Publications by authors named "Andrew J Hill"

82 Publications

Taking a local government perspective for economic evaluation of a population-level programme to promote exercise.

Health Policy 2021 Mar 4. Epub 2021 Mar 4.

Centre for Health Economics, University of York, YO105DD Heslington, UK.

Background: In order to tackle the issue of physical inactivity, local governments have implemented population-level programmes to promote exercise. While evidence is accumulating on the cost-effectiveness of these interventions, studies have typically adopted a health sector perspective for economic evaluation. This approach has been challenged as it does not allow for key concerns by local governments, which are primary stakeholders, to be addressed.

Objectives: To show how taking a local government perspective for economic evaluation can be implemented in practice and this may affect the economic conclusions.

Methods: Based on data from a case study, the health equity impact of the intervention and its opportunity cost from a service provider viewpoint were assessed. The cost-effectiveness implications of a change in perspective were subsequently estimated by means of scenario analysis.

Findings: The intervention was found to provide adult residents living in the most deprived city areas with greater health benefits compared with the rest of the population. However, a negative net equity impact was found in the short-term. The opportunity cost of the intervention was estimated to be substantially lower than its financial cost (£2.77 per person/year), with significant implications for decision-making.

Conclusions: Taking a local government perspective can affect the conclusions drawn from the economic evaluation of population-level programmes to promote exercise, and therefore influence decision making.
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http://dx.doi.org/10.1016/j.healthpol.2021.02.012DOI Listing
March 2021

Copula Models for Addressing Sample Selection in the Evaluation of Public Health Programmes: An Application to the Leeds Let's Get Active Study.

Appl Health Econ Health Policy 2021 Jan 11. Epub 2021 Jan 11.

Department of Applied Health Research, University College London, London, UK.

Sample selectivity is a recurrent problem in public health programmes and poses serious challenges to their evaluation. Traditional approaches to handle sample selection tend to rely on restrictive assumptions. The aim of this paper is to illustrate a copula-based selection model to handle sample selection in the evaluation of public health programmes. Motivated by a public health programme to promote physical activity in Leeds (England), we describe the assumptions underlying the copula selection, and its relative advantages compared with commonly used approaches to handle sample selection, such as inverse probability weighting and Heckman's selection model. We illustrate the methods in the Leeds Let's Get Active programme and show the implications of method choice for estimating the effect on individual's physical activity. The programme was associated with increased physical activity overall, but the magnitude of its effect differed according to adjustment method. The copula selection model led to a similar effect to the Heckman's approach but with relatively narrower 95% confidence intervals. These results remained relatively similar when different model specifications and alternative distributional assumptions were considered. The copula selection model can address important limitations of traditional approaches to address sample selection, such as the Heckman model, and should be considered in the evaluation of public health programmes, where sample selection is likely to be present.
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http://dx.doi.org/10.1007/s40258-020-00629-xDOI Listing
January 2021

A human cell atlas of fetal chromatin accessibility.

Science 2020 11;370(6518)

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.

The chromatin landscape underlying the specification of human cell types is of fundamental interest. We generated human cell atlases of chromatin accessibility and gene expression in fetal tissues. For chromatin accessibility, we devised a three-level combinatorial indexing assay and applied it to 53 samples representing 15 organs, profiling ~800,000 single cells. We leveraged cell types defined by gene expression to annotate these data and cataloged hundreds of thousands of candidate regulatory elements that exhibit cell type-specific chromatin accessibility. We investigated the properties of lineage-specific transcription factors (such as POU2F1 in neurons), organ-specific specializations of broadly distributed cell types (such as blood and endothelial), and cell type-specific enrichments of complex trait heritability. These data represent a rich resource for the exploration of in vivo human gene regulation in diverse tissues and cell types.
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http://dx.doi.org/10.1126/science.aba7612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785298PMC
November 2020

Modelling the impact of physical activity on public health: A review and critique.

Health Policy 2020 10 7;124(10):1155-1164. Epub 2020 Aug 7.

Centre for Health Economics, University of York, YO105DD Heslington UK.

Background: While several reviews have assessed economic evaluations of physical activity in public health and, in most cases, found the interventions to be cost-effective, the validity of the conclusions reached depends on the appropriateness of the modelling methods used in the individual studies.

Objective: To provide an overview and critique of modelling approaches and key structural assumptions used in applied studies to estimate the impact of physical activity on population health.

Methods: Electronic databases were systematically searched for relevant model-based economic evaluations. A thematic approach was used to assess the modelling studies. The critique determined the appropriateness of the modelling frameworks and plausibility of key structural assumptions.

Results: Twenty-five models were identified. Cohort models were most frequently used. High variability in the modelling of downstream diseases was found across studies analysing similar populations. Structural assumptions regarding the dynamics of change of physical activity were unrealistic in most cases. Heterogeneity was addressed in only a few studies, while health equity concerns were, at best, acknowledged by authors.

Conclusions: This literature is predominantly characterised by modelling approaches that may not adequately address the complexities associated with representing the physical activity behaviour- population health process. A consensus on how to model the impact of physical activity on public health and development of a reference model could help reduce these sources of uncertainty.
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http://dx.doi.org/10.1016/j.healthpol.2020.07.015DOI Listing
October 2020

Cognitive and behavioural strategies employed to overcome "lapses" and prevent "relapse" among weight-loss maintainers and regainers: A qualitative study.

Clin Obes 2020 Oct 7;10(5):e12395. Epub 2020 Aug 7.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

While many behavioural weight management programmes are effective in the short-term, post-programme weight regain is common. Overcoming "lapses" and preventing "relapse" has been highlighted as important in weight-loss maintenance, but little is known on how this is achieved. This study aimed to compare the cognitive and behavioural strategies employed to overcome "lapses" and prevent "relapse" by people who had regained weight or maintained weight-loss after participating in a weight management programme. By investigating differences between groups, we intended to identify strategies associated with better weight-loss maintenance. Semi-structured interviews were conducted with 26 participants (58% female) recruited from the 5-year follow-up of the Weight Loss Referrals for Adults in Primary Care (WRAP) trial (evaluation of a commercial weight-loss programme). Participants who had lost ≥5% baseline weight during the active intervention were purposively sampled according to 5-year weight trajectories (n = 16 'Regainers', n = 10 'Maintainers'). Interviews were audio-recorded, transcribed verbatim, and analysed thematically. Key differences in strategies were that Maintainers continued to pay attention to their dietary intake, anticipated and planned for potential lapses in high-risk situations, and managed impulses using distraction techniques. Regainers did not report making plans, used relaxed dietary monitoring, found distraction techniques to be ineffective and appeared to have difficulty navigating food within interpersonal relationships. This study is one of the longest qualitative follow-ups of a weight loss trial to date, offering unique insights into long-term maintenance. Future programmes should emphasize strategies focusing on self-monitoring, planning and managing interpersonal relationships to help participants successfully maintain weight-loss in the longer-term.
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http://dx.doi.org/10.1111/cob.12395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116423PMC
October 2020

Cost-effectiveness of a proportionate universal offer of free exercise: Leeds Let's Get Active.

J Public Health (Oxf) 2020 Aug 5. Epub 2020 Aug 5.

Centre for Health Economics, University of York, York YO10 5DD, UK.

Background: The purpose of this paper is to assess the cost-effectiveness of a proportionate universal programme to reduce physical inactivity (Leeds Let us Get Active (LLGA)) in adults.

Methods: A continuous-time Markov chain model was developed to assess the cost implications and QALY gains associated with increases in physical activity levels across the adult population. A parametric survival analysis approach was applied to estimate the decay of intervention effect over time. Baseline model data were obtained from previous economic models, population-based surveys and other published literature. A cost-utility analysis was conducted from a health care sector perspective over the programme duration (39 months). Scenario and probabilistic sensitivity analyses were performed to test the robustness of cost-effectiveness results.

Results: In total, 51 874 adult residents registered to the programme and provided baseline data,19.5% of which were living in deprived areas. Under base case assumptions, LLGA was found to be likely to be cost-effective. However, variations in key structural assumptions showed sensitivity of the results.

Conclusions: Results from this study suggest a non-negligible level of uncertainty regarding the effectiveness, and therefore, cost-effectiveness of a universal offer of free leisure centre-based exercise that targets hard to reach groups. Further data collection and a shift towards prospective evaluations are needed.
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http://dx.doi.org/10.1093/pubmed/fdaa113DOI Listing
August 2020

Multimodal single-cell analysis reveals distinct radioresistant stem-like and progenitor cell populations in murine glioma.

Glia 2020 12 4;68(12):2486-2502. Epub 2020 Jul 4.

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Radiation therapy is part of the standard of care for gliomas and kills a subset of tumor cells, while also altering the tumor microenvironment. Tumor cells with stem-like properties preferentially survive radiation and give rise to glioma recurrence. Various techniques for enriching and quantifying cells with stem-like properties have been used, including the fluorescence activated cell sorting (FACS)-based side population (SP) assay, which is a functional assay that enriches for stem-like tumor cells. In these analyses, mouse models of glioma have been used to understand the biology of this disease and therapeutic responses, including the radiation response. We present combined SP analysis and single-cell RNA sequencing of genetically-engineered mouse models of glioma to show a time course of cellular response to radiation. We identify and characterize two distinct tumor cell populations that are inherently radioresistant and also distinct effects of radiation on immune cell populations within the tumor microenvironment.
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http://dx.doi.org/10.1002/glia.23866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586969PMC
December 2020

Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes.

Nat Commun 2020 05 27;11(1):2539. Epub 2020 May 27.

Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs.
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http://dx.doi.org/10.1038/s41467-019-12438-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253413PMC
May 2020

Clinical and cost-effectiveness of a diabetes education and behavioural weight management programme versus a diabetes education programme in adults with a recent diagnosis of type 2 diabetes: study protocol for the Glucose Lowering through Weight management (GLoW) randomised controlled trial.

BMJ Open 2020 04 28;10(4):e035020. Epub 2020 Apr 28.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, Cambridgeshire, UK.

Introduction: People with type 2 diabetes (T2D) can improve glycaemic control or even achieve remission through weight loss and reduce their use of medication and risk of cardiovascular disease. The Glucose Lowering through Weight management (GLoW) trial will evaluate whether a tailored diabetes education and behavioural weight management programme (DEW) is more effective and cost-effective than a diabetes education (DE) programme in helping people with overweight or obesity and a recent diagnosis of T2D to lower their blood glucose, lose weight and improve other markers of cardiovascular risk.

Methods And Analysis: This study is a pragmatic, randomised, single-blind, parallel group, two-arm, superiority trial. We will recruit 576 adults with body mass index>25 kg/m and diagnosis of T2D in the past 3 years and randomise them to a tailored DEW or a DE programme. Participants will attend measurement appointments at a local general practitioner practice or research centre at baseline, 6 and 12 months. The primary outcome is 12-month change in glycated haemoglobin. The effect of the intervention on the primary outcome will be estimated and tested using a linear regression model (analysis of covariance) including randomisation group and adjusted for baseline value of the outcome and the randomisation stratifiers. Participants will be included in the group to which they were randomised, under the intention-to-treat principle. Secondary outcomes include 6-month and 12-month changes in body weight, body fat percentage, systolic and diastolic blood pressure and lipid profile; probability of achieving good glycaemic control; probability of achieving remission from diabetes; probability of losing 5% and 10% body weight and modelled cardiovascular risk (UKPDS). An intention-to-treat within-trial cost-effectiveness analysis will be conducted from NHS and societal perspectives using participant-level data. Qualitative interviews will be conducted with participants to understand why and how the programme achieved its results and how participants manage their weight after the programme ends.

Ethics And Dissemination: Ethical approval was received from East of Scotland Research Ethics Service on 15 May 2018 (18/ES/0048). This protocol (V.3) was approved on 19 June 2019. Findings will be published in peer-reviewed scientific journals and communicated to other stakeholders as appropriate.

Trial Registration Number: ISRCTN18399564.
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http://dx.doi.org/10.1136/bmjopen-2019-035020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213851PMC
April 2020

Third-wave cognitive behaviour therapies for weight management: A systematic review and network meta-analysis.

Obes Rev 2020 07 17;21(7):e13013. Epub 2020 Mar 17.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

This systematic review and network meta-analysis synthesized evidence on the effects of third-wave cognitive behaviour therapies (3wCBT) on body weight, and psychological and physical health outcomes in adults with overweight or obesity. Studies that included a 3wCBT for the purposes of weight management and measured weight or body mass index (BMI) pre-intervention and ≥ 3 months post-baseline were identified through database searches (MEDLINE, CINAHL, Embase, Cochrane database [CENTRAL], PsycINFO, AMED, ASSIA, and Web of Science). Thirty-seven studies were eligible; 21 were randomized controlled trials (RCT) and included in the network meta-analyses. Risk of bias was assessed using RoB2, and evidence quality was assessed using GRADE. Random-effects pairwise meta-analysis found moderate- to high-quality evidence suggesting that 3wCBT had greater weight loss than standard behavioural treatment (SBT) at post-intervention (standardized mean difference [SMD]: -0.09, 95% confidence interval [CI]: -0.22, 0.04; N = 19; I = 32%), 12 months (SMD: -0.17, 95% CI: -0.36, 0.02; N = 5; I = 33%), and 24 months (SMD: -0.21, 95% CI: -0.42, 0.00; N = 2; I = 0%). Network meta-analysis compared the relative effectiveness of different types of 3wCBT that were not tested in head-to-head trials up to 18 months. Acceptance and commitment therapy (ACT)-based interventions had the most consistent evidence of effectiveness. Only ACT had RCT evidence of effectiveness beyond 18 months. Meta-regression did not identify any specific intervention characteristics (dose, duration, delivery) that were associated with greater weight loss. Evidence supports the use of 3wCBT for weight management, specifically ACT. Larger trials with long-term follow-up are needed to identify who these interventions work for, their most effective components, and the most cost-effective method of delivery.
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http://dx.doi.org/10.1111/obr.13013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379202PMC
July 2020

Is Weight Bias Evident in Peer Interactions Between Young and Older Children?

Obesity (Silver Spring) 2020 02 23;28(2):333-338. Epub 2019 Dec 23.

Division of Psychological & Social Medicine, Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK.

Objective: This study aimed to investigate whether weight bias is apparent in young and older children's interactions during a paired reading activity.

Methods: One hundred seventy-two children (57% girls) read a book in which the main character, "Alfie," was portrayed either as average weight or as having obesity. Younger children (mean = 6.1 years) were paired with a same-sex older child (mean = 9.5 years). Questions within and at the end of the story prompted discussion. Children's conversations were analyzed according to valence (emotional tone). Nonverbal behavior was noted via observation.

Results: Pairs of children reading about the Alfie character with obesity made significantly more negative and fewer positive comments when offering story completions. Just one pair of boys spoke about him being "fat." There was no evidence that older children passed negative attitudes to younger children. Covertly expressed weight bias was more common. There was more frequent laughter while reading about the character with obesity, and two pairs made nonverbal reference to Alfie's appearance.

Conclusions: Covert weight bias was apparent in the interactions of some of these children, but overt weight bias was rare. There is a need to establish a better chronology of children's awareness of, and attitudes toward, obesity and how they are acquired.
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http://dx.doi.org/10.1002/oby.22686DOI Listing
February 2020

Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling.

Sci Adv 2019 11 13;5(11):eaax4249. Epub 2019 Nov 13.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

The genetic bases for most human sleep disorders and for variation in human sleep quantity and quality are largely unknown. Using the zebrafish, a diurnal vertebrate, to investigate the genetic regulation of sleep, we found that epidermal growth factor receptor (EGFR) signaling is necessary and sufficient for normal sleep levels and is required for the normal homeostatic response to sleep deprivation. We observed that EGFR signaling promotes sleep via mitogen-activated protein kinase/extracellular signal-regulated kinase and RFamide neuropeptide signaling and that it regulates RFamide neuropeptide expression and neuronal activity. Consistent with these findings, analysis of a large cohort of human genetic data from participants of European ancestry revealed that common variants in genes within the EGFR signaling pathway are associated with variation in human sleep quantity and quality. These results indicate that EGFR signaling and its downstream pathways play a central and ancient role in regulating sleep and provide new therapeutic targets for sleep disorders.
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http://dx.doi.org/10.1126/sciadv.aax4249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853770PMC
November 2019

A pooled single-cell genetic screen identifies regulatory checkpoints in the continuum of the epithelial-to-mesenchymal transition.

Nat Genet 2019 09 2;51(9):1389-1398. Epub 2019 Sep 2.

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

Integrating single-cell trajectory analysis with pooled genetic screening could reveal the genetic architecture that guides cellular decisions in development and disease. We applied this paradigm to probe the genetic circuitry that controls epithelial-to-mesenchymal transition (EMT). We used single-cell RNA sequencing to profile epithelial cells undergoing a spontaneous spatially determined EMT in the presence or absence of transforming growth factor-β. Pseudospatial trajectory analysis identified continuous waves of gene regulation as opposed to discrete 'partial' stages of EMT. KRAS was connected to the exit from the epithelial state and the acquisition of a fully mesenchymal phenotype. A pooled single-cell CRISPR-Cas9 screen identified EMT-associated receptors and transcription factors, including regulators of KRAS, whose loss impeded progress along the EMT. Inhibiting the KRAS effector MEK and its upstream activators EGFR and MET demonstrates that interruption of key signaling events reveals regulatory 'checkpoints' in the EMT continuum that mimic discrete stages, and reconciles opposing views of the program that controls EMT.
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http://dx.doi.org/10.1038/s41588-019-0489-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756480PMC
September 2019

Nutrition transition, overweight and obesity among rural-to-urban migrant women in Kenya.

Public Health Nutr 2019 12 4;22(17):3200-3210. Epub 2019 Jun 4.

Nuffield Centre for International Health and Development (NCIHD), Leeds Institute of Health Sciences, University of Leeds, Worsley Building, Leeds LS2 9NL, UK.

Objective: To assess the effect of rural-to-urban migration on nutrition transition and overweight/obesity risk among women in Kenya.

Design: Secondary analysis of data from nationally representative cross-sectional samples. Outcome variables were women's BMI and nutrition transition. Nutrition transition was based on fifteen different household food groups and was adjusted for socio-economic and demographic characteristics. Stepwise backward multiple ordinal regression analysis was applied.

Setting: Kenya Demographic and Health Survey 2014.

Participants: Rural non-migrant, rural-to-urban migrant and urban non-migrant women aged 15-49 years (n 6171).

Results: Crude data analysis showed rural-to-urban migration to be associated with overweight/obesity risk and nutrition transition. After adjustment for household wealth, no significant differences between rural non-migrants and rural-to-urban migrants for overweight/obesity risk and household consumption of several food groups characteristic of nutrition transition (animal-source, fats and sweets) were observed. Regardless of wealth, migrants were less likely to consume main staples and legumes, and more likely to consume fruits and vegetables. Identified predictive factors of overweight/obesity among migrant women were age, duration of residence in urban area, marital status and household wealth.

Conclusions: Our analysis showed that nutrition transition and overweight/obesity risk among rural-to-urban migrants is apparent with increasing wealth in urban areas. Several predictive factors were identified characterising migrant women being at risk for overweight/obesity. Future research is needed which investigates in depth the association between rural-to-urban migration and wealth to address inequalities in diet and overweight/obesity in Kenya.
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http://dx.doi.org/10.1017/S1368980019001204DOI Listing
December 2019

Mood and appetite: Their relationship with discretionary and total daily energy intake.

Physiol Behav 2019 08 11;207:122-131. Epub 2019 May 11.

The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Charles Perkins Centre, University of Sydney, NSW 2006, Australia.

Background: Negative affect is shown consistently to promote unhealthy food choices and dietary intake in laboratory studies. However, this relationship in naturalistic settings is less clear and previous research is limited by dietary assessment methodology and neglects to account for several important moderating variables. This observational study aimed to examine the association of negative affect and other psychological factors associated with eating behaviour simultaneously with discretionary energy intake and total energy intake, and whether these were moderated by emotional eating predisposition or age, sex and weight status.

Methods: One hundred adults completed a four-day food diary, a concurrent end-of-day questionnaire that assessed daily affect and experience of appetite, and the Three Factor Eating Questionnaire to assess trait eating behaviour. Food diaries provided data on participants' daily intake of total energy and of "discretionary items" (specific energy-dense and nutrient poor foods and beverages as defined by the Australian Guide to Healthy Eating). Stepwise random effects models were used to estimate the association of end-of-day ratings, trait eating behaviour and personal factors, and their interactions, with discretionary and total energy intake.

Results: Daily rated negative affect and appetite were significantly and positively associated with discretionary intake, such that a one unit increase in each scale was associated with eating 139 kJ/d [SE 61] and 194 kJ/d [SE 68] more discretionary energy, respectively. Negative affect and its interaction with emotional eating were consistently, positively associated with discretionary energy intake. This relationship was strongest in younger participants (β = -4.9 [SE 2.2], p < .05). There was no interaction with sex or weight status. Total energy intake was not associated with negative affect nor its interaction with emotional eating but was consistently associated with appetite.

Conclusion: When personal factors (age, sex, BMI), trait eating behaviours and daily rated negative affect and appetite are considered simultaneously, daily discretionary intake is associated most strongly with negative affect. Individuals, particularly young adults, may be more likely to overeat discretionary energy on days that negative affect is rated more highly. However, this may not necessarily translate into greater total energy intake which was most consistently associated with daily rated appetite.
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http://dx.doi.org/10.1016/j.physbeh.2019.05.011DOI Listing
August 2019

Modelling the Association between Core and Discretionary Energy Intake in Adults with and without Obesity.

Nutrients 2019 Mar 22;11(3). Epub 2019 Mar 22.

The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia.

Background: Many dietary recommendations for weight control rely on the assumption that greater core food intake will displace intake of energy-dense discretionary foods and beverages. However, there is little evidence to support these assumptions. This study examined the naturalistic relationship between daily core and discretionary energy intake, and with discretionary food and discretionary beverage intake, separately. The impact of weight status on these associations was also examined.

Method: One hundred participants completed a four-day (non-consecutive) estimated food diary. Discretionary foods and beverages were identified by reference to the Australian Dietary Guidelines. Non-discretionary items were considered core items. Simultaneous-equation random effects models using disaggregated dietary data controlling for sociodemographic variables were used to determine the association between various dietary components.

Result: Core energy intake correlated negatively with discretionary energy intake (cross-equation correlation, ρ = -0.49 (95% CI: -0.57, -0.39)). Its correlation with discretionary foods (-0.47 (-0.56, -0.37)) was stronger than that with discretionary beverages (-0.19 (-0.30, -0.07)) The correlation between core energy intake and discretionary energy intake was significantly stronger in participants who did not have obesity (-0.67 (-0.71, -0.50)) than those with obesity (-0.32 (-0.46, -0.17)) ( = 0.0002).

Conclusions: Core and discretionary energy intake share an inverse and potentially bidirectional, relationship that appears to be stronger with discretionary foods than discretionary beverages. These relationships were significantly weaker in participants with obesity which may indicate less precise dietary compensation in these individuals. While strategies that promote greater intake of core foods may assist with weight maintenance in individuals of healthy weight, its impact in individuals with obesity may be limited. These strategies should be accompanied by direct messages to reduce commensurately the intake of discretionary items, with special attention paid to discretionary beverage consumption.
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http://dx.doi.org/10.3390/nu11030683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471653PMC
March 2019

MRI diagnosis of suprascapular neuropathy using spinoglenoid notch distension.

Radiol Med 2019 Jul 5;124(7):643-652. Epub 2019 Mar 5.

Department of Orthopaedic Surgery, University of Tennessee College of Medicine, Chattanooga, 975 East Third St., Hospital Box 260, Chattanooga, TN, 37403, USA.

Purpose: To assess the use of a spinoglenoid notch distension measurement as a radiographic marker on MRI to aid the diagnosis of suprascapular neuropathy.

Methods: Spinoglenoid notch distension was compared on MRI by blinded independent observers for two patient cohorts: one group with an electromyography/nerve conduction study confirmed diagnosis of suprascapular neuropathy who underwent arthroscopic suprascapular nerve decompression, and a control group of patients aged 18-30 years with a normal shoulder MRI.

Results: Sixty suprascapular nerve patients (average age 52 years) were compared to 47 control patients (average age 24 years). Intra-rater and inter-rater reliability showed excellent agreement between reviewers for all measurements. There was a significant difference in the mean spinoglenoid notch distension for the SSN group (m = 8.36, SD = 2.42) compared to the control group (m = 5.7, SD = 1.56); [t(212) = 9.40, p < 0.0001].

Conclusion: The spinoglenoid notch distension is significantly increased in patients with suprascapular neuropathy. We hypothesize that hypertrophy of the transverse scapular ligament creates a venous obstruction resulting in varicosities of the suprascapular vein which runs with the nerve under the ligament. This distends the spinoglenoid notch and can be enlarged in cases of suprascapular neuropathy which is evident on MRI.
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http://dx.doi.org/10.1007/s11547-019-01005-zDOI Listing
July 2019

The single-cell transcriptional landscape of mammalian organogenesis.

Nature 2019 02 20;566(7745):496-502. Epub 2019 Feb 20.

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

Mammalian organogenesis is a remarkable process. Within a short timeframe, the cells of the three germ layers transform into an embryo that includes most of the major internal and external organs. Here we investigate the transcriptional dynamics of mouse organogenesis at single-cell resolution. Using single-cell combinatorial indexing, we profiled the transcriptomes of around 2 million cells derived from 61 embryos staged between 9.5 and 13.5 days of gestation, in a single experiment. The resulting 'mouse organogenesis cell atlas' (MOCA) provides a global view of developmental processes during this critical window. We use Monocle 3 to identify hundreds of cell types and 56 trajectories, many of which are detected only because of the depth of cellular coverage, and collectively define thousands of corresponding marker genes. We explore the dynamics of gene expression within cell types and trajectories over time, including focused analyses of the apical ectodermal ridge, limb mesenchyme and skeletal muscle.
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http://dx.doi.org/10.1038/s41586-019-0969-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434952PMC
February 2019

A Genome-wide Framework for Mapping Gene Regulation via Cellular Genetic Screens.

Cell 2019 01 3;176(1-2):377-390.e19. Epub 2019 Jan 3.

Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98105, USA; Howard Hughes Medical Institute, Seattle, WA 98105, USA. Electronic address:

Over one million candidate regulatory elements have been identified across the human genome, but nearly all are unvalidated and their target genes uncertain. Approaches based on human genetics are limited in scope to common variants and in resolution by linkage disequilibrium. We present a multiplex, expression quantitative trait locus (eQTL)-inspired framework for mapping enhancer-gene pairs by introducing random combinations of CRISPR/Cas9-mediated perturbations to each of many cells, followed by single-cell RNA sequencing (RNA-seq). Across two experiments, we used dCas9-KRAB to perturb 5,920 candidate enhancers with no strong a priori hypothesis as to their target gene(s), measuring effects by profiling 254,974 single-cell transcriptomes. We identified 664 (470 high-confidence) cis enhancer-gene pairs, which were enriched for specific transcription factors, non-housekeeping status, and genomic and 3D conformational proximity to their target genes. This framework will facilitate the large-scale mapping of enhancer-gene regulatory interactions, a critical yet largely uncharted component of the cis-regulatory landscape of the human genome.
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http://dx.doi.org/10.1016/j.cell.2018.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690346PMC
January 2019

The relationship between obesity and tertiary education outcomes: a systematic review.

Int J Obes (Lond) 2019 11 21;43(11):2125-2133. Epub 2018 Nov 21.

Boden Institute, Charles Perkins Centre, University of Sydney, Sydney, Australia.

Previous reviews have documented an overall weak or uncertain association between obesity and school-based educational attainment in children and young people. However, up to half of young adults will go on to further college or university education by age 30. The study aim was to systematically review evidence on the association between obesity and tertiary education outcomes in young men and women. A search of multiple databases, including Embase, Global Health, ERIC, Medline, PsycInfo, and Science Citation Index was conducted in March 2018. Cross-sectional and longitudinal studies were included that reported on young people aged 16+, an association between obesity and academic achievement, and a comparison to healthy weight students. Risk of bias was assessed using criteria from the STROBE checklist. From 1297 records, 16 studies met all inclusion criteria. All six cross-sectional studies and 8/10 longitudinal studies reported lower educational achievement by students with obesity. All longitudinal studies were at low risk of bias but four cross-sectional studies were at medium risk and two at high risk of bias. Three of four studies showed reduced enrolment, in 6/8 graduation was less likely, and all 6 studies reporting on performance showed this was lower in those with obesity. Five of nine studies reported that obesity had a greater impact on educational achievement for women. Overall, there is compelling evidence of weight bias in that students with obesity do less well in tertiary education than their healthy weight peers. It is likely that university/college attainment is less impacted by socio-economic factors than school-based achievement. A better understanding of the processes that underpin this weight bias is needed, including stakeholder (student, staff) experiences of weight stigma, perceived or enacted. Responsive actions could mirror those to address disability or gender bias, or in health promotion in tertiary education settings.
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http://dx.doi.org/10.1038/s41366-018-0256-1DOI Listing
November 2019

Joint profiling of chromatin accessibility and gene expression in thousands of single cells.

Science 2018 09 30;361(6409):1380-1385. Epub 2018 Aug 30.

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

Although we can increasingly measure transcription, chromatin, methylation, and other aspects of molecular biology at single-cell resolution, most assays survey only one aspect of cellular biology. Here we describe sci-CAR, a combinatorial indexing-based coassay that jointly profiles chromatin accessibility and mRNA (CAR) in each of thousands of single cells. As a proof of concept, we apply sci-CAR to 4825 cells, including a time series of dexamethasone treatment, as well as to 11,296 cells from the adult mouse kidney. With the resulting data, we compare the pseudotemporal dynamics of chromatin accessibility and gene expression, reconstruct the chromatin accessibility profiles of cell types defined by RNA profiles, and link cis-regulatory sites to their target genes on the basis of the covariance of chromatin accessibility and transcription across large numbers of single cells.
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http://dx.doi.org/10.1126/science.aau0730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571013PMC
September 2018

A Single-Cell Atlas of In Vivo Mammalian Chromatin Accessibility.

Cell 2018 08 2;174(5):1309-1324.e18. Epub 2018 Aug 2.

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA. Electronic address:

We applied a combinatorial indexing assay, sci-ATAC-seq, to profile genome-wide chromatin accessibility in ∼100,000 single cells from 13 adult mouse tissues. We identify 85 distinct patterns of chromatin accessibility, most of which can be assigned to cell types, and ∼400,000 differentially accessible elements. We use these data to link regulatory elements to their target genes, to define the transcription factor grammar specifying each cell type, and to discover in vivo correlates of heterogeneity in accessibility within cell types. We develop a technique for mapping single cell gene expression data to single-cell chromatin accessibility data, facilitating the comparison of atlases. By intersecting mouse chromatin accessibility with human genome-wide association summary statistics, we identify cell-type-specific enrichments of the heritability signal for hundreds of complex traits. These data define the in vivo landscape of the regulatory genome for common mammalian cell types at single-cell resolution.
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http://dx.doi.org/10.1016/j.cell.2018.06.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158300PMC
August 2018

Third-wave cognitive behaviour therapies for weight management: systematic review and network meta-analysis protocol.

BMJ Open 2018 08 1;8(7):e023425. Epub 2018 Aug 1.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

Introduction: Behavioural and cognitive behavioural programmes are commonly used to assist with weight management, but there is considerable scope to improve their effectiveness, particularly in the longer term. Third-wave cognitive behaviour therapies (CBTs) have this potential and are increasingly used. This systematic review will assess the effect of third-wave CBTs for weight management on weight, psychological and physical health outcomes in adults with overweight or obesity.

Methods And Analysis: The systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance. We will include studies of any third-wave CBTs focusing on weight loss or weight maintenance for adults with a body mass index (BMI) ≥25kg/m. Eligible study designs will be randomised control trials, non-randomised trials, prospective cohort and case series. Outcomes of interest will be body weight/BMI, psychological and physical health, and adherence. We will search the following databases from inception to 16 January 2018: MEDLINE, CINAHL, Embase, Cochrane database (CENTRAL), PsycINFO, AMED, ASSIA and Web of Science. The search strategy will be based on the concepts: (1) third-wave CBTs and (2) overweight, obesity or weight management. No restrictions will be applied. We will search reference lists of relevant reviews and included articles. Two independent reviewers will screen articles for eligibility using a two-stage process. Two independent reviewers will extract data, assess risk of bias using Risk of Bias 2.0, Risk of Bias in Non-randomised studies of Interventions or Risk of Bias in Non-randomised Studies of Exposures checklist and assess quality using the Grading of Recommendations Assessment, Development and Evaluation tool. A random-effects network meta-analysis of outcomes, and sub-group analyses and meta-regression will be conducted, where data permit. If not appropriate, a narrative synthesis will be undertaken.

Ethics And Dissemination: Ethical approval is not required as no primary data will be collected. The completed systematic review will be disseminated in a peer-reviewed journal, presented at conferences and used to inform the development of a weight management programme.

Prospero Registration Number: CRD42018088255.
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http://dx.doi.org/10.1136/bmjopen-2018-023425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074635PMC
August 2018

Split cGAL, an intersectional strategy using a split intein for refined spatiotemporal transgene control in .

Proc Natl Acad Sci U S A 2018 04 26;115(15):3900-3905. Epub 2018 Mar 26.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125;

Bipartite expression systems, such as the GAL4-UAS system, allow fine manipulation of gene expression and are powerful tools for interrogating gene function. Recently, we established cGAL, a GAL4-based bipartite expression system for transgene control in , where a single promoter dictates the expression pattern of a cGAL driver, which then binds target upstream activation sequences to drive expression of a downstream effector gene. Here, we report a split strategy for cGAL using the split intein gp41-1 for intersectional control of transgene expression. Split inteins are protein domains that associate, self-excise, and covalently ligate their flanking peptides together. We split the DNA binding domain and transcriptional activation domain of cGAL and fused them to the N terminal of gp41-1-N-intein and the C terminal of gp41-1-C-intein, respectively. In cells where both halves of cGAL are expressed, a functional cGAL driver is reconstituted via intein-mediated protein splicing. This reconstitution allows expression of the driver to be dictated by two promoters for refined spatial control or spatiotemporal control of transgene expression. We apply the split cGAL system to genetically access the single pair of MC neurons (previously inaccessible with a single promoter), and reveal an important role of protein kinase A in rhythmic pharyngeal pumping in Thus, the split cGAL system gives researchers a greater degree of spatiotemporal control over transgene expression, and will be a valuable genetic tool in for dissecting gene function with finer cell-specific resolution.
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http://dx.doi.org/10.1073/pnas.1720063115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899461PMC
April 2018

On the design of CRISPR-based single-cell molecular screens.

Nat Methods 2018 04 19;15(4):271-274. Epub 2018 Feb 19.

Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

Several groups recently coupled CRISPR perturbations and single-cell RNA-seq for pooled genetic screens. We demonstrate that vector designs of these studies are susceptible to ∼50% swapping of guide RNA-barcode associations because of lentiviral template switching. We optimized a published alternative, CROP-seq, in which the guide RNA also serves as the barcode, and here confirm that this strategy performs robustly and doubled the rate at which guides are assigned to cells to 94%.
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http://dx.doi.org/10.1038/nmeth.4604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882576PMC
April 2018

Genetic and neuronal regulation of sleep by neuropeptide VF.

Elife 2017 11 6;6. Epub 2017 Nov 6.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.

Sleep is an essential and phylogenetically conserved behavioral state, but it remains unclear to what extent genes identified in invertebrates also regulate vertebrate sleep. RFamide-related neuropeptides have been shown to promote invertebrate sleep, and here we report that the vertebrate hypothalamic RFamide neuropeptide VF (NPVF) regulates sleep in the zebrafish, a diurnal vertebrate. We found that NPVF signaling and -expressing neurons are both necessary and sufficient to promote sleep, that mature peptides derived from the NPVF preproprotein promote sleep in a synergistic manner, and that stimulation of -expressing neurons induces neuronal activity levels consistent with normal sleep. These results identify NPVF signaling and -expressing neurons as a novel vertebrate sleep-promoting system and suggest that RFamide neuropeptides participate in an ancient and central aspect of sleep control.
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http://dx.doi.org/10.7554/eLife.25727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705210PMC
November 2017

Guided Self-help for Eating Disorders: A Systematic Review and Metaregression.

Eur Eat Disord Rev 2017 05 9;25(3):148-164. Epub 2017 Mar 9.

Leeds Institute of Health Sciences, School of Medicine, University of Leeds, UK.

Background: Evidence-based self-help is a recommended first stage of treatment for mild-moderate eating disorders. The provision of guidance enhances outcome. The literature evaluating exclusively 'guided' self-help (GSH) has not been systematically reviewed.

Methods: The aim was to establish the effectiveness of GSH for reducing global eating disorder psychopathology and abstinence from binge eating, compared with controls. Results were pooled using random effects meta-analysis and heterogeneity explored using metaregression.

Results: Thirty randomised controlled trials met the inclusion criteria. Results showed an overall effect of GSH on global eating disorder psychopathology (-0.46) and binge abstinence (-0.20). There was strong evidence for an association between diagnosis of binge eating disorder and binge abstinence.

Discussion: Current interventions need to be adapted to address features other than binge eating. Further research is required to help us understand the effectiveness of GSH in children and young people, invariably high dropout rates and how technology can enhance interventions. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.
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http://dx.doi.org/10.1002/erv.2507DOI Listing
May 2017

Obesity in Children and the 'Myth of Psychological Maladjustment': Self-Esteem in the Spotlight.

Authors:
Andrew J Hill

Curr Obes Rep 2017 Mar;6(1):63-70

Academic Unit of Psychiatry and Behavioural Sciences Institute of Health Sciences, University of Leeds School of Medicine, Level 10, Worsley Building, Clarendon Way, Leeds, LS2 9NL, UK.

Purpose Of Review: There are contrasting views regarding the psychological well-being of children with obesity. Responding to limitations of existing evidence, Jane Wardle in 2005 argued for a 'myth of psychological maladjustment'. This review looks again at self-esteem.

Recent Findings: The different characterisations of self-esteem each offer value. Global self-esteem is reduced in nearly all studies of youth with obesity. Dimensional self-esteem reveals physical appearance, athletic and social competence as the most affected areas, confirmed by research that has operationalised low self-competence. Children with obesity are also more likely to be victimised by their peers, generally and for their fatness. Victims who bully others appear to preserve some aspects of self-esteem. A relatively small proportion of youth with obesity has low self-esteem, but those with severe and persistent obesity are especially compromised. Weight loss is only weakly associated with improved self-competence suggesting the value of resilience and asset approaches to improving well-being.
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http://dx.doi.org/10.1007/s13679-017-0246-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359371PMC
March 2017