The Effect of Defects and Surface Modification on Biomolecular Assembly and Transport

Nanoscale transport using the kinesin-microtubule (MT) biomolecular system has been successfully used in a wide range of nanotechnological applications including self-assembly, nanofluidic transport, and biosensing. Most of these applications use the ‘gliding motility geometry’, in which surface-adhered kinesin motors attach and propel MT filaments across the surface, a process driven by ATP hydrolysis. It has been demonstrated that active assembly facilitated by these biomolecular motors results in complex, non-equilibrium nanostructures currently unattainable through conventional self-assembly methods. In particular, MTs functionalized with biotin assemble into rings and spools upon introduction of streptavidin and/or streptavidin-coated nanoparticles. Upon closer examination of these structures using fluorescence and electron microscopy, the structures revealed a level of irregularity including kinked and coiled domains, as well as in- and out- of -plane loops. In this work, we describe the effects of large scale “defective” segments (i.e. non-biotinylated MTs) on active assembly of nanocomposite spools. We demonstrate the preferential removal of the defective portions from spools during assembly to overcome structurally induced strain in regions that lack biotin-streptavidin bonds. Additionally, we show how the level of defective MTs affect the morphology and physical properties of the resulting nanostructures.Further, we explore alternative nanostructures for controlling transport using the kinesin-MT biomolecular system. Guiding MT transport has been achieved using lithographically patterning physical and chemical features, which have been shown to limit the MT trajectories, causing MTs to escape the barriers and lead to stalling or complete loss of MTs. Here, we demonstrate reliable guiding and transport of MTs on three different chemically modified, and structurally varying surfaces using 1) self-assembled monolayers (SAMs) with varying functional groups, 2) Fetal-bovine serum (FBS) coated SAMs to generate protein patterns, and 3) silicification of the FBS coated SAMs to preserve the surface. Overall, the work presented in this dissertation provides crucial insights for future development of dynamic and adaptable hybrid nanostructures, as well as provides biocompatible patterns to modulate MT motility with the goal of advancing self-regulating, multi-functional materials

Selecting genetic operators to maximise preference satisfaction in a workforce scheduling and routing problem

The Workforce Scheduling and Routing Problem (WSRP) is a combinatorial optimisation problem that involves scheduling and routing of workforce. Tackling this type of problem often requires handling a considerable number of requirements, including customers and workers preferences while minimising both operational costs and travelling distance. This study seeks to determine effective combinations of genetic operators combined with heuristics that help to find good solutions for this constrained combinatorial optimisation problem. In particular, it aims to identify the best set of operators that help to maximise customers and workers preferences satisfaction. This paper advances the understanding of how to effectively employ different operators within two variants of genetic algorithms to tackle WSRPs. To tackle infeasibility, an initialisation heuristic is used to generate a conflict-free initial plan and a repair heuristic is used to ensure the satisfaction of constraints. Experiments are conducted using three sets of real-world Home Health Care (HHC) planning problem instances

Adaptive multiple crossover genetic algorithm to solve Workforce Scheduling and Routing Problem

The Workforce Scheduling and Routing Problem refers to the assignment of personnel to visits, across various geographical locations. Solving this problem demands tackling numerous scheduling and routing constraints while aiming to minimise the operational cost. One of the main obstacles in designing a genetic algorithm for this problem is selecting the best set of operators that enable better performance in a Genetic Algorithm (GA). This paper presents an adaptive multiple crossover genetic algorithm to tackle the combined setting of scheduling and routing problems. A mix of problem-specific and traditional crossovers are evaluated by using an online learning process to measure the operator's effectiveness. Best performing operators are given high application rates and low rates are given to the worse performing ones. Application rates are dynamically adjusted according to the learning outcomes in a non-stationary environment. Experimental results show that the combined performances of all the operators works better than using one operator in isolation. This study makes a contribution to advance our understanding of how to make effective use of crossover operators on this highly-constrained optimisation problem

Adaptive multiple crossover genetic algorithm to solve Workforce Scheduling and Routing Problem

The Workforce Scheduling and Routing Problem refers to the assignment of personnel to visits, across various geographical locations. Solving this problem demands tackling numerous scheduling and routing constraints while aiming to minimise the operational cost. One of the main obstacles in designing a genetic algorithm for this problem is selecting the best set of operators that enable better performance in a Genetic Algorithm (GA). This paper presents an adaptive multiple crossover genetic algorithm to tackle the combined setting of scheduling and routing problems. A mix of problem-specific and traditional crossovers are evaluated by using an online learning process to measure the operator's effectiveness. Best performing operators are given high application rates and low rates are given to the worse performing ones. Application rates are dynamically adjusted according to the learning outcomes in a non-stationary environment. Experimental results show that the combined performances of all the operators works better than using one operator in isolation. This study makes a contribution to advance our understanding of how to make effective use of crossover operators on this highly-constrained optimisation problem

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research