Optimal dimensional synthesis of planar parallel manipulators with respect to workspaces.

Please read the abstract in the section 00front of this documentThesis (PhD(Mechanical Engineering))--University of Pretoria, 2006.Mechanical and Aeronautical Engineeringunrestricte

Elevation as a proxy for mosquito-borne Zika virus transmission in the Americas.

INTRODUCTION: When Zika virus (ZIKV) first began its spread from Brazil to other parts of the Americas, national-level travel notices were issued, carrying with them significant economic consequences to affected countries. Although regions of some affected countries were likely unsuitable for mosquito-borne transmission of ZIKV, the absence of high quality, timely surveillance data made it difficult to confidently demarcate infection risk at a sub-national level. In the absence of reliable data on ZIKV activity, a pragmatic approach was needed to identify subnational geographic areas where the risk of ZIKV infection via mosquitoes was expected to be negligible. To address this urgent need, we evaluated elevation as a proxy for mosquito-borne ZIKV transmission. METHODS: For sixteen countries with local ZIKV transmission in the Americas, we analyzed (i) modelled occurrence of the primary vector for ZIKV, Aedes aegypti, (ii) human population counts, and (iii) reported historical dengue cases, specifically across 100-meter elevation levels between 1,500m and 2,500m. Specifically, we quantified land area, population size, and the number of observed dengue cases above each elevation level to identify a threshold where the predicted risks of encountering Ae. aegypti become negligible. RESULTS: Above 1,600m, less than 1% of each country's total land area was predicted to have Ae. aegypti occurrence. Above 1,900m, less than 1% of each country's resident population lived in areas where Ae. aegypti was predicted to occur. Across all 16 countries, 1.1% of historical dengue cases were reported above 2,000m. DISCUSSION: These results suggest low potential for mosquito-borne ZIKV transmission above 2,000m in the Americas. Although elevation is a crude predictor of environmental suitability for ZIKV transmission, its constancy made it a pragmatic input for policy decision-making during this public health emergency

Functional characterisation of cis-regulatory elements governing dynamic Eomes

The T-box transcription factor (TF) Eomes is a key regulator of cell fate decisions during early mouse development. The cis-acting regulatory elements that direct expression in the anterior visceral endoderm (AVE), primitive streak (PS) and definitive endoderm (DE) have yet to be defined. Here, we identified three gene-proximal enhancer-like sequences (PSE_a, PSE_b and VPE) that faithfully activate tissue specific expression in transgenic embryos. However, targeted deletion experiments demonstrate that PSE_a and PSE_b are dispensable and only the VPE is required for optimal Eomes expression in vivo Embryos lacking this enhancer display variably penetrant defects in anterior-posterior axis orientation and DE formation. Chromosome conformation capture experiments reveal VPE-promoter interactions embryonic stem cells (ESC), prior to gene activation. The locus resides in a large (500kb) pre-formed compartment in ESC and activation during DE differentiation occurs in the absence of 3D structural changes. ATAC-seq analysis reveals that VPE, PSE_a, and four additional putative enhancers display increased chromatin accessibility in DE associated with Smad2/3 binding coincident with transcriptional activation. In contrast, activation of the Eomes target genes Foxa2 and Lhx1 is associated with higher order chromatin reorganisation. Thus diverse regulatory mechanisms govern activation of lineage specifying TFs during early development

Mucormycosis: an emerging disease?

ABSTRACTMucormycosis is the third invasive mycosis in order of importance after candidiasis and aspergillosis and is caused by fungi of the class Zygomycetes. The most important species in order of frequency is Rhizopus arrhizus (oryzae). Identification of the agents responsible for mucormycosis is based on macroscopic and microscopic morphological criteria, carbohydrate assimilation and the maximum temperature compatible with its growth. The incidence of mucormycosis is approximately 1.7 cases per 1000 000 inhabitants per year, and the main risk-factors for the development of mucormycosis are ketoacidosis (diabetic or other), iatrogenic immunosuppression, use of corticosteroids or deferoxamine, disruption of mucocutaneous barriers by catheters and other devices, and exposure to bandages contaminated by these fungi. Mucorales invade deep tissues via inhalation of airborne spores, percutaneous inoculation or ingestion. They colonise a high number of patients but do not cause invasion. Mucormycosis most commonly manifests in the sinuses (39%), lungs (24%), skin (19%), brain (9%), and gastrointestinal tract (7%), in the form of disseminated disease (6%), and in other sites (6%). Clinical diagnosis of mucormycosis is difficult, and is often made at a late stage of the disease or post-mortem. Confirmation of the clinical form requires the combination of symptoms compatible with histological invasion of tissues. The probable diagnosis of mucormycosis requires the combination of various clinical data and the isolation in culture of the fungus from clinical samples. Treatment of mucormycosis requires a rapid diagnosis, correction of predisposing factors, surgical resection, debridement and appropriate antifungal therapy. Liposomal amphotericin B is the therapy of choice for this condition. Itraconazole is considered to be inappropriate and there is evidence of its failure in patients suffering from mucormycosis. Voriconazole is not active in vitro against Mucorales, and failed when used in vivo. Posaconazole and ravuconazole have good activity in vitro. The overall rate of mortality of mucormycosis is approximately 40%

Global, regional, and national burden of osteoarthritis, 1990–2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021

Background Osteoarthritis is the most common form of arthritis in adults, characterised by chronic pain and loss of mobility. Osteoarthritis most frequently occurs after age 40 years and prevalence increases steeply with age. WHO has designated 2021–30 the decade of healthy ageing, which highlights the need to address diseases such as osteoarthritis, which strongly affect functional ability and quality of life. Osteoarthritis can coexist with, and negatively effect, other chronic conditions. Here we estimate the burden of hand, hip, knee, and other sites of osteoarthritis across geographies, age, sex, and time, with forecasts of prevalence to 2050. Methods In this systematic analysis for the Global Burden of Disease Study, osteoarthritis prevalence in 204 countries and territories from 1990 to 2020 was estimated using data from population-based surveys from 26 countries for knee osteoarthritis, 23 countries for hip osteoarthritis, 42 countries for hand osteoarthritis, and US insurance claims for all of the osteoarthritis sites, including the other types of osteoarthritis category. The reference case definition was symptomatic, radiographically confirmed osteoarthritis. Studies using alternative definitions from the reference case definition (for example self-reported osteoarthritis) were adjusted to reference using regression models. Osteoarthritis severity distribution was obtained from a pooled meta-analysis of sources using the Western Ontario and McMaster Universities Arthritis Index. Final prevalence estimates were multiplied by disability weights to calculate years lived with disability (YLDs). Prevalence was forecast to 2050 using a mixed-effects model. Findings Globally, 595 million (95% uncertainty interval 535–656) people had osteoarthritis in 2020, equal to 7·6% (95% UI 6·8–8·4) of the global population, and an increase of 132·2% (130·3–134·1) in total cases since 1990. Compared with 2020, cases of osteoarthritis are projected to increase 74·9% (59·4–89·9) for knee, 48·6% (35·9–67·1) for hand, 78·6% (57·7–105·3) for hip, and 95·1% (68·1–135·0) for other types of osteoarthritis by 2050. The global age-standardised rate of YLDs for total osteoarthritis was 255·0 YLDs (119·7–557·2) per 100 000 in 2020, a 9·5% (8·6–10·1) increase from 1990 (233·0 YLDs per 100 000, 109·3–510·8). For adults aged 70 years and older, osteoarthritis was the seventh ranked cause of YLDs. Age-standardised prevalence in 2020 was more than 5·5% in all world regions, ranging from 5677·4 (5029·8–6318·1) per 100 000 in southeast Asia to 8632·7 (7852·0–9469·1) per 100 000 in high-income Asia Pacific. Knee was the most common site for osteoarthritis. High BMI contributed to 20·4% (95% UI –1·7 to 36·6) of osteoarthritis. Potentially modifiable risk factors for osteoarthritis such as recreational injury prevention and occupational hazards have not yet been explored in GBD modelling. Interpretation Age-standardised YLDs attributable to osteoarthritis are continuing to rise and will lead to substantial increases in case numbers because of population growth and ageing, and because there is no effective cure for osteoarthritis. The demand on health systems for care of patients with osteoarthritis, including joint replacements, which are highly effective for late stage osteoarthritis in hips and knees, will rise in all regions, but might be out of reach and lead to further health inequity for individuals and countries unable to afford them. Much more can and should be done to prevent people getting to that late stage

The global, regional, and national burden of adult lip, oral, and pharyngeal cancer in 204 countries and territories:A systematic analysis for the Global Burden of Disease Study 2019

Importance Lip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.Objective To analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence Review The incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.Findings In 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and Relevance In this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts

Global injury morbidity and mortality from 1990 to 2017 : results from the Global Burden of Disease Study 2017

Correction:Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.Peer reviewe

Estimating global injuries morbidity and mortality : methods and data used in the Global Burden of Disease 2017 study

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.Peer reviewe

Adolescent transport and unintentional injuries: a systematic analysis using the Global Burden of Disease Study 2019

Background: Globally, transport and unintentional injuries persist as leading preventable causes of mortality and morbidity for adolescents. We sought to report comprehensive trends in injury-related mortality and morbidity for adolescents aged 10–24 years during the past three decades. Methods: Using the Global Burden of Disease, Injuries, and Risk Factors 2019 Study, we analysed mortality and disability-adjusted life-years (DALYs) attributed to transport and unintentional injuries for adolescents in 204 countries. Burden is reported in absolute numbers and age-standardised rates per 100 000 population by sex, age group (10–14, 15–19, and 20–24 years), and sociodemographic index (SDI) with 95% uncertainty intervals (UIs). We report percentage changes in deaths and DALYs between 1990 and 2019. Findings: In 2019, 369 061 deaths (of which 214 337 [58%] were transport related) and 31·1 million DALYs (of which 16·2 million [52%] were transport related) among adolescents aged 10–24 years were caused by transport and unintentional injuries combined. If compared with other causes, transport and unintentional injuries combined accounted for 25% of deaths and 14% of DALYs in 2019, and showed little improvement from 1990 when such injuries accounted for 26% of adolescent deaths and 17% of adolescent DALYs. Throughout adolescence, transport and unintentional injury fatality rates increased by age group. The unintentional injury burden was higher among males than females for all injury types, except for injuries related to fire, heat, and hot substances, or to adverse effects of medical treatment. From 1990 to 2019, global mortality rates declined by 34·4% (from 17·5 to 11·5 per 100 000) for transport injuries, and by 47·7% (from 15·9 to 8·3 per 100 000) for unintentional injuries. However, in low-SDI nations the absolute number of deaths increased (by 80·5% to 42 774 for transport injuries and by 39·4% to 31 961 for unintentional injuries). In the high-SDI quintile in 2010–19, the rate per 100 000 of transport injury DALYs was reduced by 16·7%, from 838 in 2010 to 699 in 2019. This was a substantially slower pace of reduction compared with the 48·5% reduction between 1990 and 2010, from 1626 per 100 000 in 1990 to 838 per 100 000 in 2010. Between 2010 and 2019, the rate of unintentional injury DALYs per 100 000 also remained largely unchanged in high-SDI countries (555 in 2010 vs 554 in 2019; 0·2% reduction). The number and rate of adolescent deaths and DALYs owing to environmental heat and cold exposure increased for the high-SDI quintile during 2010–19. Interpretation: As other causes of mortality are addressed, inadequate progress in reducing transport and unintentional injury mortality as a proportion of adolescent deaths becomes apparent. The relative shift in the burden of injury from high-SDI countries to low and low–middle-SDI countries necessitates focused action, including global donor, government, and industry investment in injury prevention. The persisting burden of DALYs related to transport and unintentional injuries indicates a need to prioritise innovative measures for the primary prevention of adolescent injury. Funding: Bill & Melinda Gates Foundation

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707