A study of genetic polymorphism underlying idiosyncratic hepatotoxicity due to anti-tuberculosis medications

Anti-tuberculosis drug-induced liver injury is a rare but serious adverse drug reaction. This study aimed to identity specific genes conferring susceptibility to this serious adverse drug reaction, especially in relation to isoniazid treatment and to study the underlying mechanism for toxicity. Anti-tuberculosis drug-induced liver injury cases (n=26) and community controls (n=90) from Europe and South Asia were genotyped for polymorphisms in NAT2, GST genes, CYP2E1, PXR and SOD2. NAT2 slow acetylators were more susceptible to liver injury (OR=4.60; 95% CI=1.47-14.44). The GSTM1 null genotype was more common in cases than controls (OR=2.91; 95% CI=1.14-7.43). Risk of liver injury was significantly increased in subjects with combined NAT2 slow acetylator and GSTM1 null genotype (OR=3.71; 95% CI=1.48-9.31). No significant effects were seen for the other genotypes studied except that a GSTA4 haplotype was slightly more common in liver injury cases. The contribution of NAT2 genotype to isoniazid toxicity was examined using an in vitro overexpression approach. Stable expression of either NAT2*4 or NAT*5 constructs in HepG2 cells had small effects on reduced glutathione to oxidised glutathione ratio and apoptosis. These changes were consistent with higher NAT2 activity increasing isoniazid toxicity. In addition, overexpression and siRNA knockdown approaches showed protective roles for GSTA1 and A4 against isoniazid toxicity. The relevance of combinations of anti-tuberculosis drugs to overall toxicity was investigated by studies in human hepatocytes and LS180 cells. In the LS180 cells, rifampicin coadministation with isoniazid resulted in a small but significant decrease in both isoniazid and pyrazinamide toxicity. Studies on the isoniazid-rifampicin combination in human hepatocytes gave inconsistent findings but a decrease in cell toxicity due to isoniazid by pretreatment with rifampicin was seen in some donors. Increased expression of the carboxyesterase gene CES2 was seen in LS180 cells and in some hepatocytes and could represent a protective effect.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Simulation of Industrialised Building System components production

The construction of IBS building should starts with the production of the IBS components and the production process is the main activity concerned in the IBS production plant. Having an optimum production line to manufacture the required IBS elements within targeted time and limited number of reusable steel mould is very important. In this study, workstation organization method has been adopted in the production of IBS component of beam and column. Witness 2001 simulation software has been used to model and simulate the most optimum production line set up. Here, two production lines set up have been proposed to complete the production of IBS beam and column between two and three months time with limited number of reusable steel mould to supply for the construction of medium size single storey IBS housing project ranging from 100 to 300 units. A contingency production line set up which able to complete the production of required IBS components within a month time with increased number of reusable steel mould has also been proposed. Number of resources such as workstation, tool, storage area and labour has been determined from the proposal. The proposed production line can be applied in the planning and cost estimating of IBS production plant set up

In-hospital Mortality among Unplanned Admissions to a Medical Intensive Care Unit

Abstract Objective: Despite advances in medicine, adverse clinical events, especially cardio-respiratory arrests, still occur in hospitalized patients. Unplanned Intensive Care Unit (ICU) admissions are frequently a result of this failure to recognize or appropriately treat the 'pre-arrest' period, when signs of physiologic deterioration are often evident. Although survival rates to hospital discharge for cardiac arrests are universally poor, the patterns of clinical deterioration and outcome of unplanned medical ICU admissions is not well studied. We aim to evaluate whether unplanned medical ICU admissions are associated with higher inhospital mortality. Measurements and results: A total of 423 admissions of which 37 (8.7%) were unplanned and 386 (91.3%) were planned. Data was analyzed using SPSS 12.0.1, and Pearson Chi-square for comparison. P value <0.05 considered to be statistically signifi cant. There was a statistically signifi cant difference in hospital mortality between planned (54 deaths, 14%) and unplanned admissions (25 deaths, 67.6%), (p <0.001). All but 1 patient in the unplanned group required intubation. Desaturation was the commonest reason for unplanned admissions, followed closely by sudden cardiorespiratory collapse and hypotension. Conclusions: The high mortality rate among unplanned medical ICU admissions is a cause for concern. Implementing a system of early critical illness detection and specialist intervention may help reduce such mortality as well as provide more defi nitive planned palliative decisions

Towards a global partnership model in interprofessional education for cross-sector problem-solving

Objectives A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available. Methods This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in students’ data. Results We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretest–posttest differences in students’ readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in students’ social interaction anxiety after the IPE simulation. Conclusions The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Mortality of emergency abdominal surgery in high-, middle- and low-income countries

Background: Surgical mortality data are collected routinely in high-income countries, yet virtually no low- or middle-income countries have outcome surveillance in place. The aim was prospectively to collect worldwide mortality data following emergency abdominal surgery, comparing findings across countries with a low, middle or high Human Development Index (HDI). Methods: This was a prospective, multicentre, cohort study. Self-selected hospitals performing emergency surgery submitted prespecified data for consecutive patients from at least one 2-week interval during July to December 2014. Postoperative mortality was analysed by hierarchical multivariable logistic regression. Results: Data were obtained for 10 745 patients from 357 centres in 58 countries; 6538 were from high-, 2889 from middle- and 1318 from low-HDI settings. The overall mortality rate was 1⋅6 per cent at 24 h (high 1⋅1 per cent, middle 1⋅9 per cent, low 3⋅4 per cent; P < 0⋅001), increasing to 5⋅4 per cent by 30 days (high 4⋅5 per cent, middle 6⋅0 per cent, low 8⋅6 per cent; P < 0⋅001). Of the 578 patients who died, 404 (69⋅9 per cent) did so between 24 h and 30 days following surgery (high 74⋅2 per cent, middle 68⋅8 per cent, low 60⋅5 per cent). After adjustment, 30-day mortality remained higher in middle-income (odds ratio (OR) 2⋅78, 95 per cent c.i. 1⋅84 to 4⋅20) and low-income (OR 2⋅97, 1⋅84 to 4⋅81) countries. Surgical safety checklist use was less frequent in low- and middle-income countries, but when used was associated with reduced mortality at 30 days. Conclusion: Mortality is three times higher in low- compared with high-HDI countries even when adjusted for prognostic factors. Patient safety factors may have an important role. Registration number: NCT02179112 (http://www.clinicaltrials.gov)

Simulation of industrialised building system components production

The construction of IBS building starts with the production of the IBS components and the production process is the main activity concern in the IBS production plant. Having an optimum production line to manufacture the required IBS elements within targeted time and limited number of reusable steel mould is very important. In this study, workstation organization method has been adopted in the production of IBS beam and column. Witness 2001 simulation software has been used to model and simulate the most optimum production line set up. Basically, two production lines set up have been proposed to complete the production of IBS beam and column between two and three months time with limited number of reusable steel mould to supply for the construction of medium size single storey IBS housing project ranging from 100 to 300 units. A contingency production line set up which able to complete the production of required IBS components within a month time with increased number of reusable steel mould has also been proposed. Number of resources such as workstation, tool, storage area and labour has been determined from the proposal. The proposed production line can be applied in the planning and cost estimating of IBS production plant set up

Development of an IC for isolated speech recognition using high-level synthesis approach

An integrated circuit for recognition of speaker-independent isolated speech words using high-level synthesis approach was developed, designed, fabricated and tested.RG 14/9

Enhanced coulomb counting method for estimating state-of-charge and state-of-health of lithium-ion batteries

The coulomb counting method is expedient for state-of-charge (SOC) estimation of lithium-ion batteries with high charging and discharging efficiencies. The charging and discharging characteristics are investigated and reveal that the coulomb counting method is convenient and accurate for estimating the SOC of lithium-ion batteries. A smart estimation method based on coulomb counting is proposed to improve the estimation accuracy. The corrections are made by considering the charging and operating efficiencies. Furthermore, the state-of-health (SOH) is evaluated by the maximum releasable capacity. Through the experiments that emulate practical operations, the SOC estimation method is verified to demonstrate the effectiveness and accuracy.Coulomb counting method Lithium-ion battery State-of-charge State-of-health

Singapore's 5 decades of dengue prevention and control-implications for global dengue control

This paper summarises the lessons learnt in dengue epidemiology, risk factors, and prevention in Singapore over the last half a century, during which Singapore evolved from a city of 1.9 million people to a highly urban globalised city-state with a population of 5.6 million. Set in a tropical climate, urbanisation among green foliage has created ideal conditions for the proliferation of Aedes aegypti and Aedes albopictus, the mosquito vectors that transmit dengue. A vector control programme, largely for malaria, was initiated as early as 1921, but it was only in 1966 that the Vector Control Unit (VCU) was established to additionally tackle dengue haemorrhagic fever (DHF) that was first documented in the 1960s. Centred on source reduction and public education, and based on research into the bionomics and ecology of the vectors, the programme successfully reduced the Aedes House Index (HI) from 48% in 1966 to <5% in the 1970s. Further enhancement of the programme, including through legislation, suppressed the Aedes HI to around 1% from the 1990s. The current programme is characterised by 4 key features: (i) proactive inter-epidemic surveillance and control that is stepped up during outbreaks; (ii) risk-based prevention and intervention strategies based on advanced data analytics; (iii) coordinated inter-sectoral cooperation between the public, private, and people sectors; and (iv) evidence-based adoption of new tools and strategies. Dengue seroprevalence and force of infection (FOI) among residents have substantially and continuously declined over the 5 decades. This is consistent with the observation that dengue incidence has been delayed to adulthood, with severity highest among the elderly. Paradoxically, the number of reported dengue cases and outbreaks has increased since the 1990s with record-breaking epidemics. We propose that Singapore's increased vulnerability to outbreaks is due to low levels of immunity in the population, constant introduction of new viral variants, expanding urban centres, and increasing human density. The growing magnitude of reported outbreaks could also be attributed to improved diagnostics and surveillance, which at least partially explains the discord between rising trend in cases and the continuous reduction in dengue seroprevalence. Changing global and local landscapes, including climate change, increasing urbanisation and global physical connectivity are expected to make dengue control even more challenging. The adoption of new vector surveillance and control tools, such as the Gravitrap and Wolbachia technology, is important to impede the growing threat of dengue and other Aedes-borne diseases.Published versio