Adjusting the effect of integrating antiretroviral therapy and tuberculosis treatment on mortality for non-compliance : an instrumental variables analysis using a time-varying exposure.

Doctoral Degree. University of KwaZulu-Natal, Pietermaritzburg.In South Africa and elsewhere, research has shown that the integration of antiretroviral therapy (ART) and tuberculosis (TB) treatment saves lives. The randomised controlled trials (RCTs) which provided this compelling evidence used intent-to-treat (ITT) strategy as part of their primary analysis. As much as ITT is protected against selection bias caused by both measured and unmeasured confounders, but it is capable of drawing results towards the null and underestimate the e ectiveness of treatment if there is too much non-compliance. To adjust for non-compliance, \as-treated"and \per-protocol"comparisons are commonly made. These contrast study participants according to their received treatment, regardless of the treatment arm to which they were assigned, or limit the analysis to participants who followed the protocol. Such analyses are generally biased because the subgroups which they compare often lack comparability. In view of the shortcomings of the \as-treated"and \per-protocol"analyses, our objective was to account for non-compliance by using instrumental variables (IV) analysis to estimate the e ect of ART initiation during TB treatment on mortality. Furthermore, to capture the full complexity of compliance behaviour outside the TB treatment duration, we developed a novel IV-methodology for a time-varying measure of compliance to ART. This is an important contribution to the IV literature since IV-methodology for the e ect of a time-varying exposure on a time-to-event endpoint is currently lacking. In RCTs, IV analysis enable us to make use of the comparability o ered by randomisation and thereby have the capability of adjusting for unmeasured and measured confounders; they have the further advantage of yielding results that are less sensitive to random measurement error in the exposure. In order to carry out IV analysis, one needs to identify a variable called an instrument, which needs to satisfy three important assumptions. To apply the IV methodology, we used data from Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial which was conducted by the Centre for the AIDS Programme of Research in South Africa. This trial enrolled HIV and TB co-infected patients who were assigned to start ART either early or late during TB treatment or after TB treatment completion. The results from IV analysis demonstrate that survival bene t of fully integrating TB treatment and ART is even higher than what has been reported in the ITT analysis since non-compliance has been accounted for

Comparing different thrombolytic dosing regimens for treatment of acute pulmonary embolism

Background\ud Optimal dosing of recombinant tissue-type plasminogen activator (rt-PA) is important in treating pulmonary thromboembolism (PTE).\ud \ud Methods\ud Objective\ud The aim of this study was to compare the efficacy and safety of a 50 mg/2 h rt-PA regimen with a 100 mg/2 h rt-PA regimen in patients with acute PTE.\ud \ud Design\ud A prospective, randomized, open label trial.\ud \ud Setting\ud A multicenter trial in China.\ud \ud Subjects\ud 118 patients with acute PTE and either hemodynamic instability or massive pulmonary artery obstruction.\ud \ud Intervention\ud Patients were randomly assigned to receive a treatment regimen of either rt-PA at 50 mg/2 h (n = 65) or 100 mg/2 h (n = 53).\ud \ud Outcomes\ud The efficacy was determined by observing the improvements of right ventricular dysfunctions (RVDs) on echocardiograms, lung perfusion defects on ventilation perfusion lung scans, and pulmonary artery obstructions on CT angiograms. The adverse events, including death, bleeding, and PTE recurrence, was also evaluated.\ud \ud Results\ud Progressive improvements in RVDs, lung perfusion defects, and pulmonary artery obstructions were found to be similar in both treatment groups. This is true for patients with either hemodynamic instability or massive pulmonary artery obstruction. Three (6%) patients in the rt-PA 100 mg/2 h group and one (2%) in the rt-PA 50 mg/2 h group died as the result of either PTE or bleeding. Importantly, the 50 mg/2 h rt-PA regimen resulted in less bleeding tendency than the 100 mg/2 h regimen (3% vs. 10%), especially in patients with a body weight, 65 kg (14.8% vs. 41.2%, P = 0.049). No fatal recurrent PTE was found in either group.\ud \ud Conclusions\ud Compared with the 100 mg/2 h regimen, the 50 mg/2 h rt-PA regimen exhibits similar efficacy and perhaps better safety in patients with acute PTE. These findings support the notion that optimizing rt-PA dosing is worthwhile when treating patients with PTE

Pushing the envelope to reduce sedation in critically ill patients

Background\ud Standard treatment of critically ill patients undergoing mechanical ventilation is continuous sedation. Daily interruption of sedation has a beneficial effect, and in the general intensive care unit of Odense University Hospital, Denmark, standard practice is a protocol of no sedation. We aimed to establish whether duration of mechanical ventilation could be reduced with a protocol of no sedation versus daily interruption of sedation.\ud \ud Methods\ud Of 428 patients assessed for eligibility, we enrolled 140 critically ill adult patients who were undergoing mechanical ventilation and were expected to need ventilation for more than 24 h. Patients were randomly assigned in a 1:1 ratio (unblinded) to receive: no sedation (n = 70 patients); or sedation (20 mg/mL propofol for 48 h, 1 mg/mL midazolam thereafter) with daily interruption until awake (n = 70, control group). Both groups were treated with bolus doses of morphine (2.5 or 5 mg). The primary outcome was the number of days without mechanical ventilation in a 28-day period, and we also recorded the length of stay in the intensive care unit (from admission to 28 days) and in hospital (from admission to 90 days). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00466492.\ud \ud Findings\ud 27 patients died or were successfully extubated within 48 h, and, as per our study design, were excluded from the study and statistical analysis. Patients receiving no sedation had significantly more days without ventilation (n = 55; mean 13.8 days, SD 11.0) than did those receiving interrupted sedation (n = 58; mean 9.6 days, SD 10.0; mean difference 4.2 days, 95% CI 0.3-8.1; p = 0.0191). No sedation was also associated with a shorter stay in the intensive care unit (HR 1.86, 95% CI 1.05-3.23; p = 0.0316), and, for the first 30 days studied, in hospital (3.57, 1.52-9.09; p = 0.0039), than was interrupted sedation. No difference was recorded in the occurrences of accidental extubations, the need for CT or MRI brain scans, or ventilator-associated pneumonia. Agitated delirium was more frequent in the intervention group than in the control group (n = 11, 20% vs. n = 4, 7%; p = 0.0400).\ud \ud Interpretation\ud No sedation of critically ill patients receiving mechanical ventilation is associated with an increase in days without ventilation. A multicentre study is needed to establish whether this effect can be reproduced in other facilities

Understanding genetics of sepsis: will new technology help?

High-throughput techniques, such as genome-wide scans, will allow genotyping of a large number of single-nucleotide polymorphisms throughout the human genome. There is intense interest to apply this technology to understand genetics of complex traits, including severe sepsis. To effectively utilize this technology, large cohorts of septic patients will have to be recruited. Careful attention should be paid to different aspects of study design and analyses as large, multicenter cohorts are assembled for genome-wide association studies

Functional outcomes following surgical treatment of chronically unreduced simple elbow dislocations : a retrospective review

CITATION: Yende, T., Senoge, M. E. & Ferreira, N. 2018. Functional outcomes following surgical treatment of chronically unreduced simple elbow dislocations : a retrospective review. SA Orthopaedic Journal, 17(3):33-38, doi:10.17159/2309-8309/2018/v17n4a4a.The original publication is available at http://journal.saoa.org.za/index.php/saojBackground: Chronic elbow dislocations are rare injuries that present late for orthopaedic management. The delay in presentation is frequently due to patients not seeking treatment after the initial injury, poor access to health care, inadequate initial treatment of acute dislocation or initial missed diagnosis. Chronic simple elbow dislocations refer to dislocations that remain unreduced for more than two weeks and are not associated with fractures. This study aims to evaluate the outcome of surgically treated chronic elbow dislocations. Methods: A retrospective review of all patients who were treated for chronic simple elbow dislocations between September 2009 and August 2014 was undertaken. Further information regarding return to function was obtained from the records or telephonic consultation with the patients. Nine patients were included for final analysis. Results: Nine patients were eligible for the study. Three patients were employed, three were scholars and three were unemployed. All patients were able to return to premorbid function with minor limitations due to occasional pain. According to the Mayo Elbow Performance Index (MEPI) score, two patients had excellent outcomes, three good and three fair. One could not be scored as there was no recorded scoring on the file and telephonic contact was unsuccessful. The range of motion varied from 20° of extension to 140° of flexion. One patient developed a stiff elbow but was able to adapt to activities of daily living. Conclusion: Surgical treatment of chronically unreduced simple elbow dislocations offers satisfactory outcome with minimal complications and should be considered for all patients presenting with this condition.http://journal.saoa.org.za/index.php/saoj/article/view/269Publisher's versio

Diabetes and sepsis outcomes – it is not all bad news

Patients with diabetes mellitus have an increased risk of developing infections and sepsis. In this issue of Critical Care Esper and colleagues report on a large survey, involving 12.5 million sepsis cases, that examined the impact of pre-existing diabetes on organ dysfunction during sepsis. Their main conclusion was that diabetes patients, relative to non-diabetics, were less likely to develop respiratory failure and more likely to develop renal failure during the course of sepsis

An Exploratory Study of Women Leadership in the South African Charismatic Church Through an African Women Practical Theology Lens

Practical Theology and Missiolog

Modelling CD4+ count over time in HIV positive patients initiated on HAART in South Africa using linear mixed models.

Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2009.HIV is among the highly infectious and pathogenic diseases with a high mortality rate. The spread of HIV is in uenced by several individual based epidemiological factors such as age, gender, mobility, sexual partner pro le and the presence of sexually transmitted infections (STI). CD4+ count over time provided the rst surrogate marker of HIV disease progression and is currently used for clinical management of HIV-positive patients. The CD4+ count as a key disease marker is repeatedly measured among those individuals who test HIV positive to monitor the progression of the disease since it is known that HIV/AIDS is a long wave event. This gives rise to what is commonly known as longitudinal data. The aim of this project is to determine if the patients' weight, baseline age, sex, viral load and clinic site, in uences the rate of change in CD4+ count over time. We will use data of patients who commenced highly active antiretroviral therapy (HAART) from the Center for the AIDS Programme of Research in South Africa (CAPRISA) in the AIDS Treatment Project (CAT) between June 2004 and September 2006, including two years of follow-up for each patient. Analysis was done using linear mixed models methods for longitudinal data. The results showed that larger increase in CD4+ count over time was observed in females and individuals who were younger. However, upon tting baseline log viral load in the model instead of the log viral at all visits was that, larger increase in CD4+ count was observed in females, individuals who were younger, had higher baseline log viral load and lower weight