Early outcomes of thrombolysis for acute ischaemic stroke in a South African tertiary care centre

Includes abstract.Includes bibliographical references.Stroke is an important cause of death and disability in sub-Saharan Africa. Recombinant tissue plasminogen activator (tPA) thrombolysis is effective in treating acute ischaemic stroke, but may not be a viable option in developing countries. This prospective observational study was designed to assess the short-termoutcomes and safety of tPA for the treatment of stroke at Groote Schuur Hospital.Data was collected from January 2000 to February 2012, and included patients witha clinical diagnosis of acute stroke with onset of stroke symptoms within 4.5 hours ofreceiving thrombolysis. Exclusion criteria were based on the National Institute ofNeurological Disorders and Stroke (NINDS) rt-PA trial protocol (upper age limit was 75 years). Primary outcomes were the proportion of patients achieving significant early neurological recovery defined as an improvement of 4 or more points on the National Institutes of Health stroke scale (NIHSS) score and functional independence defined as a modified Rankin score of 2 or less at discharge. The primary safety measures were the rates of symptomatic intracranial haemorrhage (SICH) and death. From January 2000 to February 2011 42 patients were thrombolysed, with a mean time to tPA infusion of 160 minutes (standard deviation (SD) 50; range 60 - 270). By discharge the median NIHSS score fell from 14 (interquartile range (IQR) 10.5 - 17) to 7.5 (IQR 1 - 15); 28 (66.7%) achieved significant neurological improvement, and 17 (40.5%) were functionally independent. Two patients (4.8%) suffered SICH and there were 3 (7.1%) deaths. Thrombolysis in routine clinical practice in a South African setting has similar safety and early efficacy outcomes to controlled trials and open-label studies in developing and developed countries

Analyzing the Effects of Credit Rating Changes, the Recent Financial Crisis and Other Variables on Firms\u27 Debt Levels

This paper utilizes a sample of firms over the years 2000–2009 to test the effects of credit rating changes, the financial crisis, interest rates, and other variables on short-term, long-term, and total debt levels on the balance sheet. Each independent variable was created using a one year lag in order to run the regressions. The values of these variables from the previous year are being analyzed to see if they can predict debt levels for the following year. The results of this paper suggest that levels of long-term and total debt are somewhat reliant on and are positively correlated with the federal funds rate. The results indicate that short-term debt levels are much harder to predict, but they appear to be negatively correlated with the financial crisis. Long-term debt levels were also affected by this variable, but were positively correlated with it. Z-score was a significant predictor of all types of debt, and was positively correlated with each. In an effort to acquire as many data points as possible for the regressions, strict data filtration techniques were used. This limited the sample to 177 firms. The overall insignificance of the results in this study suggest that further research on what drives debt levels on the balance sheet is necessary. This will generate a greater understanding of firm behavior both inside and outside of a financial crisis

Optimising linezolid use for drug-resistant tuberculosis: pharmacokinetics, toxicity, and resistance

Background: Rifampicin-resistant tuberculosis (RR-TB) accounts for an expanding proportion of incident global TB cases and is a major barrier to global tuberculosis control. There is a need for more effective, safe, and well-tolerated drugs. Linezolid is a repurposed oxazolidinone antimicrobial with bactericidal activity against M. tuberculosis. Guidelines recommend linezolid as a preferred antituberculosis agent for RR-TB, and it is widely used in national programmes. The major drawback of linezolid is dose-related mitochondrial toxicity that may be treatment limiting. The incidence and risk factors for linezolid adverse events have not been systematically studied in TB programmes, particularly in populations from sub-Saharan Africa with high rates of HIV co-infection, which could increase the risk of toxicity. Exposure-response relationships for linezolid toxicity are also not well characterised. In addition, limited data exist on clinical associations and genotypic correlates of linezolid resistance in M. tuberculosis, needed to inform strategies for resistance testing. My thesis aimed to address these knowledge gaps to optimise use of this important agent in RR-TB. Methods: We conducted a prospective observational cohort study among patients with RR-TB across three sites in South Africa to characterise the pharmacokinetics (PK) and clinical toxicity of linezolid in programmatic settings with high HIV prevalence. Participants were followed for up to 24 months after linezolid initiation. We did monthly screening for peripheral and optic neuropathy, and collected clinical samples for toxicity outcomes, drug concentrations, and mitochondrial DNA analysis. Intensive PK sampling was performed on a subgroup of participants. Drug exposure was described using non-compartmental analysis and mixed effects modelling was used to analyse toxicity outcomes. For the resistance aims, we did a separate retrospective cohort study of patients with RR-TB and linezolid-based treatment failure at two TB referral hospitals in South Africa. Clinical information was extracted and recovered isolates underwent linezolid minimum inhibitory concentration (MIC) testing and targeted sequencing of rrl and rplC. Results: Among 30 participants enrolled in the intensive PK study, linezolid exposure was related to body weight and age, but not HIV positivity. The standard 600 mg dose achieved the PK efficacy target at wild type MIC values, but trough concentrations 5 were above the putative toxicity threshold in almost 60%. 151 participants, 63% HIVpositive, were enrolled in the prospective cohort. Premature discontinuation of linezolid for toxicity was common but grade 3 or 4 adverse events occurred in 22 (15%). Linezolid trough concentration, male sex, and age (but not HIV-positivity) were independently associated with a decrease in haemoglobin > 2 g/dL. Trough linezolid concentration of 2.5 mg/L or higher resulted in optimal model performance to describe changing haemoglobin and was strongly associated with treatment-emergent anaemia. Single nucleotide polymorphisms 2706A>G and 3010G>A in mitochondrial DNA were not associated with linezolid toxicity. Thirty-nine patients with linezolidbased treatment failure were identified in the retrospective cohort, 13 (33%) of whom had phenotypic or genotypic linezolid resistance after a median duration of 22 months linezolid therapy. All isolates with phenotypic resistance were associated with known resistance mutations, most frequently due to the T460C substitution in rplC. Conclusions: Our PK analysis confirmed the narrow therapeutic index of linezolid and there was no effect of HIV on linezolid exposure. Severe adverse events were uncommon at the standard dose of 600 mg daily and HIV co-infection was not independently associated with linezolid toxicity. Linezolid trough concentration of 2.5 mg/L should be evaluated as a target for therapeutic drug monitoring as a strategy to reduce toxicity. Resistance occurred late and was predicted by a limited number of mutations. Screening for genotypic resistance should be considered for patients with a positive culture after 4 months of linezolid therapy. These findings support current linezolid dosing in TB programmes

Burden of pneumocystis pneumonia in HIV-infected adults in sub-Saharan Africa: protocol for a systematic review

BACKGROUND: Reports from Africa have suggested that pneumocystis pneumonia (PCP) is a less important cause of morbidity than in the developed world. However, more recent studies have shown high seroprevalence rates of P. jirovecii in healthy individuals with HIV as well as high rates of clinical disease in African children. This suggests that PCP may be more common in Africa than was previously recognised. Understanding the contribution of PCP to disease in HIV-infected individuals in sub-Saharan Africa (SSA) has important implications for diagnosis, management and resource allocation. We therefore propose to conduct a systematic review and meta-analysis in order to investigate the burden of PCP in this population.METHODS AND DESIGN:We plan to search electronic databases and reference lists of relevant articles published from 1995 to May 2013 using broad terms for pneumocystis, HIV/AIDS and sub-Saharan Africa. Studies will be included if they provide clear diagnostic criteria for PCP and well-defined study populations or mortality data (denominator). A novel quality score assessment tool has been developed to ensure fidelity to inclusion criteria, minimise risk of selection bias between reviewers and to assess quality of outcome ascertainment. This will be applied to eligible full-text articles. We will extract data using a standardised form and perform descriptive and quantitative analysis to assess PCP prevalence, mortality and case fatality, as well as the quality of included studies. This review protocol has been published in the PROSPERO International Prospective Register of systematic reviews, registration number CRD42013005530.DISCUSSION:Our planned review will contribute to the diagnosis and management of community-acquired pneumonia in HIV-infected individuals in SSA by systematically assessing the burden of PCP in this population. We also describe a novel quality assessment tool that may be applied to other prevalence reviews

Community-based care of stroke patients in a rural african setting

Background: In order to develop a community based-model of stroke care we assessed discharge planning of stroke patients, available resources, and continuity of care between hospital and community in a remote rural setting in South Africa. We sought to determine outcomes, family participation and support needs, as well as implementation of secondary prevention strategies. Methods: Thirty consecutive stroke patients from the local hospital were assessed clinically (including Barthel Index and modified Rankin scores) at time of discharge. Patients were re-assessed three months after discharge in their homes by a trained field worker using a structured questionnaire. Results: Two thirds of all families received no stroke education before discharge. At discharge 27 (90%) were either bed or chair-bound. All the patients were discharged into family care as there was no stroke rehabilitation facility available to the community. Of 30 patients recruited, 20 (66.7%) were alive at 3 months, 9 (30%) were deceased, and 1 was lost to follow-up. At 3 months, 55% of survivors were independently mobile as compared with 10% at discharge. A total of 13 (65%) patients in our cohort were visited by home-based carers. Only 45% reported taking aspirin at 3 months. Conclusions: The 3 month mortality rate was high. Most survivors improved functionally but were left with significant disability. Measures to improve family education and the level of home-based care can be introduced in a model of stroke care attempting to reduce carer strain and improve functional disability in rural stroke patients

Assessing healthcare quality using routine data: evaluating the performance of the national tuberculosis programme in South Africa

ObjectiveTo assess the performance of healthcare facilities by means of indicators based on guidelines for clinical care of TB, which is likely a good measure of overall facility quality.MethodsWe assessed quality of care in all public health facilities in South Africa using graphical, correlation and locally weighted kernel regression analysis of routine TB test data.ResultsFacility performance falls short of national standards of care. Only 74% of patients with TB provided a second specimen for testing, 18% received follow‐up testing and 14% received drug resistance testing. Only resistance testing rates improved over time, tripling between 2004 and 2011. National awareness campaigns and changes in clinical guidelines had only a transient impact on testing rates. The poorest performing facilities remained at the bottom of the rankings over the period of study.ConclusionThe optimal policy strategy requires both broad‐based policies and targeted resources to poor performers. This approach to assessing facility quality of care can be adapted to other contexts and also provides a low‐cost method for evaluating the effectiveness of proposed interventions. Devising targeted policies based on routine data is a cost‐effective way to improve the quality of public health care provided.ObjectifEvaluer la performance des établissements de santé au moyen d’indicateurs basés sur des directives pour les soins cliniques de la tuberculose (TB), qui sont probablement une bonne mesure de la qualité globale des établissements.MéthodesNous avons évalué la qualité des soins dans tous les établissements de santé publique en Afrique du Sud à l’aide d’une analyse de régression graphique, de corrélation et localement pondérée des données de dépistage de routine de la TB.RésultatsLa performance des établissements ne respecte pas les normes nationales de soins. Seuls 74% des patients TB ont fourni un deuxième échantillon pour les tests, 18% ont reçu des tests de suivi et 14% ont reçu des tests de résistance aux médicaments. Seuls les taux de dépistage de la résistance se sont améliorés au cours du temps, en triplant entre 2004 et 2011. Les campagnes de sensibilisation nationales et les changements apportés aux directives cliniques n’ont eu qu’un impact transitoire sur les taux de dépistage. Les établissements avec la plus mauvaise performance sont restés au bas du classement au cours de la période étudiée.ConclusionLa stratégie politique optimale requiert à la fois des politiques générales et des ressources ciblées pour la mauvaise performance. Cette méthode d’évaluation de la qualité des soins peut être adaptée à d’autres contextes et procure également une méthode peu coûteuse pour évaluer l’efficacité des interventions proposées. L’élaboration de politiques ciblées basées sur des données de routine est un moyen rentable pour améliorer la qualité des soins de santé publique fournis.Mots‐clésqualité des soins, mesure de la qualité, prestation des soins de santé, politique de santé, tuberculose, résistance aux antibiotiques, Afrique du SudObjetivoEvaluar el desempeño de los centros sanitarios por medio de indicadores basados en guías para la atención clínica de la TB, lo cual podría ser una buena medida de la calidad general de las instalaciones.MétodosHemos evaluado la calidad de la atención en centros sanitarios públicos de Sudáfrica mediante análisis gráficos, correlaciones y regresiones ponderadas de Kernel utilizando datos rutinarios de TB.ResultadosEl desempeño de los centros está por debajo de los estándares nacionales de cuidado. Solo un 74% de los pacientes con TB proveyeron un segundo espécimen para pruebas, un 18% recibió pruebas de seguimiento, y un 14% pruebas de resistencia a medicamentos. Solo mejoraron a lo largo del tiempo las tasas de las pruebas de resistencia, triplicándose entre el 2004‐2011. Las campañas de concienciación nacionales y los cambios en las guías clínicas solo tenían un impacto transitorio sobre las tasas de las pruebas. Los centros con los peores resultados continuaron en lo más bajo de la clasificación a lo largo del periodo de estudio.ConclusiónLa estrategia óptima requiere tanto el uso de políticas de base amplia como de recursos dirigidos a quienes tienen un peor desempeño. Esta aproximación para evaluar la calidad de la atención de los centros puede adaptarse a otros contextos, y también provee un método de bajo coste para evaluar la efectividad de las intervenciones propuestas. La elaboración de políticas orientadas, basadas en datos rutinarios, es una forma coste‐efectiva de mejorar la calidad de la atención sanitaria pública.Palabras clavecalidad de la atención, calidad de medidas, entrega de atención sanitaria, política sanitaria, tuberculosis, resistencia a antibióticos, SudáfricaPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135966/1/tmi12819.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135966/2/tmi12819_am.pd