Leslie London

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

Neurobehavioral and neurodevelopmental effects of pesticide exposures

The association between pesticide exposure and neurobehavioral and neurodevelopmental effects is an area of increasing concern. This symposium brought together participants to explore the neurotoxic effects of pesticides across the lifespan. Endpoints examined included neurobehavioral, affective and neurodevelopmental outcomes among occupational (both adolescent and adult workers) and non-occupational populations (children). The symposium discussion highlighted many challenges for researchers concerned with the prevention of neurotoxic illness due to pesticides and generated a number of directions for further research and policy interventions for the protection of human health, highlighting the importance of examining potential long-term effects across the lifespan arising from early adolescent, childhood or prenatal exposure.

Long-term respiratory health effects of the herbicide, paraquat, among workers in the Western Cape

OBJECTIVE: To evaluate the possible effects of paraquat spraying among workers on deciduous fruit farms in the Western Cape, South Africa. Paraquat is a commonly used herbicide world wide and is a well documented cause of pulmonary fibrosis in studies of laboratory animals and in humans after exposure to a high dose (usually accidental or as parasuicide). The respiratory effects of long term, low dose exposure to paraquat have not been fully evaluated. METHODS: A cross sectional study of 126 workers. Administered questionnaires generated information on exposure, respiratory symptoms, and potential confounding variables. Spirometry and gas transfer were measured and chest radiographs performed. Oxygen desaturation on exercise testing was by oximetry during a modified stage one exercise test. RESULTS: No association was found between long term exposure to paraquat and reported symptoms, spirometry (forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC) and gas transfer (TLCO and KCO) or chest radiography. Multivariate analysis showed a significant relation between measures of long term exposure to paraquat and arterial oxygen desaturation during exercise independent of short term exposure. CONCLUSION: Previous studies have not shown a significant relation between measures of exposure to paraquat and standard tests of lung function. Arterial oxygen desaturation during exercise represents a more sensitive test. The findings indicate that working with paraquat under usual field conditions is associated with abnormal exercise physiology in a dose dependent fashion independent of recent exposure and acute poisoning events.

Evaluation of the quality of informed consent in a vaccine field trial in a developing country setting

BackgroundInformed consent is an ethical and legal requirement for research involving human participants. However, few studies have evaluated the process, particularly in Africa.Participants in a case control study designed to identify correlates of immune protection against tuberculosis (TB) in South Africa. This study was in turn nested in a large TB vaccine efficacy trial.The aim of the study was to evaluate the quality of consent in the case control study, and to identify factors that may influence the quality of consent.Cross-sectional study conducted over a 4 month period.MethodsConsent was obtained from parents of trial participants. These parents were asked to complete a questionnaire that contained questions about the key elements of informed consent (voluntary participation, confidentiality, the main risks and benefits, etc.). The recall (success in selecting the correct answers) and understanding (correctness of interpretation of statements presented) were measured.ResultsThe majority of the 192 subjects interviewed obtained scores greater than 75% for both the recall and understanding sections. The median score for recall was 66%; interquartile range (IQR) = 55%–77% and for understanding 75% (IQR = 50%–87%). Most (79%) were aware of the risks and 64% knew that they participated voluntarily. Participants who had completed Grade 7 at school and higher were more likely (OR = 4.94; 95% CI = 1.57 – 15.55) to obtain scores greater than 75% for recall than those who did not. Participants who were consented by professional nurses who had worked for more than two years in research were also more likely (OR = 2.62; 95% CI = 1.35–5.07) to obtain such scores for recall than those who were not.ConclusionNotwithstanding the constraints in a developing country, in a population with low levels of literacy and education, the quality of informed consent found in this study could be considered as building blocks for establishing acceptable standards for public health research. Education level of respondents and experience of research staff taking the consent were associated with good quality informed consent.

Ethical Oversight of Public Health Research: Can Rules and IRBs Make a Difference in Developing Countries?

Controversies in the conduct of international research continue to pose challenges for the system of ethical review, particularly for developing countries. Although the concept of vulnerability is key to addressing these challenges, ethical review has typically ignored the agency of vulnerable participants and groups in determining what kind of review process is needed. Concurrent with developments shaping the new public health that seek to operationalize empowerment of communities by placing them as initiators and organizers of their own health, ethical review of public health research must find ways to recognize the agency of vulnerable individuals, groups, and communities in the review process if it is to address effectively the ethical dilemmas currently evident in collaborative international research.

'Even if you're positive, you still have rights because you are a person': human rights and the reproductive choice of HIV-positive persons.

Global debates in approaches to HIV/AIDS control have recently moved away from a uniformly strong human rights-based focus. Public health utilitarianism has become increasingly important in shaping national and international policies. However, potentially contradictory imperatives may require reconciliation of individual reproductive and other human rights with public health objectives. Current reproductive health guidelines remain largely non prescriptive on the advisability of pregnancy amongst HIV-positive couples, mainly relying on effective counselling to enable autonomous decision making by clients. Yet, health care provider values and attitudes may substantially impact on the effectiveness of non prescriptive guidelines,particularly where social norms and stereotypes regarding childbearing are powerful, and where providers are subjected to dual loyalty pressures, with potentially adverse impacts on rights of service users. Data from a study of user experiences and perceptions of reproductive and HIV/AIDS services are used to illustrate a rights analysis of how reproductive health policy should integrate a rights perspective into the way services engage with HIV-positive persons and their reproductive choices. The analysis draws on recognised tools developed to evaluate health policies for their human rights impacts and on a model developed for health equity research in South Africa to argue for greater recognition of agency on the part of persons affected by HIV/AIDS in the development and content of policies on reproductive choices. We conclude by proposing strategies that are based upon a synergy between human rights and public health approaches to policy on reproductive health choices for persons with HIV/AIDS.

Alcohol consumption amongst South African farm workers: a challenge for post-apartheid health sector transformation.

A cross-sectional analytical study was conducted amongst farm workers in the deciduous fruit industry in South Africa to assess levels of alcohol consumption and abuse, and to explore the impact of the DOP system, whereby farm workers are paid in part with alcohol, on indicators of alcohol consumption. High levels of alcohol consumption were found. On the CAGE and a shortened version of the MAST questionnaires, 87 and 65%, respectively, had responses indicating problem drinking. Close to half of the sample consumed more grams of alcohol per week than considered safe drinking (210 g) and 9.3% consumed amounts in excess of dangerous drinking (>490 g/week). Almost one-fifth (19.4%) of workers interviewed reported current use of the DOP system, and 47.8% of workers had experience of one or more farms in the past where the DOP system had been used. Workers with past experience of the DOP system were 9.8 times less likely to be asbstainers than colleagues without exposure to the DOP system. The pervasive effects of excessive alcohol consumption, and its relationship to past and current DOP practices pose substantial public health challenges to the transformation of health services currently underway in South Africa.

Farmers' knowledge, practices and injuries associated with pesticide exposure in rural farming villages in Tanzania

BackgroundPesticides in Tanzania are extensively used for pest control in agriculture. Their usage and unsafe handling practices may potentially result in high farmer exposures and adverse health effects.The aim of this study was to describe farmers’ pesticide exposure profile, knowledge about pesticide hazards, experience of previous poisoning, hazardous practices that may lead to Acute Pesticide Poisoning (APP) and the extent to which APP is reported.MethodsThe study involved 121 head- of-household respondents from Arumeru district in Arusha region. Data collection involved administration of a standardised questionnaire to farmers and documentation of storage practices. Unsafe pesticide handling practices were assessed through observation of pesticide storage, conditions of personal protective equipment (PPE) and through self-reports of pesticide disposal and equipment calibration.ResultsPast lifetime pesticide poisoning was reported by 93% of farmers. The agents reported as responsible for poisoning were Organophosphates (42%) and WHO Class II agents (77.6%).Storage of pesticides in the home was reported by 79% of farmers. Respondents with higher education levels were significantly less likely to store pesticides in their home (PRR High/Low = 0.3; 95% CI = 0.1-0.7) and more likely to practice calibration of spray equipment (PRR High/Low = 1.2; 95% CI = 1.03-1.4). However, knowledge of routes of exposure was not associated with safety practices particularly for disposal, equipment wash area, storage and use of PPE . The majority of farmers experiencing APP in the past (79%) did not attend hospital and of the 23 farmers who did so in the preceding year, records could be traced for only 22% of these cases.ConclusionsThe study found a high potential for pesticide exposure in the selected community in rural Tanzania, a high frequency of self-reported APP and poor recording in hospital records. Farmers’ knowledge levels appeared to be unrelated to their risk. Rather than simply focusing on knowledge-based strategies, comprehensive interventions are needed to reduce both exposure and health risks, including training, improvements in labeling, measures to reduce cost barriers to the adoption of safe behaviours, , promotion of control measures other than PPE and support for Integrated Pest Management (IPM).

Use of a crop and job specific exposure matrix for retrospective assessment of long term exposure in studies of chronic neurotoxic effects of agrichemicals

RATIONALE: Job exposure matrices (JEMs) are widely used in occupational epidemiology, particularly when biological or environmental monitoring data are scanty. However, as with most exposure estimates, JEMs may be vulnerable to misclassification. OBJECTIVES: To estimate the long term exposure of farm workers based on a JEM developed for use in a study of the neurotoxic effects of organophosphates and to evaluate the repeatability and validity of the JEM. METHODS: A JEM was constructed with secondary data from industry and expert opinion of the estimate of agrichemical exposure within every possible job activity in the JEM to weight job days for exposure to organophosphates. Cumulative lifetime and average intensity exposure of organophosphate exposure were calculated for 163 pesticide applicators and 84 controls. Repeat questionnaires were given to 29 participants three months later to test repeatability of measurements. The ability of JEM based exposure to predict a known marker of organophosphate exposure was used to validate the JEM. RESULTS: Cumulative lifetime exposure as measured in kg organophosphate exposure, was significantly associated with erythrocyte cholinesterase concentrations (partial r2 = 5%; p < 0.01), controlled for a range of confounders. Repeatability in a subsample of 29 workers of the estimates of cumulative (Pearsons r = 0.67; 95% confidence interval (95% CI) 0.41 to 0.83), and average lifetime intensity of exposure (Pearsons r = 0.60 95% CI 0.31 to 0.79) was adequate. CONCLUSION: The JEM seems promising for farming settings, particularly in developing countries where data on chemical application and biological monitoring are unavailable.

Symptoms of psychological distress and suicidal ideation among banana workers with a history of poisoning by organophosphate or n-methyl carbamate pesticides

Objectives Neuropsychiatric disorders and increased suicide rates have been associated with exposure to cholinesterase inhibiting organophosphates. This study examined symptoms of psychological distress, including suicidal ideation, among banana workers in Costa Rica previously exposed to a cholinesterase inhibiting pesticide. Methods 78 workers who had received medical attention 1–3 years previously for occupational pesticide poisoning were recruited: 54 had been exposed to organophosphate, 24 to carbamate, and 43 and 35, respectively, had single and multiple poisoning episodes with a cholinesterase inhibitor. Referents were 130 non-poisoned workers randomly selected from company payrolls. Psychological distress symptoms during the month prior to interview were obtained using the Brief Symptom Inventory (BSI), which has a general severity index and nine subscale scores. Differences in abnormal BSI scores (T score≥63) were assessed through multivariate logistic regression for all poisoned and for subcategories of poisoned as compared to non-poisoned workers. Results Organophosphate poisoned workers reported significantly more symptoms than non-poisoned on all but one symptom dimension. Significant trends of increasing symptoms with increasing number of previous poisonings were seen for somatisation, obsessive-compulsiveness, interpersonal sensitivity, depression and anxiety. Carbamate poisoned workers only had increased scores for somatisation. The ORs for suicidal thoughts were: all poisoned 3.58 (95% CI 1.45 to 8.84); organophosphate poisoned 3.72 (1.41 to 9.81); carbamate poisoned 2.57 (0.73 to 9.81); and 2.65 and 4.98, respectively for 1 and ≥2 poisonings (trend p=0.01). Conclusions This cross-sectional study showed a relationship between acute occupational poisoning with organophosphates and psychological distress including suicidal ideation. Stronger designs are needed to address causality.