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

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Effect of washing on accelerated carbonation of incineration bottom ash

This project serves to investigate the effect of washing on accelerated carbonation of incineration bottom ash (IBA), before utilizing or recycling them for environmental purposes. The focus was divided into 3 sections. The first part was to evaluate the optimal parameters for washing. Washing was conducted using deionized water as the main solvent. Preliminary investigations showed that performing 1-hour of washing with a liquid to solid (L/S) ratio of 10 was effective in removing soluble salts (i.e. chlorides and sulfates) from IBA. The second part of the project was focused on evaluating the effectiveness of washing on accelerated carbonation on IBA. After carbonation, the total inorganic carbon (TIC) content in washed IBA was observed to be higher as compared to unwashed IBA, thus indicating that washing was able to improve the carbonation efficiency in IBA. In terms of moisture content, IBA containing 15%MC proved to be the most effective for 35°C carbonation. The last part was to monitor the leaching behavior of heavy metals and soluble salts after washing and carbonation. 24-hour leaching tests were conducted using deionized water as the leachant. Carbonation was able to reduce the leaching of zinc and lead effectively. Washing coupled with carbonation was capable of reducing significant amounts of barium, copper, chlorides, dissolved organic carbon (DOC) and total nitrogen (TN) being leached out from the IBA leachates. However, carbonation was not effective in reducing the leaching of chromium, molybdenum and antimony. Washing coupled together with carbonation did not seem to solve this problem either. One interesting result was that the leaching of sulfates increased after carbonation. Carbonation may have caused the decomposition of ettringite in IBA to form soluble gypsum, causing sulfates to be leached out from the IBA leachates (Alba et al., 2001). This means that the formation of sulfates after carbonation is directly proportional to the carbonation efficiency. Implementing washing together with carbonation causes the leaching of sulfates to increase further, implying that washing indeed has the potential to improve the efficiency of the carbonation process. All in all, the implementation of washing together with accelerated carbonation yields positive results. Washing seems to benefit the carbonation process and reduce the leaching behavior of most heavy metals and chlorides. Further studies will be required to solve the increased leaching of chromium, molybdenum, antimony and sulfates from IBA after washing and carbonation.Bachelor of Engineering (Environmental Engineering

Accelerated carbonation of different size fractions of MSW IBA and the effect on leaching

Accelerated carbonation has been studied as a treatment method for MSW IBA, and the main advantage is that it can shorten the treatment duration from months to days, compared to natural weathering. This study investigated the effect of accelerated carbonation on different size fractions of IBA collected from two incineration plants in Singapore. The different size fractions were ground to <425 μm to minimise the influence of morphological difference on carbonation efficiency from that of chemical and mineralogical differences. Total element content was carried out for IBA collected from both incineration plants and the different size fractions. XRD was also used to analyse the mineralogical composition of IBA. Results showed that the degree of carbonation decreased as the size increased, which in turn corresponded to decreasing total Ca content and portlandite phase. The leaching behaviour of Pb, Zn, Cu, Cr and soluble constituents like DOC, Cl−, and SO42− were evaluated. It was found that carbonation resulted in the reduction of leaching of most constituents, except Cl− and SO42−. The reduction in leaching after carbonation can be attributed to the decrease in pH and formation of secondary minerals, rather than the precipitation of calcite. The research also suggested that since the leaching of soluble constituents from untreated IBA is mainly from the fine fractions and the fine fractions are more reactive to accelerated carbonation, size separation is beneficial in improving the carbonation efficiency and reducing the volume of IBA that needs to be treated, which can potentially reduce the treatment cost of IBA.Accepted versio

Influence of moisture content and temperature on degree of carbonation and the effect on Cu and Cr leaching from incineration bottom ash

This study investigated the influence of moisture content and temperature on the degree of carbonation of municipal solid waste (MSW) incineration bottom ash (IBA) from two different incineration plants in Singapore. The initial rate of carbonation was affected by the nominal moisture content used. Carbonation temperature seemed to play a part in changing the actual moisture content of IBA during carbonation, which in turn affected the degree of carbonation. Results showed that 2 h of carbonation was sufficient for the samples to reach a relatively high degree of carbonation that was close to the degree of carbonation observed after 1 week of carbonation. Both Cu and Cr leaching also showed significant reduction after only 2 h of carbonation. Therefore, the optimum moisture content and temperature were selected based on 2 h of carbonation. The optimum moisture content was 15% for both incineration plants while the optimum temperature was different for the two incineration plants, at 35 °C and 50 °C. The effect on Cu and Cr leaching from IBA after accelerated carbonation was evaluated as a function of carbonation time. Correlation coefficient, Pearson’s R, was used to determine the dominant leaching mechanism. The reduction in Cu leaching was found to be contributed by both formation of carbonate mineral and reduction of DOC leaching. On the other hand, Cr leaching seemed to be dominantly controlled by pH.Accepted versio

Values and lifestyles of young Singaporeans

Indeks Bibliografi hlm. 163-164vii, 170 hlm. : il. ; 22 cm