. The colonial origins of French America’s divergence from the rest of North America are thus partly institutional

Geothermal energy

Discussion of geothermal technology and an assessment of impacts from development - for general public

Loss of detectability and indeterminate results: Challenges facing HIV infant diagnosis in South Africa’s expanding ART programme

Background. Early infant diagnosis with rapid access to treatment has been found to reduce HIV-associated infant mortality and morbidity considerably. In line with international standards, current South African guidelines advocate routine HIV-1 polymerase chain reaction (PCR) testing at 6 weeks of age for all HIV-exposed infants and ‘fast-track’ entry into the HIV treatment programme for those who test positive. Importantly, testing occurs within the context of increasing efforts at prevention of mother-to-child transmission (PMTCT) by means of maternal and infant antiretroviral therapy (ART). In addition, infants already initiated on combination ART (cART) may be retested with PCR assays for ‘confirmatory’ purposes, including assessment prior to adoption. The potential for cART to compromise the sensitivity of HIV-1 PCR assays has been described, although there are limited and conflicting data regarding the effect of PMTCT regimens on HIV-1 PCR diagnostic sensitivity.Methods. We describe a case series of three infants with different ART exposures in whom HIV diagnosis, confirmation or the result of retesting for adoption purposes were uncertain.Results. These cases demonstrate that ART can be associated with a loss of detectability of HIV, leading to ‘false-negative’ HIV-1 PCR results in infants on cART. Furthermore, current PMTCT practices may lead to repeatedly indeterminate results with a subsequent delay in initiation of cART.Conclusion. The sensitivity of HIV-1 PCR assays needs to be re-evaluated within the context of different ART exposures, and diagnostic algorithms should be reviewed accordingly

Co‐designing a toolkit for evidence‐based decision making in conservation: Processes and lessons

Funder: Arcadia Fund; doi: http://dx.doi.org/10.13039/100012088Funder: MAVA Foundation; doi: http://dx.doi.org/10.13039/100013324Improving the effectiveness of conservation practice requires better use of evidence. Since 2004, researchers from the Conservation Evidence group (University of Cambridge) have engaged with over 1100 named practitioners, policymakers, funders and other academics from across the world to identify needs and develop a range of principles, tools and resources to embed evidence in decision making. The goal of this engagement (the Conservation Evidence Programme) was to deliver improved conservation practice leading to benefits for nature and society. Together, we developed a theory of change with five key strategies for delivering change, alongside a freely available Evidence Toolkit to support decision makers in achieving that change. The authors describe the toolkit, a collection of freely available tools and resources developed by the collaborative programme, and how co‐design, employing different levels of partner engagement, enabled its development. Reflecting on our experiences highlighted a number of insights and recommendations, including the need to identify where deep engagement is a necessary condition for success; the importance of collective agreement of the roles of different partners; the need to consider how to facilitate uptake of new tools or practices, particularly where that requires changes to organisational practices or culture; and the importance of establishing processes/channels for ongoing engagement with stakeholders, with a willingness to be flexible and open to incorporating new suggestions and perspectives as needed. The Conservation Evidence Programme has enabled practitioners, funders and policymakers to become part of a network of forward‐thinking organisations that is working collaboratively to help drive more effective conservation practice through improved evidence use