The thrombin generation capability of the Chacma baboon (Papio ursinus): implications for haemostatic disease models.

Baboon models are often used to investigate haemostatic diseases, such as acquired thrombotic thrombocytopenic purpura or bacterial sepsis-induced disseminated intravascular coagulation, and their potential treatment with novel drugs. Thrombin generation is vital for these models, and an important potential therapeutic target. We investigated the thrombin generation profile of the Chacma baboon (Papio ursinus - a common pre-clinical model) including the effects of sex and ABO blood group. Thrombin generation curves, lag times, peak heights, times-to-peak, velocity indexes and Endogenous Thrombin Potentials (ETPs) of 40 adult Chacma baboons were assessed and compared with normal human plasma, using a low concentration of tissue factor (1 pM) and phospholipids. Reference intervals were calculated, and results compared between O and non-O ABO blood groups, and between males and females. Lag times of all baboons fell within the human reference interval. Most animals (n = 32; 80%) had times-to-peak above, and velocity indexes and peak heights markedly below (n = 27; 68%) the human range. However, 97.5% of baboons had an ETP above the human reference interval, indicating greater overall thrombin generation. ABO blood group had no effect, but males (n = 14; 35%) had less potent thrombin generation than females (n = 26; 65%), with significantly longer lag times (p = 0.0475), lower peak thrombin concentrations (p = 0.0203), and lower ETPs (p = 0.0238). Chacma baboons have greater overall endogenous thrombin generation potentials than humans, which is even more prominent in females. This should be considered when designing future baboon model experiments involving the haemostatic system, or when evaluating novel therapies in these animals.

Estimating the changing burden of disease attributable to alcohol use in South Africa for 2000, 2006 and 2012.

BACKGROUND: Alcohol use was one of the leading contributors to South Africa (SA)'s disease burden in 2000, accounting for 7% of deaths and disability-adjusted life years (DALYs) in the first South African Comparative Risk Assessment Study (SACRA1). Since then, patterns of alcohol use have changed, as has the epidemiological evidence pertaining to the role of alcohol as a risk factor for infectious diseases, most notably HIV/AIDS and tuberculosis (TB). OBJECTIVES: To estimate the burden of disease attributable to alcohol use by sex and age group in SA in 2000, 2006 and 2012. METHODS: The analysis follows the World Health Organization (WHO)'s comparative risk assessment methodology. Population attributable fractions (PAFs) were calculated from modelled exposure estimated from a systematic assessment and synthesis of 17 nationally representative surveys and relative risks based on the global review by the International Model of Alcohol Harms and Policies. PAFs were applied to the burden of disease estimates from the revised second South African National Burden of Disease Study (SANBD2) to calculate the alcohol-attributable burden for deaths and DALYs for 2000, 2006 and 2012. We quantified the uncertainty by observing the posterior distribution of the estimated prevalence of drinkers and mean use among adult drinkers (≥15 years old) in a Bayesian model. We assumed no uncertainty in the outcome measures. RESULTS: The alcohol-attributable disease burden decreased from 2000 to 2012 after peaking in 2006, owing to shifts in the disease burden, particularly infectious disease and injuries, and changes in drinking patterns. In 2012, alcohol-attributable harm accounted for an estimated 7.1% (95% uncertainty interval (UI) 6.6 - 7.6) of all deaths and 5.6% (95% UI 5.3 - 6.0) of all DALYs. Attributable deaths were split three ways fairly evenly across major disease categories: infectious diseases (36.4%), non-communicable diseases (32.4%) and injuries (31.2%). Top rankings for alcohol-attributable DALYs for specific causes were TB (22.6%), HIV/AIDS (16.0%), road traffic injuries (15.9%), interpersonal violence (12.8%), cardiovascular disease (11.1%), cancer and cirrhosis (both 4%). Alcohol remains an important contributor to the overall disease burden, ranking fifth in terms of deaths and DALYs. CONCLUSION: Although reducing overall alcohol use will decrease the burden of disease at a societal level, alcohol harm reduction strategies in SA should prioritise evidence-based interventions to change drinking patterns. Frequent heavy episodic (i.e. binge) drinking accounts for the unusually large share of injuries and infectious diseases in the alcohol-attributable burden of disease profile. Interventions should focus on the distal causes of heavy drinking by focusing on strategies recommended by the WHO's SAFER initiative.

Estimating the changing disease burden attributable to smoking in South Africa for 2000, 2006 and 2012.

BACKGROUND: Ongoing quantification of the disease burden attributable to smoking is important to monitor and strengthen tobacco control policies. OBJECTIVES: To estimate the attributable burden due to smoking in South Africa for 2000, 2006 and 2012. METHODS: We estimated attributable burden due to smoking for selected causes of death in South African (SA) adults aged ≥35 years for 2000, 2006 and 2012. We combined smoking prevalence results from 15 national surveys (1998 - 2017) and smoking impact ratios using national mortality rates. Relative risks between smoking and select causes of death were derived from local and international data. RESULTS: Smoking prevalence declined from 25.0% in 1998 (40.5% in males, 10.9% in females) to 19.4% in 2012 (31.9% in males, 7.9% in females), but plateaued after 2010. In 2012 tobacco smoking caused an estimated 31 078 deaths (23 444 in males and 7 634 in females), accounting for 6.9% of total deaths of all ages (17.3% of deaths in adults aged ≥35 years), a 10.5% decline overall since 2000 (7% in males; 18% in females). Age-standardised mortality rates (and disability-adjusted life years (DALYs)) similarly declined in all population groups but remained high in the coloured population. Chronic obstructive pulmonary disease accounted for most tobacco-attributed deaths (6 373), followed by lung cancer (4 923), ischaemic heart disease (4 216), tuberculosis (2 326) and lower respiratory infections (1 950). The distribution of major causes of smoking-attributable deaths shows a middle- to high-income pattern in whites and Asians, and a middle- to low-income pattern in coloureds and black Africans. The role of infectious lung disease (TB and LRIs) has been underappreciated. These diseases comprised 21.0% of deaths among black Africans compared with only 4.3% among whites. It is concerning that smoking rates have plateaued since 2010. CONCLUSION: The gains achieved in reducing smoking prevalence in SA have been eroded since 2010. An increase in excise taxes is the most effective measure for reducing smoking prevalence. The advent of serious respiratory pandemics such as COVID-19 has increased the urgency of considering the role that smoking cessation/abstinence can play in the prevention of, and post-hospital recovery from, any condition.

Estimating the changing burden of disease attributable to high fasting plasma glucose in South Africa for 2000, 2006 and 2012.

BACKGROUND: Worldwide, higher-than-optimal fasting plasma glucose (FPG) is among the leading modifiable risk factors associated with all- cause mortality and disability-adjusted life years (DALYs) due to the direct sequelae of diabetes and the increased risk for cardiovascular and chronic kidney disease. OBJECTIVES: To report deaths and DALYs of health outcomes attributable to high FPG by age and sex for South Africa (SA) for 2000, 2006 and 2012. METHODS: Comparative risk assessment methodology was used to estimate the burden attributable to high FPG. A meta-regression analysis was performed using data from national and small-area studies to estimate the population distribution of FPG and diabetes prevalence. Attributable fractions were calculated for selected health outcomes and applied to local burden estimates from the second South African National Burden of Disease Study (SANBD2). Age-standardised rates were calculated using World Health Organization world standard population weights. RESULTS: We estimated a 5% increase in mean FPG from 5.31 (95% confidence interval (CI) 5.18 - 5.43) mmol/L to 5.57 (95% CI 5.41 - 5.72) mmol/L and a 75% increase in diabetes prevalence from 7.3% (95% CI 6.7 - 8.3) to 12.8% (95% CI 11.9 - 14.0) between 2000 and 2012. The age-standardised attributable death rate increased from 153.7 (95% CI 126.9 - 192.7) per 100 000 population in 2000 to 203.5 (95% CI 172.2 - 240.8) per 100 000 population in 2012, i.e. a 32.4% increase. During the same period, age-standardised attributable DALY rates increased by 43.8%, from 3 000 (95% CI 2 564 - 3 602) per 100 000 population in 2000 to 4 312 (95% CI 3 798 - 4 916) per 100 000 population in 2012. In each year, females had similar attributable death rates to males but higher DALY rates. A notable exception was tuberculosis, with an age-standardised attributable death rate in males double that in females in 2000 (14.3 v. 7.0 per 100 000 population) and 2.2 times higher in 2012 (18.4 v. 8.5 per 100 000 population). Similarly, attributable DALY rates were higher in males, 1.7 times higher in 2000 (323 v. 186 per 100 000 population) and 1.6 times higher in 2012 (502 v. 321 per 100 000 population). Between 2000 and 2012, the age-standardised death rate for chronic kidney disease increased by 98.3% (from 11.7 to 23.1 per 100 000 population) and the DALY rate increased by 116.9% (from 266 to 578 per 100 000 population). CONCLUSION: High FPG is emerging as a public health crisis, with an attributable burden doubling between 2000 and 2012. The consequences are costly in terms of quality of life, ability to earn an income, and the economic and emotional burden on individuals and their families. Urgent action is needed to curb the increase and reduce the burden associated with this risk factor. National data on FPG distribution are scant, and efforts are warranted to ensure adequate monitoring of the effectiveness of the interventions.

Estimating the changing burden of disease attributable to high body mass index in South Africa for 2000, 2006 and 2012.

BACKGROUND: A high body mass index (BMI) is associated with several cardiovascular diseases, diabetes and chronic kidney disease, cancers, and other selected health conditions. OBJECTIVES: To quantify the deaths and disability-adjusted life years (DALYs) attributed to high BMI in persons aged ≥20 years in South Africa (SA) for 2000, 2006 and 2012. METHODS: The comparative risk assessment (CRA) methodology was followed. Meta-regressions of the BMI mean and standard deviation from nine national surveys spanning 1998 - 2017 were conducted to provide estimates by age and sex for adults aged ≥20 years. Population attributable fractions were calculated for selected health outcomes using relative risks identified by the Global Burden of Disease Study (2017), and applied to deaths and DALY estimates from the second South African National Burden of Disease Study to estimate the burden attributed to high BMI in a customised Microsoft Excel workbook. Monte Carlo simulation-modelling techniques were used for the uncertainty analysis. BMI was assumed to follow a log-normal distribution, and the theoretical minimum value of BMI below which no risk was estimated was assumed to follow a uniform distribution from 20 kg/m2 to 25 kg/m2. RESULTS: Between 2000 and 2012, mean BMI increased by 6% from 27.7 kg/m2 (95% confidence interval (CI) 27.6 - 27.9) to 29.4 kg/m2 (95% CI 29.3 - 29.5) for females, and by 3% from 23.9 kg/m2 (95% CI 23.7 - 24.1) to 24.6 kg/m2 (95% CI 24.5 - 24.8) for males. In 2012, high BMI caused 58 757 deaths (95% uncertainty interval (UI) 46 740 - 67 590) or 11.1% (95% UI 8.8 - 12.8) of all deaths, and 1.42 million DALYs (95% UI 1.15 - 1.61) or 6.9% (95% UI 5.6 - 7.8) of all DALYs. Over the study period, the burden in females was ~1.5 - 1.8 times higher than that in males. Type 2 diabetes mellitus became the leading cause of death attributable to high BMI in 2012 (n=12 382 deaths), followed by hypertensive heart disease (n=12 146), haemorrhagic stroke (n=9 141), ischaemic heart disease (n=7 499) and ischaemic stroke (n=4 044). The age-standardised attributable DALY rate per 100 000 population for males increased by 6.6% from 3 777 (95% UI 2 639 - 4 869) in 2000 to 4 026 (95% UI 2 831 - 5 115) in 2012, while it increased by 7.8% for females from 6 042 (95% UI 5 064 - 6 702) to 6 513 (95% UI 5 597 - 7 033). CONCLUSION: Average BMI increased between 2000 and 2012 and accounted for a growing proportion of total deaths and DALYs. There is a need to develop, implement and evaluate comprehensive interventions to achieve lasting change in the determinants and impact of overweight and obesity, particularly among women.

Estimating the burden of disease attributable to a diet low in fruit and vegetables in South Africa for 2000, 2006 and 2012.

BACKGROUND: Low intake of fruit and vegetables is associated with an increased risk of various non-communicable diseases, including major causes of death and disability such as cardiovascular disease, diabetes mellitus and cancers. Diets low in fruit and vegetables are prevalent in the South African (SA) population, and average intake is well below the internationally recommended threshold. OBJECTIVES: To estimate the burden of disease attributable to a diet low in fruit and vegetables by sex and age group in SA for the years 2000, 2006 and 2012. METHODS: We followed World Health Organization and Global Burden of Disease Study comparative risk assessment methodology. Population attributable fractions - calculated from fruit and vegetable intake estimated from national and local surveys and relative risks for health outcomes based on the current literature - were applied to the burden estimates from the second South African National Burden of Disease Study (SANBD2). Outcome measures included deaths and disability-adjusted life years (DALYs) lost from ischaemic heart disease, stroke, type 2 diabetes, and five categories of cancers. RESULTS: Between 2000 and 2012, the average intake of fruit of the SA adult population (≥25 years) declined by 7%, from 48.5 g/d (95% uncertainty interval (UI) 46.6 - 50.5) to 45.2 g/d (95% UI 42.7 - 47.6). Vegetable intake declined by 25%, from 146.9 g/d (95% UI 142.3 - 151.8) to 110.5 g/d (95% UI 105.9 - 115.0). In 2012, these consumption patterns are estimated to have caused 26 423 deaths (95% UI 24 368 - 28 006), amounting to 5.0% (95% UI 4.6 - 5.3%) of all deaths in SA, and the loss of 514 823 (95% UI 473 508 - 544 803) healthy life years or 2.5% (95% UI 2.3 - 2.6%) of all DALYs. Cardiovascular disease comprised the largest proportion of the attributable burden, with 83% of deaths and 84% of DALYs. Age-standardised death rates were higher for males (145.1 deaths per 100 000; 95% UI 127.9 - 156.2) than for females (108.0 deaths per 100 000; 95% UI 96.2 - 118.1); in both sexes, rates were lower than those observed in 2000 (-9% and -12%, respectively). CONCLUSION: Despite the overall reduction in standardised death rates observed since 2000, the absolute burden of disease attributable to inadequate intake of fruit and vegetables in SA remains of significant concern. Effective interventions supported by legislation and policy are needed to reverse the declining trends in consumption observed in most age categories and to curb the associated burden.

Overview.

BACKGROUND: South Africa (SA) faces multiple health challenges. Quantifying the contribution of modifiable risk factors can be used to identify and prioritise areas of concern for population health and opportunities for health promotion and disease prevention interventions. OBJECTIVE: To estimate the attributable burden of 18 modifiable risk factors for 2000, 2006 and 2012. METHODS: Comparative risk assessment (CRA), a standardised and systematic approach, was used to estimate the attributable burden of 18 risk factors. Risk exposure estimates were sourced from local data, and meta-regressions were used to model the parameters, depending on the availability of data. Risk-outcome pairs meeting the criteria for convincing or probable evidence were assessed using relative risks against a theoretical minimum risk exposure level to calculate either a potential impact fraction or population attributable fraction (PAF). Relative risks were sourced from the Global Burden of Disease, Injuries, and Risk Factors (GBD) study as well as published cohort and intervention studies. Attributable burden was calculated for each risk factor for 2000, 2006 and 2012 by applying the PAF to estimates of deaths and years of life lost from the Second South African National Burden of Disease Study (SANBD2). Uncertainty analyses were performed using Monte Carlo simulation, and age-standardised rates were calculated using the World Health Organization standard population. RESULTS: Unsafe sex was the leading risk factor across all years, accounting for one in four DALYs (26.6%) of the estimated 20.6 million DALYs in 2012. The top five leading risk factors for males and females remained the same between 2000 and 2012. For males, the leading risks were (in order of descending rank): unsafe sex; alcohol consumption; interpersonal violence; tobacco smoking; and high systolic blood pressure; while for females the leading risks were unsafe sex; interpersonal violence; high systolic blood pressure; high body mass index; and high fasting plasma glucose. Since 2000, the attributable age-standardised death rates decreased for most risk factors. The largest decrease was for household air pollution (-41.8%). However, there was a notable increase in the age-standardised death rate for high fasting plasma glucose (44.1%), followed by ambient air pollution (7%). CONCLUSION: This study reflects the continued dominance of unsafe sex and interpersonal violence during the study period, as well as the combined effects of poverty and underdevelopment with the emergence of cardiometabolic-related risk factors and ambient air pollution as key modifiable risk factors in SA. Despite reductions in the attributable burden of many risk factors, the study reveals significant scope for health promotion and disease prevention initiatives and provides an important tool for policy makers to influence policy and programme interventions in the country.

Prophylaxis is the new standard of care in patients with haemophilia.

Randomised controlled clinical trial evidence on prophylaxis as optimal care for patients with haemophilia was generated more than a decade ago. However, this knowledge has not translated into clinical practice in South Africa (SA) owing to many barriers to prophylaxis. These include the high treatment burden imposed by prophylaxis (frequent injections two to four times a week), the need for intravenous access to administer replacement clotting factor therapies, and the higher volume of clotting factor required compared with episodic treatment. The recently introduced non-factor therapies in haemophilia care have addressed many of these barriers. For example, emicizumab, which is currently the only globally approved non-factor therapy, can be administered subcutaneously less frequently (weekly, fortnightly or every 4 weeks) and has led to global adoption of prophylaxis as the standard of care in haemophilia by the bleeding disorders community. Haemophilia A is the most prevalent clotting factor deficiency in SA, with >2 000 people diagnosed to date. However, only a few of these patients are currently on prophylaxis. In this 'In Practice' article, we review the rationale for prophylaxis, outline its goals and benefits, and provide evidence-based guidance on which haemophilia patients should be prioritised for emicizumab prophylaxis. This consensus guidance facilitates the adoption of prophylaxis as a national policy and the new standard of care in haemophilia in SA.

Heparin-induced thrombocytopenia: An update for the COVID-19 era.

The increased use of heparin during the current COVID-19 pandemic has highlighted the risk of a rare but potentially serious complication of heparin therapy, viz. heparin-induced thrombocytopenia (HIT). This is a short review on the pharmacology of heparin and its derivatives, and the pathophysiology of HIT. Guidance on laboratory testing for and clinical management of HIT is presented in accordance with international guidelines. There are important similarities and differences between HIT and the new entity of vaccine-induced immune thrombotic thrombocytopenia, also known as thrombosis with thrombocytopenia syndrome, which clinicians need to be aware of.

The effects of streptokinase in a Chacma baboon (Papio ursinus) model of acquired thrombotic thrombocytopenic purpura.

TTP is a life-threatening disorder with limited pharmaceutical treatment options. Recently, the potential of streptokinase in the treatment of acquired TTP was demonstrated in humans in vitro, and in vivo in a mouse model. We aimed to determine the in vitro and in vivo effects of streptokinase in an established Papio ursinus model of acquired TTP. In vitro: VWF activities & multimer patterns and thromboelastograms were assessed with increasing concentrations of streptokinase. In vivo: After induction of TTP, escalating streptokinase doses (ranging from 50,000 to 900,000 IU) were administered, and the effects of streptokinase assessed on peripheral blood counts, fibrinolysis, VWF activities & multimer patterns and thromboelastograms. In an extension of the study, high-dose streptokinase (1,500,000-3,000,000 IU) was administered to another baboon. After spiking, fibrinolysis with loss of large VWF multimers was observed at [2200 IU/mL]-roughly equivalent to 1,500,000 IU. However, administration of escalating intravenous streptokinase doses had no in vivo effect on the TTP phenotype, and in vivo increases in plasmin activity were mild when compared with baseline, even at high doses. Minimal effect on VWF multimer patterns was observed but only at doses ≥ 1500,000 IU. Streptokinase is not effective in resolving TTP in a Papio ursinus model of TTP, possibly due to limited activation of the baboon fibrinolytic system. Modifications to this model, the use of alternative higher animal models, or alternative thrombolytics, should be considered to establish proof-of-concept.

Quantification of U, Th and specific radionuclides in coal from selected coal fired power plants in South Africa.

Most of South Africa's energy is derived from the combustion of coal in pulverized coal-fired power plants (CFPP). However, when compared with the rest of the world, limited information regarding the main radioactive elements (U and Th) and specific radionuclides of interest (K40, Ra226 and Th232) from South African CFPP is available in the public domain. This paper aims to quantify the U, Th and specific radionuclides found in the coal used in selected South African CFPP in comparison to world averages found in literature. The U and Th concentrations were obtained by ICP-MS. The main radionuclides, K40, Ra226 and Th238, were quantified using gamma spectrometry. The U concentration and Th concentrations for the coal used in all the power plants was above the world average of 1.9 mg/kg and 3.2 mg/kg respectively. The coals with the highest Th content originated from the Mpumalanga power plant, while the U content in the Freestate power plant samples was the highest of the three. The concentrations of the K40 were between 88.43±10.75-110.76±8.92 Bq/kg, which are in-line with world averages of 4-785 Bq/kg. Similarly, the Ra226 and Th232 values were between 21.69±2.83-52.63±4.04 Bq/kg and 19.91±1.24-22.97±1.75 Bq/kg respectively, which are also in line with the world averages of 1-206 Bq/kg and 1-170 Bq/kg respectively. Radiological hazard indices such as radium equivalent (Raeq); external hazard index (Hex) and internal hazard index (Hin), that were estimated from these average radionuclide concentrations were less than the prescribed values found in literature. This indicated that no significant health risk was posed by the coal being used from these coal fields.

Home therapy for inherited bleeding disorders in South Africa: Results of a modified Delphi consensus process.

BACKGROUND: Optimal care of patients with inherited bleeding disorders requires that bleeding episodes are treated early, or still better prevented, through extension of patient care beyond hospital-based treatment to home-based therapy. In South Africa (SA), adoption of home therapy is variable, in part owing to lack of consensus among healthcare providers on what constitutes home therapy, which patients should be candidates for it, how it should be monitored, and what the barriers to home therapy are. OBJECTIVES: To conduct a modified Delphi process in order to establish consensus on home therapy among haemophilia healthcare providers in SA. METHODS: Treaters experienced in haemophilia care were invited to participate in a consensus-seeking process conducted in three rounds. In round 1, provisional statements around home therapy were formulated as questions and collated in a structured list. In rounds 2 and 3, evolving versions of the questionnaire were administered to participants. Consensus was defined as ≥70% agreement among the participants. RESULTS: The panel composition included an equal number of physicians and non-physicians. The participation rate was 100% through all three consensus rounds. The group reached consensus for 92% of the statements. Consensus of 100% was reached on starting home therapy in paediatric patients, requiring all patients on home therapy to sign informed consent and indemnity, and providing round-the-clock support for patients on home therapy. CONCLUSIONS: The home therapy consensus statements in this report have the potential to translate to policy on home therapy and to guide the initiation, practice and evaluation of home therapy programmes in SA.

[Erythroderma revealing IPEX syndrome]. / Érythrodermie révélatrice d'un syndrome IPEX.

BACKGROUND: Primary immunodeficiencies are rare and frequently life-threatening conditions in the first year of life. They may present with isolated skin manifestations and the absence of other clinical signs may delay diagnosis and management of the disease. Herein we describe a case of IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome) that illustrates this situation. PATIENTS AND METHODS: A 2.5-month-old boy was seen with a psoriasiform eruption. Despite applications of topical steroids, skin lesions progressed to severe exfoliative ichtyosiform erythroderma. A skin biopsy showed keratinocyte necrosis with a dense, epidermotropic, lymphocytic CD8+ infiltrate. The infant presented increased serum IgE and eosinophilia. He developed an enteropathy with severe and profuse diarrhea, septicemia and hypovolemic shock that led to sudden cardiac arrest. DNA analysis revealed a mutation in the FOXP3 gene, confirming IPEX syndrome. A favorable outcome was achieved following allogeneic bone marrow transplant. DISCUSSION: IPEX syndrome is characterized by early secretory enteropathy with profuse diarrhea, dermatitis and diabetes mellitus. Onset usually occurs within the first weeks or months of life, and the natural course of the disease is often lethal. Cutaneous manifestations appear to be mostly eczematiform, psoriasiform or ichthyosiform. These may be the first sign of the disease and a common inflammatory skin disorder may be wrongly diagnosed. The severity of the lesions and their limited response to topical steroids should alert the clinician. CONCLUSION: The early onset of severe cutaneous manifestations with persistent lesions and poor response to topical steroids should lead to an early skin biopsy. If histopathological changes show a cytotoxic lymphocytic infiltrate with keratinocyte necrosis, a diagnosis of primary immunodeficiency must be considered enabling rapid intitation of specific management.

Comparison of ADAMTS13 and Von Willebrand factor levels and activities, and plasminogen levels, in plasma products currently available for the treatment of thrombotic thrombocytopenic purpura in South Africa.

OBJECTIVE: Thrombotic thrombocytopenic purpura (TTP) results from a deficiency in the Von Willebrand factor (VWF) cleaving protease, ADAMTS13. Treatment involves plasma exchange (PEX) therapy with either fresh frozen plasma (FFP), cryosupernatant (CSP) or solvent/detergent-treated plasma (SDP), available in South Africa as Bioplasma FDP. The aim of the study was to generate in vitro data on these products, and to explore possible differences between the products that may offer treatment advantages. METHODS: Twenty samples per product (FFP, CSP and Bioplasma FDP) were analysed for levels and activities of ADAMTS13 and VWF. Plasminogen levels, a proposed physiological back-up system for ADAMTS13, were also determined. FFP and CSP samples were subanalysed according to ABO blood group. Samples were analysed by means of commercially available ELISA assays. RESULTS: All samples had normal/high ADAMTS13 activity (Median activity for SDP = 94.0%, CSP = 80.5%, FFP = 122.0%) and plasminogen levels. The VWF content was mostly normal for Bioplasma FDP, typically deficient for CSP and mostly deficient for FFP, which was an unexpected finding. Depending on the parameter, Bioplasma FDP was the most standardised, with coefficients of variation (CV) from 14.1% to 27.3%, while FFP showed great inter-individual variation (CV 24.6% to 208.6%). Statistically significant differences were found across products (P ≤ 0.0095), and ABO blood groups (P = 0.0001). CONCLUSION: All three products can be used for the treatment of TTP. The choice of product depends on the need for additional viral safety, costs, product availability and the perceived impact of within-product variations.

Home therapy for inherited bleeding disorders in south Africa: results of a modified delphi consensus process

Background. Optimal care of patients with inherited bleeding disorders requires that bleeding episodes are treated early, or still better prevented, through extension of patient care beyond hospital-based treatment to home-based therapy. In South Africa (SA), adoption of home therapy is variable, in part owing to lack of consensus among healthcare providers on what constitutes home therapy, which patients should be candidates for it, how it should be monitored, and what the barriers to home therapy are.Objectives. To conduct a modified Delphi process in order to establish consensus on home therapy among haemophilia healthcare providers in SA.Methods. Treaters experienced in haemophilia care were invited to participate in a consensus-seeking process conducted in three rounds. In round 1, provisional statements around home therapy were formulated as questions and collated in a structured list. In rounds 2 and 3, evolving versions of the questionnaire were administered to participants. Consensus was defined as ≥70% agreement among the participants.Results. The panel composition included an equal number of physicians and non-physicians. The participation rate was 100% through all three consensus rounds. The group reached consensus for 92% of the statements. Consensus of 100% was reached on starting home therapy in paediatric patients, requiring all patients on home therapy to sign informed consent and indemnity, and providing round-the-clock support for patients on home therapy.Conclusions. The home therapy consensus statements in this report have the potential to translate to policy on home therapy and to guide the initiation, practice and evaluation of home therapy programmes in SA

Multi-targeted directed ligands for Alzheimer's disease: design of novel lead coumarin conjugates.

Alzheimer's Disease (AD) is a neurodegenerative disease characterized by central nervous system insults with progressive cognitive (memory, attention) and non-cognitive (anxiety, depression) impairments. Pathophysiological events affect predominantly cholinergic neuronal loss and dysfunctions of the dopaminergic system. The aim of the current study was to design multi-targeted directed lead structures based on the coumarin scaffold with inhibitory properties at two key enzymes in disease relevant systems, i.e. acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Conventional and microwave synthetic methods were utilized to synthesize coumarin scaffold-based novel morpholino, piperidino, thiophene and erucic acid conjugates. Biological assays indicated that the coumarin-morpholine ether conjugate BPR 10 was the most potent hMAO-B inhibitor. The coumarin-piperidine conjugates BPR 13 and BPR 12 were the most potent inhibitors of eeAChE at 100 µM and 1 µM, respectively. Molecular modelling studies were conducted with Accelrys® Discovery Studio® V3.1.1 utilising the published hMAO-B (2V61) and hAChE (4EY7) crystal structures. Compound BPR 10 occupies both the entrance and substrate cavities of the active site of MAO-B. BPR 13 resides in both the peripheral anionic site (PAS) and the catalytic anionic site (CAS) of hAChE. This study demonstrated that the coumarin scaffold serves as a promising pharmacophore for MTDLs design.

Magnetotactic bacteria used to generate electricity based on Faraday's law of electromagnetic induction.

Magnetotactic bacteria (MTB) have the unique ability to produce magnetic particles surrounded by a biomembrane to form the magnetosome organelle. Therefore, MTB have novel physical and magnetic properties and have consequently been used in several biotechnological applications. The magnetic properties of these micro-organisms and their magnetosomes have, however, never been used for the generation of electricity as described in this letter. Comparisons were made between, firstly, the electricity generated from purified magnetosomes, MTB culture (bacterial cells with magnetosomes) and sterile, liquid growth medium (control). Secondly, the electricity generated by a dilution series of purified magnetosomes were compared. A statistically significant difference was found between the voltage measured from the purified magnetosomes (highest voltage), MTB culture (lower voltage) and liquid growth medium (lowest voltage). In the dilution series, the voltage measured increased as the magnetosome concentration increased, but only up to an optimum concentration (0·0376 mg ml-1 ). In this study, we have demonstrated that a significantly higher voltage than that of the control could be measured when MTB or purified magnetosomes were pumped through a solenoid by applying Faraday's law of electromagnetic induction. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides proof-of-concept of electromagnetic induction using magnetosomes or magnetotactic bacteria in an experimental setup based on the law of Faraday. The concept of using these bacteria or their biomineralized magnetic nanoparticles as a biological alternative in low voltage electricity generation has the potential to be further explored and developed.

Performance evaluation of the microINR® point-of-care INR-testing system.

INTRODUCTION: Point-of-care International Normalised Ratio (INR) testing is used frequently. We evaluated the microINR® POC system for accuracy, precision and measurement repeatability, and investigated instrument and test chip variability and error rates. METHODS: Venous blood INRs of 210 patients on warfarin were obtained with Thromborel® S on the Sysmex CS-2100i® analyser and compared with capillary blood microINR® values. Precision was assessed using control materials. Measurement repeatability was calculated on 51 duplicate finger-prick INRs. Triplicate finger-prick INRs using three different instruments (30 patients) and three different test chip lots (29 patients) were used to evaluate instrument and test chip variability. RESULTS: Linear regression analysis of microINR® and Sysmex CS2100i® values showed a correlation coefficient of 0.96 (P < .0001) and a positive proportional bias of 4.4%. Dosage concordance was 93.8% and clinical agreement 95.7%. All acceptance criteria based on ISO standard 17593:2007 system accuracy requirements were met. Control material coefficients of variation (CV) varied from 6.2% to 16.7%. The capillary blood measurement repeatability CV was 7.5%. No significant instrument (P = .93) or test chip (P = .81) variability was found, and the error rate was low (2.8%). CONCLUSION: The microINR® instrument is accurate and precise for monitoring warfarin therapy.

Barriers to physical activity in coronary artery disease patients: Development and validation of a new scale.

OBJECTIVE: To develop and validate a self-report questionnaire to measure barriers to regular physical activity (PA) in patients with stable coronary artery disease (CAD). METHODS: Phase 1: 17 patients completed a semi-structured interview. After grouping and reformulating the reported barriers, their pertinence was reevaluated by the patients. Then, a decision algorithm was used to select items. A principal component analysis was performed to determine content validity. Phase 2: 49 patients completed the questionnaire resulting from phase 1 twice, 7 days apart, and questionnaires to evaluate depression, anxiety, and the level of physical activity. Construct validity was evaluated by analysis of Spearman's correlation coefficient between the total score for the questionnaire and a convergent dimension (anxiety), as well as a divergent dimension (Dijon physical activity score). Internal consistency was evaluated by Cronbach's alpha coefficient. Test-retest reliability was evaluated by the intraclass coefficient (ICC). RESULTS: Eleven items were selected after phase 1. The questionnaire presented good face validity and the content validity seemed satisfactory after analysis of the literature by the experts. Construct validity was moderate. Internal consistency was very good (Cronbach's α>0.81). Reproducibility was excellent with an ICC at 0.95. Feasibility was good with less than 3minutes to complete the questionnaire. CONCLUSION: This questionnaire presents good psychometric properties. A further prospective study should evaluate sensitivity to change and help determine a threshold value indicating the need for a specific behavioral strategy to alleviate barriers to physical activity in these patients.

Emerging Trends in Non-Communicable Disease Mortality in South Africa; 1997 - 2010

OBJECTIVES:National trends in age-standardised death rates (ASDRs) for non-communicable diseases (NCDs) in South Africa (SA) were identified between 1997 and 2010.METHODS:As part of the second National Burden of Disease Study; vital registration data were used after validity checks; proportional redistribution of missing age; sex and population group; demographic adjustments for registration incompleteness; and identification of misclassified AIDS deaths. Garbage codes were redistributed proportionally to specified codes by age; sex and population group. ASDRs were calculated using mid-year population estimates and the World Health Organization world standard.RESULTS:Of 594 071 deaths in 2010; 38.9% were due to NCDs (42.6% females). ASDRs were 287/100 000 for cardiovascular diseases (CVDs); 114/100 000 for cancers (malignant neoplasms); 58/100 000 for chronic respiratory conditions and 52/100 000 for diabetes mellitus. An overall annual decrease of 0.4% was observed resulting from declines in stroke; ischaemic heart disease; oesophageal and lung cancer; asthma and chronic respiratory disease; while increases were observed for diabetes; renal disease; endocrine and nutritional disorders; and breast and prostate cancers. Stroke was the leading NCD cause of death; accounting for 17.5% of total NCD deaths. Compared with those for whites; NCD mortality rates for other population groups were higher at 1.3 for black Africans; 1.4 for Indians and 1.4 for coloureds; but varied by condition.CONCLUSIONS:NCDs contribute to premature mortality in SA; threatening socioeconomic development. While NCD mortality rates have decreased slightly; it is necessary to strengthen prevention and healthcare provision and monitor emerging trends in cause-specific mortality to inform these strategies if the target of 2% annual decline is to be achieved