Detecting risk for treatment nonresponse among families of young children with behavior problems: Candidate tailoring variables and early decision points for adaptive interventions

Heterogeneity in mental health treatment outcomes and high rates of treatment nonresponse highlight the need for adaptive interventions that align with precision mental health care approaches to tailor treatments according to individual differences in progress over time. Modern clinical trial methodologies and analytic strategies can inform dynamic mental health treatment decisions, but the potential to improve patient outcomes is only as strong as the extent to which selected tailoring variables (i.e., interim response factors that dictate whether treatment should shift course) accurately detect risk for treatment nonresponse. Identifying empirically informed tailoring variables and the most appropriate timepoint(s) to assess them (i.e., critical decision points) is essential in order to design adaptive interventions. This dissertation is comprised of three manuscripts focused on the use of early interim progress data to detect risk for mental health treatment nonresponse. First, I detail a strategy that leverages secondary data analysis to examine candidate tailoring variables at candidate critical decision points, and their relationships with treatment nonresponse. Then, I directly apply this strategy to a pooled sample of families who presented for treatment of early childhood behavior problems (N=153). This study showed that using dichotomous classifications of early interim treatment progress yielded limited utility in differentially predicting post-treatment response when examined in isolation from one another. Thus, I subsequently adopt a continuous approach to measuring early interim treatment progress and examine whether interactions between early indicators of treatment response predict symptom trajectories in a sample of families who participated in a behavioral parenting intervention (BPI) for early childhood developmental delay and behavior problems (N=70). Findings from the third paper suggest symptom response trajectories can be predicted by examining the interaction between caregiver skills and child behavior problems displayed within the first six sessions of a BPI. Collectively, this collection of work encourages the use of routine outcome monitoring to assess multiple domains of early interim treatment progress. To improve the efficiency and effectiveness of mental health care, future work should continue to use analytic approaches that capture the dynamic interplay among multiple early interim response factors that can optimally inform clinical decision-making practices throughout treatment

The impact of economic, social and environmental factors on trip satisfaction and the likelihood of visitors returning

Tourism is vital to the economy of many regions; however visitor numbers in some are stagnating. Using a novel approach, this case study of the Great Barrier Reef explores and quantifies risks to visitor numbers, utilising tourist survey data supplemented by objective data from secondary sources. Economic, social and environmental factors affecting trip satisfaction are identified, which itself is found to affect the likelihood of a tourist returning; the impact of changes on trip satisfaction and on repeat visits is then estimated. Linkages between tourism and other industries are clearly demonstrated; increased construction work, decreased water clarity and decreased perceptions of tourist safety are all estimated to significantly reduce likelihood of repeat visits and hence impact tourist revenues, placing the financial viability of the industry at risk. Future development within the region should be evaluated holistically, rather than industries such as tourism, construction, agriculture etc. each being developed in isolation

New methods for valuing, and for identifying spatial variations, in cultural services: a case study of the Great Barrier Reef

Estimating values for ecosystem services (ES) can contribute to the decision making process, reducing the risk that ES benefits are overlooked. For ES with no (direct or indirect) links to markets, valuation is a non-trivial exercise. Traditional methods require the use of hypothetical markets; the life satisfaction (LS) approach does not. LS has previously been used to estimate the value of regulating ES, but to the best of our knowledge has never been used to estimate the value of cultural services (CS). We examine the relationship between LS and a subset of CS provided by the Great Barrier Reef (GBR), (the non-use CS), using geographically weighted regression to investigate spatial variations in value. After controlling for other factors, we find income is more important to LS in the south than the north; the opposite is true for non-use CS. The coefficients are used to estimate the amount of income required to keep overall LS constant, should the non-use CS of the GBR not be preserved, estimated at $8.7 bn annually. We acknowledge the imperfections of our work, noting the need for research on better CS measures, but feel that the general approach may add another useful tool to the valuation toolbox

Integrative transcriptomic analysis reveals a multiphasic epithelial–mesenchymal spectrum in cancer and non-tumorigenic cells

Epithelial–mesenchymal transition (EMT), the conversion between rigid epithelial cells and motile mesenchymal cells, is a reversible cellular process involved in tumorigenesis, metastasis, and chemoresistance. Numerous studies have found that several types of tumor cells show a high degree of cell-to-cell heterogeneity in terms of their gene expression signatures and cellular phenotypes related to EMT. Recently, the prevalence and importance of partial or intermediate EMT states have been reported. It is unclear, however, whether there is a general pattern of cancer cell distribution in terms of the overall expression of epithelial-related genes and mesenchymal-related genes, and how this distribution is related to EMT process in normal cells. In this study, we performed integrative transcriptomic analysis that combines cancer cell transcriptomes, time course data of EMT in non-tumorigenic epithelial cells, and epithelial cells with perturbations of key EMT factors. Our statistical analysis shows that cancer cells are widely distributed in the EMT spectrum, and the majority of these cells can be described by an EMT path that connects the epithelial and the mesenchymal states via a hybrid expression region in which both epithelial genes and mesenchymal genes are highly expressed overall. We found that key patterns of this EMT path are observed in EMT progression in non-tumorigenic cells and that transcription factor ZEB1 plays a key role in defining this EMT path via diverse gene regulatory circuits connecting to epithelial genes. We performed Gene Set Variation Analysis to show that the cancer cells at hybrid EMT states also possess hybrid cellular phenotypes with both high migratory and high proliferative potentials. Our results reveal critical patterns of cancer cells in the EMT spectrum and their relationship to the EMT process in normal cells, and provide insights into the mechanistic basis of cancer cell heterogeneity and plasticity

End-Use Load Profiles for the U.S. Building Stock: Market Needs, Use Cases, and Data Gaps

States and utilities are developing increasingly ambitious energy goals. Part of the solution to meeting these goals is improving electric grid flexibility. This includes shifting electric demand to align with grid needs. Thus, identifying and using building energy efficiency and other distributed energy resources to produce the highest grid value requires highly resolved, accurate and accessible electricity end-use load profiles (EULPs). EULPs quantify how and when energy is used. Currently, few accurate and accessible end-use load profiles are available for utilities, public utility commissions, state energy offices and other stakeholders to use to prioritize investment and value energy efficiency, demand response, distributed generation and energy storage. High-quality EULPs are also critical for determining the time-sensitive value of efficiency and other distributed energy resources, and the widespread adoption of grid-interactive efficient buildings (GEBs).For example, EULPs can be used to accurately forecast energy savings in buildings or identify energy activities that can be shifted to different times of the day. This report serves as the first-year deliverable for a multiyear U.S. Department of Energy-funded project, End-Use Load Profiles for the U.S. Building Stock, that intends to produce a set of highly resolved EULPs of the U.S. residential and commercial building stock. The project team, made up of researchers from the National Renewable Energy Laboratory (NREL), Lawrence Berkeley National Laboratory (LBNL), and Argonne National Laboratory, ultimately will use calibrated physics-based building energy models to create these EULPs

Patterns and rates of viral evolution in HIV-1 subtype B infected females and males.

Biological sex differences affect the course of HIV infection, with untreated women having lower viral loads compared to their male counterparts but, for a given viral load, women have a higher rate of progression to AIDS. However, the vast majority of data on viral evolution, a process that is clearly impacted by host immunity and could be impacted by sex differences, has been derived from men. We conducted an intensive analysis of HIV-1 gag and env-gp120 evolution taken over the first 6-11 years of infection from 8 Women's Interagency HIV Study (WIHS) participants who had not received combination antiretroviral therapy (ART). This was compared to similar data previously collected from men, with both groups infected with HIV-1 subtype B. Early virus populations in men and women were generally homogenous with no differences in diversity between sexes. No differences in ensuing nucleotide substitution rates were found between the female and male cohorts studied herein. As previously reported for men, time to peak diversity in env-gp120 in women was positively associated with time to CD4+ cell count below 200 (P = 0.017), and the number of predicted N-linked glycosylation sites generally increased over time, followed by a plateau or decline, with the majority of changes localized to the V1-V2 region. These findings strongly suggest that the sex differences in HIV-1 disease progression attributed to immune system composition and sensitivities are not revealed by, nor do they impact, global patterns of viral evolution, the latter of which proceeds similarly in women and men

The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. Raw data have been deposited in the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE54810. Funding: This work was supported in part by grants to EMB from the MRC (G0501164) and BBSRC (BB/G009619/1), to EMB and NDR from the Wellcome Trust (WT093596MA), to MB from Imperial College London (Division of Investigative Sciences PhD Studentship), to HH from the ERA-NET PathoGenoMics project TRANSPAT, Austrian Science Foundation (FWF I282-B09), to SGF from the National Institutes of Health, USA (R01AI073829). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

A novel strategy for the identification of genomic islands by comparative analysis of the contents and contexts of tRNA sites in closely related bacteria

We devised software tools to systematically investigate the contents and contexts of bacterial tRNA and tmRNA genes, which are known insertion hotspots for genomic islands (GIs). The strategy, based on MAUVE-facilitated multigenome comparisons, was used to examine 87 Escherichia coli MG1655 tRNA and tmRNA genes and their orthologues in E.coli EDL933, E.coli CFT073 and Shigella flexneri Sf301. Our approach identified 49 GIs occupying ∼1.7 Mb that mapped to 18 tRNA genes, missing 2 but identifying a further 30 GIs as compared with Islander [Y. Mantri and K. P. Williams (2004), Nucleic Acids Res., 32, D55–D58]. All these GIs had many strain-specific CDS, anomalous GC contents and/or significant dinucleotide biases, consistent with foreign origins. Our analysis demonstrated marked conservation of sequences flanking both empty tRNA sites and tRNA-associated GIs across all four genomes. Remarkably, there were only 2 upstream and 5 downstream deletions adjacent to the 328 loci investigated. In silico PCR analysis based on conserved flanking regions was also used to interrogate hotspots in another eight completely or partially sequenced E.coli and Shigella genomes. The tools developed are ideal for the analysis of other bacterial species and will lead to in silico and experimental discovery of new genomic islands

The genetic relationship between female reproductive traits and six psychiatric disorders

Female reproductive behaviours have important implications for evolutionary fitness and health of offspring. Here we used the second release of UK Biobank data (N = 220,685) to evaluate the association between five female reproductive traits and polygenic risk scores (PRS) projected from genome-wide association study summary statistics of six psychiatric disorders (N = 429,178). We found that the PRS of attention-deficit/hyperactivity disorder (ADHD) were strongly associated with age at first birth (AFB) (genetic correlation of -0.68 ± 0.03), age at first sexual intercourse (AFS) (-0.56 ± 0.03), number of live births (NLB) (0.36 ± 0.04) and age at menopause (-0.27 ± 0.04). There were also robustly significant associations between the PRS of eating disorder (ED) and AFB (0.35 ± 0.06), ED and AFS (0.19 ± 0.06), major depressive disorder (MDD) and AFB (-0.27 ± 0.07), MDD and AFS (-0.27 ± 0.03) and schizophrenia and AFS (-0.10 ± 0.03). These associations were mostly explained by pleiotropic effects and there was little evidence of causal relationships. Our findings can potentially help improve reproductive health in women, hence better child outcomes. Our findings also lend partial support to the evolutionary hypothesis that causal mutations underlying psychiatric disorders have positive effects on reproductive success

Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass

Aims/hypothesis Pancreatic beta cells secrete insulin to maintain glucose homeostasis, and beta cell failure is a hallmark of type 2 diabetes. Glucose triggers insulin secretion in beta cells via oxidative mitochondrial pathways. However, it also feeds mitochondrial anaplerotic pathways, driving citrate export and cytosolic malonyl-CoA production by the acetyl-CoA carboxylase 1 (ACC1) enzyme. This pathway has been proposed as an alternative glucose-sensing mechanism, supported mainly by in vitro data. Here, we sought to address the role of the beta cell ACC1-coupled pathway in insulin secretion and glucose homeostasis in vivo. Methods Acaca, encoding ACC1 (the principal ACC isoform in islets), was deleted in beta cells of mice using the Cre/loxP system. Acaca floxed mice were crossed with Ins2cre mice (βACC1KO; life-long beta cell gene deletion) or Pdx1creER mice (tmx-βACC1KO; inducible gene deletion in adult beta cells). Beta cell function was assessed using in vivo metabolic physiology and ex vivo islet experiments. Beta cell mass was analysed using histological techniques. Results βACC1KO and tmx-βACC1KO mice were glucose intolerant and had defective insulin secretion in vivo. Isolated islet studies identified impaired insulin secretion from beta cells, independent of changes in the abundance of neutral lipids previously implicated as amplification signals. Pancreatic morphometry unexpectedly revealed reduced beta cell size in βACC1KO mice but not in tmx-βACC1KO mice, with decreased levels of proteins involved in the mechanistic target of rapamycin kinase (mTOR)-dependent protein translation pathway underpinning this effect. Conclusions/interpretation Our study demonstrates that the beta cell ACC1-coupled pathway is critical for insulin secretion in vivo and ex vivo and that it is indispensable for glucose homeostasis. We further reveal a role for ACC1 in controlling beta cell growth prior to adulthood