Academic literature on the topic 'Large-Scale Screening'

The present project discusses the application of screening techniques in large-scale simulation models with the purpose of determining whether this kind of procedures could be a substitute for or a complement to simulation-based optimization for bottleneck identification and improvement. Based on sensitivity analysis, the screening techniques consist in finding the most important factors in simulation models where there are many factors, in which presumably only a few or some of these factors are important. The screening technique selected to be studied in this project is Sequential Bifurcation. This method consists in grouping the potentially important factors, dividing the groups continuously depending on the response generated from the model of the system under study. The results confirm that the application of the Sequential Bifurcation method can considerably reduce the simulation time because of the number of simulations needed, which decreased compared with the optimization study. Furthermore, by introducing two-factor interactions in the metamodel, the results are more accurate and may even be as accurate as the results from optimization. On the other hand, it has been found that the application of Sequential Bifurcation could become a problem in terms of accuracy when there are many storage buffers in the decision variables list. Due to all of these reasons, the screening techniques cannot be a complete alternative to simulation-based optimization. However, as shown in some initial results, the combination of these two methods could yield a promising roadmap for future research, which is highly recommended by the authors of this project.

An immediate reduction in global CO2 emissions could be accomplished by replacing coal- or oil-based energy sources with purified natural gas. The most important process involved in natural gas purification is the separation of CO2 from CH4, where Pressure Swing Adsorption (PSA) technology on porous materials has emerged as a less energy demanding technology. Among porous materials which are used or could potentially be used in PSA, Metal Organic Frameworks (MOFs) have attracted particular interest owing to their record-breaking surface areas, high-porosity, and high tunability. However, the discovery of optimal MOFs for use in adsorption-based CO2 separation processes is remarkably challenging, as millions of MOFs can potentially be constructed from virtually limitless combinations of inorganic and organic secondary building units. To overcome this combinatorial problem, this thesis aims to (1) identify important design features of MOFs for CO2/CH4 separation through the investigation of currently existing MOFs as well as the high throughput computational screening of a large database of MOFs, and to (2) develop efficient computational tools for aiding the discovery of new MOF materials. To validate the computational methods and models used in this thesis, the first work of this thesis presents the computational modeling of CO2 adsorption on an experimental CuBDPMe MOF using grand canonical Monte Carlo simulations and density functional theory. The simulated CO2 adsorption isotherms are in good agreement with experiment, which confirms the accuracy of the models used in our simulations throughout this thesis. The second work of this thesis investigates the performance of an experimental MIL-47 MOF and its seven functionalized derivatives in the context of natural gas purification, and compares their performance with that of other well-known MOFs and commercially used adsorbents. The computational results show that introducing polar non-bulky functional groups on MIL-47 leads to an enhancement in its performance, and the comparison suggests that MIL-47-NO2 could be a possible candidate as a solid sorbent for natural gas purification. This study is followed by the compactional study of water effects on natural gas purification using MOFs, as traces of water is present in natural gas under pipeline specifications. From the study, it is found that water has a marginal effect on natural gas purification in hydrophobic MOFs under pipeline specifications. Following the aforementioned studies, a database of 324,500 hypothetical MOFs is screened for their performance in natural gas purification using the general protocol defined in this thesis. From the study, we identify 'hit' materials for targeted synthesis, and investigate the structure-property relationships with the intent of finding important MOF design features relevant to natural gas purification. We show that layered sheets consisting of poly-aromatic molecules separated by a perpendicular distance of roughly 7 Å are an important structural-chemical feature that leads to strong adsorption of CO2. Following the screening study, we develop efficient computational tools for the recognition of high-preforming MOFs for methane purification using Machine Learning techniques. A training set of 32,500 MOF structures was used to calibrate support vector machines (SVMs) classifiers that incorporate simple geometrical features including pore size, void fraction and surface area. The SVM machine learning classifiers can be used as a filtering tool when screening large databases. The SVM classifiers were tested on ~290,000 MOFs that were not part of the training set and could correctly identify up to 70% of high-performing MOFs while only flagging a fraction of the MOFs for more rigorous screening. As a complement to this study, we present ML classifier models for CO2/CH4 separation parameters that incorporate separately the Voronoi hologram and AP-RDF descriptors, and we compare their performance with the classifiers composed of simple geometrical descriptors. From the comparison, it is found that including AP-RDF and Voronoi hologram descriptors into the classifiers improves the performance of classifiers by 20% in capturing high-performing MOFs. Finally, from the screening data, we develop a novel chemiformatics tool, MOFFinder, for aiding in the discovery of new MOFs for CO2 scrubbing from natural gas. It has a user-friendly graphical interface to promote easy exploration of over 300,000 hypothetical MOFs. It enables synthetic chemists to find MOFs of interest by searching the database for Secondary Building Units (SBUs), geometric features, functional groups and adsorption properties. MOFFinder provides, for the first time the substructure/similarity query of porous materials for users and is publicly available on titan.chem.uottawa.ca/moffinger.

La robotique et l’automatisation des microscopes ont ouvert la voie aux cribles cellulaires à haut contenu : des marqueurs fluorescents ciblant l’ADN ou d’autres composants sont utilisés pour imager des centaines de milliers de cellules dans différentes conditions. Il a été montré que les cribles cellulaires sont efficaces pour découvrir des médicaments de nouvelles classes thérapeutiques, cad ceux qui agissent sur une nouvelle cible. Les cribles permettent d’identifier des composés prometteurs et de les caractériser en leur associant des annotations fonctionnelles, comme leur cible moléculaire ou leur mécanisme d’action (MOA).J’ai étudié l'hétérogénéité des réponses cellulaires à différents niveaux et comment cette hétérogénéité phénotypique peut être exploitée pour mieux caractériser les composés. Au premier niveau, j’ai étudié l'hétérogénéité entre patients. Nous avons montré qu’utiliser différentes lignées cellulaires dérivées de patients augmente la probabilité de prédire la cible moléculaire du composé testé. Le second niveau correspond à la diversité des réponses cellulaires de la même lignée cellulaire soumise au même traitement. Des méthodes de clustering appropriées peuvent être utilisées pour clarifier cette complexité et pour grouper les cellules en sous-populations. Les proportions de chaque sous-population par traitement permettent de prédire le bon MOA. Le troisième niveau regarde comment les sous-populations cellulaires sont organisées spatialement. J’ai trouvé que les cellules voisines s’influencent les unes les autres et affichent un phénotype similaire plus fréquemment qu’attendu par chance. Ces résultats obtenus sur une centaine de traitements montrent que des cellules génétiquement identiques ne sont pas identiques et indépendantes mais sont à l’origine d’une hétérogénéité spatiale par le lignage cellulaire et les interactions. En utilisant l’information spatiale ainsi que l'hétérogénéité phénotypique, les méthodes à noyaux de graphes améliorent la classification en MOA sous certaines conditions. Parallèlement, comme l’analyse spatiale peut s’appliquer à n’importe quelle image de microscopie, j’ai développé une librairie d’analyse Python, PySpacell, pour étudier l’aléatoire spatial de marqueurs quantitatifs et qualitatifs
Robotics and automated fluorescence microscopes have promoted high-content cell-based screenings: fluorescent probes targeting DNA or other major components are used to image hundreds of thousands of cells under many different conditions. Cell-based assays have proven to be efficient at discovering first-in-class therapeutic drugs, i.e. drugs acting on a new target. They allow to detect promising molecules and to profile them, by associating functional annotations to them, like their molecular target or mechanism of action (MOA). I studied heterogeneity of cell responses at different levels and how this phenotypic heterogeneity can be leveraged to better profile drugs. The first level is about studying heterogeneity between patients. We showed that using different patient-derived cell lines increases the chance of predicting the correct molecular target of the tested drug. The second level corresponds to the diversity of cell responses within the same cell line under the same treatment. Appropriate clustering approaches can be used to unravel this complexity and group cells into subpopulations. The proportions of each subpopulation per treatment allow to predict the correct MOA. The third level looks at how the cell subpopulations are spatially organized. I found that neighboring cells influence each others, and display a similar phenotype more frequently than expected at random. These results assessed across a hundred of treatments, show that even genetically identical cells are not all alike and independent, but create spatial heterogeneity via cell lineage and interaction. Using spatial information as well as phenotypic heterogeneity with graph kernel methods improves the MOA classification under some conditions. Alongside, as spatial analysis could be applied on any cell microscopy image, I developed a Python analysis package, pySpacell, to study spatial randomness from quantitative and qualitative cell markers

Abstract Requirements engineering (RE) is an important process in systems development. This research was carried out in the context of Very Large-Scale Requirements Engineering (VLSRE) within the scope of a requirement screening (RS) process. The RS process is defined as a front-end process for screening incoming requests, which are received in a constant flow. The goal of the RS process is to efficiently identify the most promising requests for further analysis, development and implementation while filtering out non-valuable ones as early as possible. The objective of this study was to understand the challenges related to the RS process and develop solutions to address those challenges. A qualitative research approach was utilised to achieve the research goals. The overall research process follows an action research method, in which each action research cycle includes at least one individually defined and executed case study. Action research and case studies are research methods that are well suited to studying real-life phenomena in their natural settings. This research was carried out in two case companies in the information and communication technology domain. Data from 45 interviews were analysed for preparing publications I–V, which are included in this thesis. In addition, during the longitudinal action research study described in this thesis, data from 26 interviews and 132 workshops were utilised to develop solutions for the RS process, which is an industrial implementation of the VLSRE process. The conducted action research contributes to the field of software engineering, in which such research efforts are currently lacking. This research has identified a number of significant challenges that different stakeholders face related to requirements processing and decision making in the VLSRE context. Examples of these challenges are the great number of incoming requirements, the lack of information for decision making and the feasibility of utilised tools. To address the identified challenges, a requirements architecting method was developed. The method includes a dynamic requirement template, which gathers structured information content for eliciting requests, documenting and communicating requirements and forming features while considering the needs of different stakeholders. The method was piloted, validated and deployed in industry
Tiivistelmä Tutkimus toteutettiin laajamittaisen vaatimusmäärittelyprosessin kontekstissa keskittyen vaatimusten seulontaprosessiin. Vaatimusten seulontaprosessi määritellään tuotekehityksen alkuvaiheen prosessiksi, jossa käsitellään jatkuvana vuona tulevia kehityspyyntöjä. Vaatimusten seulontaprosessissa pyritään tunnistamaan tehokkaasti lupaavimmat pyynnöt jatkoanalyysiä, tuotekehitystä ja toteutusta ajatellen sekä suodattamaan pois niin aikaisessa vaiheessa, kun mahdollista ne pyynnöt, joilla ei ole arvontuotto-odotuksia. Tutkimuksen tavoite oli ymmärtää haasteita, jotka liittyvät vaatimusten seulontaprosessiin sekä kehittää ratkaisuja näihin haasteisiin. Tutkimuksessa käytettiin laadullisen tutkimuksen menetelmiä. Kokonaisuutena tutkimusprosessi noudattaa toimintatutkimuksen periaatteita siten, että jokainen sykli tai sen vaihe sisältää yhden tai useamman itsenäisesti määritellyn tapaustutkimuksen suunnittelun ja läpiviennin. Valitut tutkimusmenetelmät soveltuvat hyvin tilanteisiin, joissa tutkimuskohteina ovat reaalimaailman ilmiöt niiden luonnollisissa ympäristöissä havainnoituina. Tutkimusaineisto kerättiin kahdesta informaatio- ja kommunikaatioteknologia-alan kohdeorganisaatiosta. Väitöskirjaan sisällytettyihin julkaisuihin I-V on analysoitu 45 haastattelun aineisto. Näiden lisäksi väitöskirjassa kuvatun pitkäkestoisen toimintatutkimuksen aikana hyödynnettiin 26 haastattelun ja 132 työpajan aineistoa kehitettäessä ratkaisuja vaatimusten seulontaprosessin haasteisiin. Vaatimusten seulontaprosessi on laajamittaisen vaatimusmäärittelyprosessin teollinen toteutus. Tutkimuksessa tunnistettiin useita merkittäviä haasteta, joita eri sidosryhmillä on liittyen vaatimusten seulontaprosessiin ja päätöksentekoon laajamittaisessa vaatimusmäärittelyprosessissa. Vaatimusten suuri määrä, päätöksentekoon tarvittavan tiedon puute ja käytössä olevien työkalujen soveltumattomuus ovat esimerkkejä tunnistetuista haasteista. Ratkaisuna haasteisiin kehitettiin vaatimusten seulonta- ja analyysimenetelmä. Kehitetty menetelmä sisältää dynaamisen vaatimusdokumentin, jonka avulla voidaan kerätä kehityspyyntöjen tietosisältö jäsennellysti, dokumentoida ja kommunikoida vaatimukset sekä muodostaa niistä tuotteisiin toteutettavia ominaisuuksia ottaen huomioon eri sidosryhmien tarpeet. Kehitetty menetelmä on koestettu, validoitu ja soveltuvin osin otettu käyttöön teollisuudessa

Cellulosic biomass is the major organic matter produced in the biosphere. The biodegradation of this cellulosic material is achieved by enzymatic activities of the cellulose degrading microorganisms. These organisms usually express a complex extracellular or a membrane bound cellulolytic system comprising combination of several cellulase enzymes. Cellulases are the group of hydrolytic enzymes capable of hydrolysing insoluble cellulose to glucose. Phlebia gigantea is an aggressive white rot basidiomycete with ability to tolerate resinous extracts on freshly cut wood and higher growth rate. This helps the fungus to colonise the sapwood preventing other fungi from becoming established. Early research on the cellulase system of this organism reported the presence of a cellulase system composed of P-glucosidase, endoglucanase and a cellobiohydrolase. Based on these unpublished studies, our aim was to obtain a complete sequence of putative cellobiohydrolase I (CbhI) from this organism. Attempts to identify and isolate the cellulase gene resulted in an incomplete cDNA sequence of I 154 bp. To understand the cellulase system, expression and regulation of the cellulase enzymatic activity was examined for incubation of P. gigantea on substrates glucose, xylose, Avicel, carboxymethyl cellulose and cellobiose. The pH, total protein and biomass production results indicated that the capacity of P. gigantea to degrade cellulose is dependent upon the nature of the carbon source and the regulation of the cellulase synthesis is repressed in the presence of simple sugars like glucose and xylose. The study employed the highly effective method of purification by affinity adsorption and purified cellulase complex in large quantity. Characterisation of the kinetic properties of this cellulase complex revealed that the rate of cellulase catalysis were optimum at pH 5.0 and temperature 50GC. The purified complex was comprised of multiple proteins and demonstrated significant CMCase and CBHase activity on zymogram analysis. The purified cellulase complex was characterised by 2D gel electrophoresis and by peptide mass finger printing using MALDI-TOF massspectrometry analysis. The 2D gel analysis of the purified cellulase complex showed 15 spots within the range of pI 3.5 to pI 7 and the molecular weight between 20KDa to 100KDa. Three protein spots were selected based on the IEF and SDS zymogram and identified using MALDI-TOF MS analysis. These proteins were identified based on the peptide mass data belonging to the 6-phospho-a-glucosidase, p-glucosidase and glycosyl hydrolase family 13 a-amylase or pullulanases, suggesting the divergent evolution of specific cellulase proteins. This study showed P. gigantea as a potential cellulase source and the cellulase complex secreted by the induction of substrate, comprises a variety of enzymes related to hydrolysis of cellulose biomass. It is evident from this and previous studies that P. gigantea cellulase complex comprises of a specific set of enzymes that possess the ability to degrade crystalline cellulose and is one of the first organisms to colonise freshly cut wood. Further studies on the cellulase system of this primary colonist may open up the prospects to utilise this organism as the potential onsite bioreactor agent, pre-treating the biomass and increasing the economic feasibility of the industrial bioenergy processes.

Metastasis is one of the critical hallmarks of malignancy tumor and the principal cause of death in patients with cancer. Cell migration is the basic and essential step in cancer metastasis process. To systematically investigate functional genes regulating cell migration and cancer metastasis on large scale, we developed a novel on-chip method, SAMcell (self-assembled cell microarray). This method was demonstrated to be particularly suitable for loss-of-function high-throughput screening because of its unique advantages. The first application of SAMcell was to screen human genome miRNAs, considering that more and more miRNAs had been proved to govern cancer metastasis. We found that over 20 % of miRNAs have migratory regulation activity in diverse cell types, indicating a general involvement of miRNAs in migratory regulation. Through triple-round screenings, we discovered miR-23b, which is down-regulated in human colon cancer samples, potently mediates the multiple steps of metastasis, including cell motility, cell growth and cell survival. In parallel, the second application of SAMcell was to screen human genome kinase genes, considering that more and more kinase genes had become successful diagnostic marker or drug targets. We found over 11% migratory kinase genes, suggesting the important role of kinase group in metastasis regulation. Through both functional screening and bioinformatics analysis, we discovered and validated 6 prospective metastasis-related kinase genes, which can be new potential targets in cancer therapy. These findings allow the understanding of regulation mechanism in human cancer progression, especially metastasis and provide the new insight into the biological and therapeutical importance of miRNAs or kinases in cancer.

碩士
國立中山大學
化學系研究所
103
Ambient mass spectrometry （AMS） is known for its unique feature to perform analysis without sample pretreatment, and has been used for direct, rapid, and real-time detection of chemical compounds. Techniques such as DESI, DART, and ELDI have been demonstrated to be useful for rapidly characterizing chemical and biological compounds. In this study, we have developed an ambient mass spectrometric technique known as thermal desorption electrospray ionization mass spectrometry （TD-ESI/MS）. A direct metallic sampling probe was used to collect analytes from sample surfaces regardless of sample size or shape. Analytes were thermally desorbed, post-ionized by reacting with charged solvent species in an electrospray plume, and the ions were subsequently detected by the mass analyzer attached to the ion source. .The residual sample on the metallic probe is rapidly removed by burning the probe with a flame from a torch. The time required to complete an analysis was less than 15 seconds. In the first study, TD-ESI/MS was used to screen phthalates [ Dibutyl Phthalate （DBP）, Dimethyl Phthalate （DMP）, Di-octyl Phthalate （DOP）, Di（2-ethylhexyl）Phthalate （DEHP）, Di-iso-nonyl Phthalate （DINP）, Benzyl Butyl Phthalate （BBP）, Di-isodecyl Phthalate （DIDP）and Diethyl Phthalate （DEP） ] on the objects in two kindergartens. Approximately one thousand samples were collected, analyzed and the results were reported within two days. Sample collection was completed in approximately 3hrs, TD-ESI/MS analysis was completed in 10 hrs, and data organization and report writing took another 5 hrs. The results indicate that approximately 30% and 20% of the objects in the two kindergartens contain higher level of phthalates. The success in screening phthalates in all the objects found in the two kindergartens suggests that performing large scale screening of phthalates in the living environment is possible. In the second study, liquid-phase microextraction （LPME） was coupled with an ambient ionization technique, known as thermal desorption electrospray ionization （TD-ESI） for rapid screening of veterinary drug residues in foods. The ambient TD-ESI ion source consisted of （1）a metal loop suspending 5 μL of organic solvent was used for analyte extraction in liquids, （2）after equilibrium among analytes, sample solution, and extraction solvent was reached, a heating oven for desorbing analytes on the LPME probe.Preliminary results of LPME/TD-ESI/MS/ showed that reproducibility tests （n=5） for 10 µg/mL of sulfonamides（sulfamethazine, sulfamethoxazole） and β-agonists （clenbuterol, salbutamol, terbutaline） were less than 7.6 % and 10.2 %, respectively. The sensitivities of sulfamethazine（m/z 279） and clenbuterol（m/z 277）improved,; where detection limits could be decreased as low as 1.0 µg/mL, and 0.1 µg/mL while using the LPME fiber as a sampling probe. Furthermore, the capacity of LPME/TD-ESI/MS for quantitative analysis was evaluated using milk, honey and pork blood spiked with spiked veterinary drugs. Excellent correlations of determination were achieved for analytes with R2values greater than 0.997、0.998 and 0.972, respectively.

Screening has long been portrayed as an inherently beneficial activity that saves lives, rather than as a complex mixture of potential benefits and harms that must be carefully weighed for each modality. The early success of the Pap smear in reducing deaths from cervical cancer may have inadvertently fostered simplistic messaging about unqualified benefits of screening. Over time, large-scale randomized controlled trials (RCTs) of prostate and other cancers have highlighted the potential harms caused by mass screening programs (especially those related to overdiagnosis and unnecessary treatment) and have revealed the counterintuitive elements involved in evaluating such programs. The criteria for evaluation now extend beyond the performance criteria of the test itself to include the net balance of benefits, risks, and costs. PSA screening, widely used in the United States since the late 1980s, has now been removed from the list of routinely recommended procedures, based on evidence from RCTs.

Most of the large-scale epidemiological studies have neglected AD, although there are some recent smaller studies that have included it. The diagnostic tools in common use, such as SCAN or SCID, either omit AD or only allow the diagnosis to be made when all other disorders have been considered. Studies using these have found a prevalence of less than 2% in the general population or among those attending primary care. Two instruments specific for AD have been published in recent years. The ADNM is a screening instrument based on the proposed ICD-11 criteria, while the DIAD is a diagnostic tool. With these instruments, the prevalence has been shown to be much higher than earlier studies indicated, and in some settings such as liaison psychiatry its frequency eclipsed that of major depression. It is likely that the enhanced status of AD will result in more epidemiological studies that incorporate AD as well as other common disorders.

Peripheral artery disease (PAD) and aortic aneurysms are common diseases which show an increasing prevalence and incidence. From community-based trials assessing ankle–brachial indices, 2–4% of the general population have been shown to be affected by PAD, which increases up to 15% in those above 70 years of age. About 30–40% of the in-hospital cases with PAD have critical limb ischaemia and suffer from a 1-year mortality of 20–40%. Abdominal aortic aneurysms (AAAs) also show a relatively high prevalence of about 1–2% in the general population as found by large-scale, systematic duplex screening. Of these, about 5% come to hospital admittance with a ruptured AAA which is still associated with an in-hospital mortality of up to 50%. The prevalence of thoracic aortic aneurysms (TAAs) was reported to be at about 0.16–0.34% in selected subgroups of the general population. The incident cases of TAAs have risen from 10/100,000 cases in the late 1980s up to about 17/100,000 cases in the first decade of this millennium. It is noteworthy that PAD and aortic aneurysms as well as their associated co-morbidities remain in many cases underdiagnosed and undertreated. This leads to a high cardiovascular morbidity and mortality which could not be obviously markedly reduced in the recent decades. Since nearly all vascular disorders are systemic diseases, not only the specific vessel bed which leads to a presentation should be assessed but also all other possible vascular manifestations should be thoroughly examined to reduce adverse events.

Background Lung cancer is the number one cause of cancer death worldwide.(1) It is the fifth most commonly diagnosed cancer in Australia (12,741 cases diagnosed in 2018) and the leading cause of cancer death.(2) The number of years of potential life lost to lung cancer in Australia is estimated to be 58,450, similar to that of colorectal and breast cancer combined.(3) While tobacco control strategies are most effective for disease prevention in the general population, early detection via low dose computed tomography (LDCT) screening in high-risk populations is a viable option for detecting asymptomatic disease in current (13%) and former (24%) Australian smokers.(4) The purpose of this Evidence Check review is to identify and analyse existing and emerging evidence for LDCT lung cancer screening in high-risk individuals to guide future program and policy planning. Evidence Check questions This review aimed to address the following questions: 1. What is the evidence for the effectiveness of lung cancer screening for higher-risk individuals? 2. What is the evidence of potential harms from lung cancer screening for higher-risk individuals? 3. What are the main components of recent major lung cancer screening programs or trials? 4. What is the cost-effectiveness of lung cancer screening programs (include studies of cost–utility)? Summary of methods The authors searched the peer-reviewed literature across three databases (MEDLINE, PsycINFO and Embase) for existing systematic reviews and original studies published between 1 January 2009 and 8 August 2019. Fifteen systematic reviews (of which 8 were contemporary) and 64 original publications met the inclusion criteria set across the four questions. Key findings Question 1: What is the evidence for the effectiveness of lung cancer screening for higher-risk individuals? There is sufficient evidence from systematic reviews and meta-analyses of combined (pooled) data from screening trials (of high-risk individuals) to indicate that LDCT examination is clinically effective in reducing lung cancer mortality. In 2011, the landmark National Lung Cancer Screening Trial (NLST, a large-scale randomised controlled trial [RCT] conducted in the US) reported a 20% (95% CI 6.8% – 26.7%; P=0.004) relative reduction in mortality among long-term heavy smokers over three rounds of annual screening. High-risk eligibility criteria was defined as people aged 55–74 years with a smoking history of ≥30 pack-years (years in which a smoker has consumed 20-plus cigarettes each day) and, for former smokers, ≥30 pack-years and have quit within the past 15 years.(5) All-cause mortality was reduced by 6.7% (95% CI, 1.2% – 13.6%; P=0.02). Initial data from the second landmark RCT, the NEderlands-Leuvens Longkanker Screenings ONderzoek (known as the NELSON trial), have found an even greater reduction of 26% (95% CI, 9% – 41%) in lung cancer mortality, with full trial results yet to be published.(6, 7) Pooled analyses, including several smaller-scale European LDCT screening trials insufficiently powered in their own right, collectively demonstrate a statistically significant reduction in lung cancer mortality (RR 0.82, 95% CI 0.73–0.91).(8) Despite the reduction in all-cause mortality found in the NLST, pooled analyses of seven trials found no statistically significant difference in all-cause mortality (RR 0.95, 95% CI 0.90–1.00).(8) However, cancer-specific mortality is currently the most relevant outcome in cancer screening trials. These seven trials demonstrated a significantly greater proportion of early stage cancers in LDCT groups compared with controls (RR 2.08, 95% CI 1.43–3.03). Thus, when considering results across mortality outcomes and early stage cancers diagnosed, LDCT screening is considered to be clinically effective. Question 2: What is the evidence of potential harms from lung cancer screening for higher-risk individuals? The harms of LDCT lung cancer screening include false positive tests and the consequences of unnecessary invasive follow-up procedures for conditions that are eventually diagnosed as benign. While LDCT screening leads to an increased frequency of invasive procedures, it does not result in greater mortality soon after an invasive procedure (in trial settings when compared with the control arm).(8) Overdiagnosis, exposure to radiation, psychological distress and an impact on quality of life are other known harms. Systematic review evidence indicates the benefits of LDCT screening are likely to outweigh the harms. The potential harms are likely to be reduced as refinements are made to LDCT screening protocols through: i) the application of risk predication models (e.g. the PLCOm2012), which enable a more accurate selection of the high-risk population through the use of specific criteria (beyond age and smoking history); ii) the use of nodule management algorithms (e.g. Lung-RADS, PanCan), which assist in the diagnostic evaluation of screen-detected nodules and cancers (e.g. more precise volumetric assessment of nodules); and, iii) more judicious selection of patients for invasive procedures. Recent evidence suggests a positive LDCT result may transiently increase psychological distress but does not have long-term adverse effects on psychological distress or health-related quality of life (HRQoL). With regards to smoking cessation, there is no evidence to suggest screening participation invokes a false sense of assurance in smokers, nor a reduction in motivation to quit. The NELSON and Danish trials found no difference in smoking cessation rates between LDCT screening and control groups. Higher net cessation rates, compared with general population, suggest those who participate in screening trials may already be motivated to quit. Question 3: What are the main components of recent major lung cancer screening programs or trials? There are no systematic reviews that capture the main components of recent major lung cancer screening trials and programs. We extracted evidence from original studies and clinical guidance documents and organised this into key groups to form a concise set of components for potential implementation of a national lung cancer screening program in Australia: 1. Identifying the high-risk population: recruitment, eligibility, selection and referral 2. Educating the public, people at high risk and healthcare providers; this includes creating awareness of lung cancer, the benefits and harms of LDCT screening, and shared decision-making 3. Components necessary for health services to deliver a screening program: a. Planning phase: e.g. human resources to coordinate the program, electronic data systems that integrate medical records information and link to an established national registry b. Implementation phase: e.g. human and technological resources required to conduct LDCT examinations, interpretation of reports and communication of results to participants c. Monitoring and evaluation phase: e.g. monitoring outcomes across patients, radiological reporting, compliance with established standards and a quality assurance program 4. Data reporting and research, e.g. audit and feedback to multidisciplinary teams, reporting outcomes to enhance international research into LDCT screening 5. Incorporation of smoking cessation interventions, e.g. specific programs designed for LDCT screening or referral to existing community or hospital-based services that deliver cessation interventions. Most original studies are single-institution evaluations that contain descriptive data about the processes required to establish and implement a high-risk population-based screening program. Across all studies there is a consistent message as to the challenges and complexities of establishing LDCT screening programs to attract people at high risk who will receive the greatest benefits from participation. With regards to smoking cessation, evidence from one systematic review indicates the optimal strategy for incorporating smoking cessation interventions into a LDCT screening program is unclear. There is widespread agreement that LDCT screening attendance presents a ‘teachable moment’ for cessation advice, especially among those people who receive a positive scan result. Smoking cessation is an area of significant research investment; for instance, eight US-based clinical trials are now underway that aim to address how best to design and deliver cessation programs within large-scale LDCT screening programs.(9) Question 4: What is the cost-effectiveness of lung cancer screening programs (include studies of cost–utility)? Assessing the value or cost-effectiveness of LDCT screening involves a complex interplay of factors including data on effectiveness and costs, and institutional context. A key input is data about the effectiveness of potential and current screening programs with respect to case detection, and the likely outcomes of treating those cases sooner (in the presence of LDCT screening) as opposed to later (in the absence of LDCT screening). Evidence about the cost-effectiveness of LDCT screening programs has been summarised in two systematic reviews. We identified a further 13 studies—five modelling studies, one discrete choice experiment and seven articles—that used a variety of methods to assess cost-effectiveness. Three modelling studies indicated LDCT screening was cost-effective in the settings of the US and Europe. Two studies—one from Australia and one from New Zealand—reported LDCT screening would not be cost-effective using NLST-like protocols. We anticipate that, following the full publication of the NELSON trial, cost-effectiveness studies will likely be updated with new data that reduce uncertainty about factors that influence modelling outcomes, including the findings of indeterminate nodules. Gaps in the evidence There is a large and accessible body of evidence as to the effectiveness (Q1) and harms (Q2) of LDCT screening for lung cancer. Nevertheless, there are significant gaps in the evidence about the program components that are required to implement an effective LDCT screening program (Q3). Questions about LDCT screening acceptability and feasibility were not explicitly included in the scope. However, as the evidence is based primarily on US programs and UK pilot studies, the relevance to the local setting requires careful consideration. The Queensland Lung Cancer Screening Study provides feasibility data about clinical aspects of LDCT screening but little about program design. The International Lung Screening Trial is still in the recruitment phase and findings are not yet available for inclusion in this Evidence Check. The Australian Population Based Screening Framework was developed to “inform decision-makers on the key issues to be considered when assessing potential screening programs in Australia”.(10) As the Framework is specific to population-based, rather than high-risk, screening programs, there is a lack of clarity about transferability of criteria. However, the Framework criteria do stipulate that a screening program must be acceptable to “important subgroups such as target participants who are from culturally and linguistically diverse backgrounds, Aboriginal and Torres Strait Islander people, people from disadvantaged groups and people with a disability”.(10) An extensive search of the literature highlighted that there is very little information about the acceptability of LDCT screening to these population groups in Australia. Yet they are part of the high-risk population.(10) There are also considerable gaps in the evidence about the cost-effectiveness of LDCT screening in different settings, including Australia. The evidence base in this area is rapidly evolving and is likely to include new data from the NELSON trial and incorporate data about the costs of targeted- and immuno-therapies as these treatments become more widely available in Australia.

Control of agro-associated pathogens is becoming increasingly difficult due to increased resistance and mounting restrictions on chemical pesticides and antibiotics. Likewise, in veterinary and human environments, there is increasing resistance of pathogens to currently available antibiotics requiring discovery of novel antibiotic compounds. These drawbacks necessitate discovery and application of microorganisms that can be used as biocontrol agents (BCAs) and the isolation of novel biologically-active compounds. This highly-synergistic one year project implemented an innovative pipeline aimed at detecting BCAs and associated biologically-active compounds, which included: (A) isolation of multidrug-resistant desert soil bacteria and root-associated bacteria from medicinal plants; (B) invitro screening of bacterial isolates against known plant, animal and human pathogens; (C) nextgeneration sequencing of isolates that displayed antagonistic activity against at least one of the model pathogens and (D) in-planta screening of promising BCAs in a model bean-Sclerotiumrolfsii system. The BCA genome data were examined for presence of: i) secondary metabolite encoding genes potentially linked to the anti-pathogenic activity of the isolates; and ii) rhizosphere competence-associated genes, associated with the capacity of microorganisms to successfully inhabit plant roots, and a prerequisite for the success of a soil amended BCA. Altogether, 56 phylogenetically-diverse isolates with bioactivity against bacterial, oomycete and fungal plant pathogens were identified. These strains were sent to Auburn University where bioassays against a panel of animal and human pathogens (including multi-drug resistant pathogenic strains such as A. baumannii 3806) were conducted. Nineteen isolates that showed substantial antagonistic activity against at least one of the screened pathogens were sequenced, assembled and subjected to bioinformatics analyses aimed at identifying secondary metabolite-encoding and rhizosphere competence-associated genes. The genome size of the bacteria ranged from 3.77 to 9.85 Mbp. All of the genomes were characterized by a plethora of secondary metabolite encoding genes including non-ribosomal peptide synthase, polyketidesynthases, lantipeptides, bacteriocins, terpenes and siderophores. While some of these genes were highly similar to documented genes, many were unique and therefore may encode for novel antagonistic compounds. Comparative genomic analysis of root-associated isolates with similar strains not isolated from root environments revealed genes encoding for several rhizospherecompetence- associated traits including urea utilization, chitin degradation, plant cell polymerdegradation, biofilm formation, mechanisms for iron, phosphorus and sulfur acquisition and antibiotic resistance. Our labs are currently writing a continuation of this feasibility study that proposes a unique pipeline for the detection of BCAs and biopesticides that can be used against phytopathogens. It will combine i) metabolomic screening of strains from our collection that contain unique secondary metabolite-encoding genes, in order to isolate novel antimicrobial compounds; ii) model plant-based experiments to assess the antagonistic capacities of selected BCAs toward selected phytopathogens; and iii) an innovative next-generation-sequencing based method to monitor the relative abundance and distribution of selected BCAs in field experiments in order to assess their persistence in natural agro-environments. We believe that this integrated approach will enable development of novel strains and compounds that can be used in large-scale operations.