A Genetic Algorithm-Based Column Generation Approach to the Passenger Rail Crew Scheduling Problem

The goal of this thesis was to develop and apply a genetic algorithm-based column generation heuristic to solve a passenger rail crew scheduling problem. The crew scheduling problem minimized the total cost of payment to crew members based on the hours on-board, hours away from a crew base, number of nights of lodging, and number of on-board and away meals. Payment regulations also dictated an overtime payment and a guaranteed salary per week. Additional problem constraints included restrictions on the maximum number of continuous working hours, maximum number of days worked per week, and minimum hours of rest. The proposed heuristic produced solutions with improvements of total cost ranging from 3.0 percent to 27.9 percent

Ester biosynthesis in kiwifruit: from genes to enzymes to pathways

The distinctive flavours of different kiwifruit (Actinidia) genotypes are determined by a unique combination of volatile compounds. We are using a genomics approach to identify genes responsible for the production of esters in kiwifruit. From an extensive database of kiwifruit ESTs we have mined acyl transferase genes, including putative alcohol acyl transferases predicted to be involved in the final step of ester biosynthesis. In this paper we report the first functional characterisation of two acyl transferases in kiwifruit, AeAT9 and AdAT17, using either transient expression in planta or by recombinant protein expression in yeast. Evidence is provided that both enzymes are alcohol acyl transferases and could potentially have roles in the biosynthesis of esters in kiwifruit. Our results suggest these two alcohol acyl transferases enzymes contribute to the production of branched, straight chain and sulphur esters

Effectiveness and minimum effective dose of app-based mobile health interventions for anxiety and depression symptom reduction: Systematic review and meta-analysis

BACKGROUND: Mobile health (mHealth) apps offer new opportunities to deliver psychological treatments for mental illness in an accessible, private format. The results of several previous systematic reviews support the use of app-based mHealth interventions for anxiety and depression symptom management. However, it remains unclear how much or how long the minimum treatment dose is for an mHealth intervention to be effective. Just-in-time adaptive intervention (JITAI) has been introduced in the mHealth domain to facilitate behavior changes and is positioned to guide the design of mHealth interventions with enhanced adherence and effectiveness. OBJECTIVE: Inspired by the JITAI framework, we conducted a systematic review and meta-analysis to evaluate the dose effectiveness of app-based mHealth interventions for anxiety and depression symptom reduction. METHODS: We conducted a literature search on 7 databases (ie, Ovid MEDLINE, Embase, PsycInfo, Scopus, Cochrane Library (eg, CENTRAL), ScienceDirect, and ClinicalTrials, for publications from January 2012 to April 2020. We included randomized controlled trials (RCTs) evaluating app-based mHealth interventions for anxiety and depression. The study selection and data extraction process followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We estimated the pooled effect size using Hedge g and appraised study quality using the revised Cochrane risk-of-bias tool for RCTs. RESULTS: We included 15 studies involving 2627 participants for 18 app-based mHealth interventions. Participants in the intervention groups showed a significant effect on anxiety (Hedge g=-.10, 95% CI -0.14 to -0.06, I2=0%) but not on depression (Hedge g=-.08, 95% CI -0.23 to 0.07, I2=4%). Interventions of at least 7 weeks\u27 duration had larger effect sizes on anxiety symptom reduction. CONCLUSIONS: There is inconclusive evidence for clinical use of app-based mHealth interventions for anxiety and depression at the current stage due to the small to nonsignificant effects of the interventions and study quality concerns. The recommended dose of mHealth interventions and the sustainability of intervention effectiveness remain unclear and require further investigation

Manipulation of flavour and aroma compound sequestration and release using a glycosyltransferase with specificity for terpene alcohols.

Glycosides are an important potential source of aroma and flavour compounds for release as volatiles in flowers and fruit. The production of glycosides is catalysed by UDP-glycosyltransferases (UGTs) that mediate the transfer of an activated nucleotide sugar to acceptor aglycones. A screen of UGTs expressed in kiwifruit (Actinidia deliciosa) identified the gene AdGT4 which was highly expressed in floral tissues and whose expression increased during fruit ripening. Recombinant AdGT4 enzyme glycosylated a range of terpenes and primary alcohols found as glycosides in ripe kiwifruit. Two of the enzyme's preferred alcohol aglycones, hexanol and (Z)-hex-3-enol, contribute strongly to the 'grassy-green' aroma notes of ripe kiwifruit and other fruit including tomato and olive. Transient over-expression of AdGT4 in tobacco leaves showed that enzyme was able to glycosylate geraniol and octan-3-ol in planta whilst transient expression of an RNAi construct in Actinidia eriantha fruit reduced accumulation of a range of terpene glycosides. Stable over-expression of AdGT4 in transgenic petunia resulted in increased sequestration of hexanol and other alcohols in the flowers. Transgenic tomato fruit stably over-expressing AdGT4 showed changes in both the sequestration and release of a range of alcohols including 3-methylbutanol, hexanol and geraniol. Sequestration occurred at all stages of fruit ripening. Ripe fruit sequestering high levels of glycosides were identified as having a less intense, earthier aroma in a sensory trial. These results demonstrate the importance of UGTs in sequestering key volatile compounds in planta and suggest a future approach to enhancing aromas and flavours in flowers and during fruit ripening. Yauk YK1, Ged C, Wang MY, Matich AJ, Tessarotto L, Cooney JM, Chervin C, Atkinson RG

Similarity of chest X-ray and thermal imaging of focal pneumonia: a randomised proof of concept study at a large urban teaching hospital

OBJECTIVE: To assess the diagnostic accuracy of thermal imaging (TI) in the setting of focal consolidative pneumonia with chest X-ray (CXR) as the gold standard. SETTING: A large, 973-bed teaching hospital in Boston, Massachusetts. PARTICIPANTS: 47 patients enrolled, 15 in a training set, 32 in a test set. Age range 10 months to 82 years (median=50 years). MATERIALS AND METHODS: Subjects received CXR with subsequent TI within 4 hours of each other. CXR and TI were assessed in blinded random order. Presence of focal opacity (pneumonia) on CXR, the outcome parameter, was recorded. For TI, presence of area(s) of increased heat (pneumonia) was recorded. Fisher\u27s exact test was used to assess the significance of the correlations of positive findings in the same anatomical region. RESULTS: With TI compared with the CXR (the outcome parameter), sensitivity was 80.0% (95% CIs 29.9% to 98.9%), specificity was 57.7% (95% CI 37.2% to 76.0%). Positive predictive value of TI was 26.7% (95% CI 8.9% to 55.2%) and its negative predictive value was 93.8% (95% CI 67.7% to 99.7%). CONCLUSIONS: This feasibility study confirms proof of concept that chest TI is consistent with CXR in suggesting similarly localised focal pneumonia with high sensitivity and negative predictive value. Further investigation of TI as a point-of-care imaging modality is warranted

26085 Key efficacy and safety of apremilast in patients with mild to moderate plaque psoriasis in the phase 3 ADVANCE trial

Background: In ADVANCE, apremilast 30 mg BID (APR) demonstrated efficacy in mild-to-moderate psoriasis vs placebo (PBO). We report subgroup analyses by baseline psoriasis-involved BSA (≤5%, \u3e5%). Methods: Biologic-naive adults with mild-to-moderate psoriasis (sPGA 2-3, BSA 2%-15%, PASI 2-15) inadequately controlled with or intolerant to ≥1 topical were randomized to APR or PBO for 16 weeks. At Week 16, endpoints were compared between treatment groups and by baseline BSA. Results: At baseline, 284 patients had BSA ≤5% (APR: 143; PBO: 141); 311 had BSA \u3e5% (APR: 154; PBO: 157). Overall, a greater proportion of APR patients achieved the primary endpoint, sPGA response (score 0/1 [clear/almost clear] with ≥2-point reduction at Week 16) vs PBO (21.6% vs 4.1%, P 5%: 54.6% vs 14.9%, P 5%: 45.4% vs 17.6%, P 5%: 50.6% vs 19.2%, P 5%: 11.0 vs 10.0 DLQI 5-point improvement (baseline DLQI \u3e5): - BSA≤5%: 56.6% vs 31.2%, P =.0002 - BSA\u3e5%: 64.4% vs 36.4%, P ˂.0001. Conclusions: Greater proportions of patients achieved efficacy outcomes and greater improvements in QOL with APR vs PBO. Comparable improvements were observed between mild and moderate subgroups

Glycan profiles of gp120 protein vaccines from four major HIV-1 subtypes produced from different host cell lines under non-GMP or GMP conditions

Envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) is an important target for the development of an HIV vaccine. Extensive glycosylation of Env is an important feature that both protects the virus from antibody responses and serves as a target for some highly potent broadly neutralizing antibodies. Therefore, analysis of glycans on recombinant Env proteins is highly significant. Here we present glycosylation profiles of recombinant gp120 proteins from four major clades of HIV-1 (A, B, C, and AE) produced either as research-grade material in 293 and CHO cells or as two independent lots of clinical material under GMP conditions. Almost all potential N-linked glycosylation sites were at least partially occupied in all proteins. The occupancy rates were largely consistent among proteins produced under different conditions, although a few sites showed substantial variability even between two GMP lots. Our data confirmed previous studies in the field showing high abundance of oligomannose on Env protein, with 40-50% of glycans having Man5-Man9 on all four proteins under all production conditions. Overall the differences in occupancy and glycan forms among Env from different subtypes produced under different conditions were less dramatic than anticipated and antigenicity analysis with a panel of six monoclonal antibodies showed that all four gp120s maintained their antibody-binding profiles, including antibodies that recognize glycan forms. Such findings have major implications to the final production of a clinical HIV vaccine including Env glycoprotein components. IMPORTANCE HIV-1 Env protein is a major target for the development of an HIV-1 vaccine. Env is covered with a large number of sugar-based glycan forms - about 50% of the Env molecular weight is composed of glycans. Glycan analysis of recombinant Env proteins is important to understand its roles in vial pathogenesis and immune responses. The current report presents the first extensive comparison of glycosylation patterns of recombinant gp120 proteins from four major clades of HIV-1 produced in two different cell lines, grown at either laboratory condition or at 50L GMP scale across different lots. Information learned in this study is valuable for the further design and production of HIV-1 Env proteins as the critical components of HIV-1 vaccine formulations

Molecular markers of risk of subsequent invasive breast cancer in women with ductal carcinoma in situ: protocol for a population-based cohort study

INTRODUCTION: Ductal carcinoma in situ (DCIS) of the breast is a non-obligate precursor of invasive breast cancer (IBC). Many DCIS patients are either undertreated or overtreated. The overarching goal of the study described here is to facilitate detection of patients with DCIS at risk of IBC development. Here, we propose to use risk factor data and formalin-fixed paraffin-embedded (FFPE) DCIS tissue from a large, ethnically diverse, population-based cohort of 8175 women with a first diagnosis of DCIS and followed for subsequent IBC to: identify/validate miRNA expression changes in DCIS tissue associated with risk of subsequent IBC; evaluate ipsilateral IBC risk in association with two previously identified marker sets (triple immunopositivity for p16, COX-2, Ki67; Oncotype DX Breast DCIS score); examine the association of risk factor data with IBC risk. METHODS AND ANALYSIS: We are conducting a series of case-control studies nested within the cohort. Cases are women with DCIS who developed subsequent IBC; controls (2/case) are matched to cases on calendar year of and age at DCIS diagnosis. We project 485 cases/970 controls in the aim focused on risk factors. We estimate obtaining FFPE tissue for 320 cases/640 controls for the aim focused on miRNAs; of these, 173 cases/346 controls will be included in the aim focused on p16, COX-2 and Ki67 immunopositivity, and of the latter, 156 case-control pairs will be included in the aim focused on the Oncotype DX Breast DCIS score®. Multivariate conditional logistic regression will be used for statistical analyses. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Institutional Review Boards of Albert Einstein College of Medicine (IRB 2014-3611), Kaiser Permanente Colorado, Kaiser Permanente Hawaii, Henry Ford Health System, Mayo Clinic, Marshfield Clinic Research Institute and Hackensack Meridian Health, and from Lifespan Research Protection Office. The study results will be presented at meetings and published in peer-reviewed journals

An approach to classifying subjective cognitive decline in community-dwelling elders

Introduction: Subjective cognitive decline (SCD) may be an early symptomatic man- ifestation of Alzheimer’s disease, though published research largely neglects how to classify SCD in community-based studies. Methods: In neuropsychologically intact Einstein Aging Study participants (n = 1115; meanage=78;63%female;30%non-White),weusedCoxmodelstoexaminetheasso- ciation between self-perceived cognitive functioning at baseline (using three different approaches) and incident amnestic mild cognitive impairment (aMCI) with covariates of age, sex, education, race/ethnicity, general (objective) cognition, depressive symp- toms, and four other SCD-related features. Results: After a median of 3 years, 198 participants developed aMCI. In models that included all the variables, self-perceived cognitive functioning was consistently asso- ciated with incident aMCI as were age, general cognition, and perceived control; apolipoprotein E (APOE) ε4 allele status was significant in one model. We set cut points that optimized the diagnostic accuracy of SCD at various time frames. Discussion: We provide an approach to SCD classification and discuss implications for cognitive aging studies