Publications by authors named "Louis Fox"

38 Publications

"Something Good Has to Come Out of the Horror": A Qualitative Examination of Cancer Survivors' Attitudes Towards Participation in Research During the First Year of the COVID-19 Pandemic.

Front Public Health 2021 29;9:741188. Epub 2021 Oct 29.

Translational Oncology and Urology Research, School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.

The first year of the COVID-19 pandemic has been highly disruptive for people with cancer. Furthermore, it has been shown that accrual to cancer trials dropped substantially in 2020. Building on findings from a previous pilot survey, the present study used qualitative methods to gain insights into attitudes towards participation in research studies amongst people who have experienced cancer, in the context of the first year of the COVID-19 pandemic. We interviewed 13 participants from the UK, who were purposively sampled, including a broad sample of cancer types, and a mixture of individuals who have and have not taken part in research previously. Participants underwent semi-structured interviews (median interview duration: 47 min) and were asked open-ended questions about their attitude towards and experiences with COVID-19, and their attitude towards research participation. In addition to this, prompts were used to ask participants about concerns that were highlighted by our previous quantitative work on this topic, such as concerns about being older or having to travel to participate. Interview transcripts were analysed using a framework analysis approach. Our findings suggest that cancer patient decision-making about research participation during an infectious disease pandemic may be a function of a basic cost-benefit analysis, which considers the benefit of taking part, either personally to themselves or to wider society. The benefit may then be weighed by the patient against the risk of being infected, which may be influenced by trust in the relevant clinicians/researchers; familiarity with the study location; provision of detailed information on safety protocols for infectious disease; and, in particular, the availability of safe transport to and from the study location. Some cancer patients say that they would be less likely to participate in a research study in the middle of an infectious disease pandemic due to an increased risk to themselves. Patients' perceived risk to themselves from participating may be ameliorated the provision of certain practical solutions that can be considered at the study protocol design stage, such as safe travel, information, and the use of staff and study sites familiar to the patient.
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http://dx.doi.org/10.3389/fpubh.2021.741188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585927PMC
November 2021

Is there a role for physical activity when treating patients with cancer with immune checkpoint inhibitors? Protocol for a scoping review.

BMJ Open 2021 10 8;11(10):e046052. Epub 2021 Oct 8.

Translational Oncology & Urology Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.

Introduction: For patients with cancer, immune checkpoint inhibitors (ICIs) produce superior long-term responses compared with alternative treatments, although at the cost of manifesting adverse immune-related events. There are many hypotheses of the impacts of physical activities in immunotherapy, but little is known about the oncological outcomes and the underlying mechanisms. This scoping review aims to identify possible physical activity interventions, their efficacy and feasibility and the potential underlying biological mechanisms responsible for their effects.

Method And Analysis: The Levac methodology framework was used along with guidance from the Joanna Briggs Institute Manual for Evidence Synthesis to inform development of this protocol. Abstracts and titles followed by full-text screening will be performed by two independent reviewers for inclusion. All studies describing the impact of physical activities and exercise interventions on cancer ICIs, with particular focus on oncological outcomes, quality of life or underling biological mechanisms, will be included. After extracting qualitative and quantitative data, they will be evaluated and summarised, respectively. Subsequently, a further consultation step with other scientists and healthcare professionals will be performed.

Ethics And Dissemination: The research findings will be published through an open-access peer-reviewed journal. The results of this scoping review will be used to inform further studies on physical impacts on immunotherapy. All data included will be from open resources, therefore, no ethical clearances are required.
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http://dx.doi.org/10.1136/bmjopen-2020-046052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504359PMC
October 2021

Global cancer research in the era of COVID-19: a bibliometric analysis.

Ecancermedicalscience 2021 7;15:1264. Epub 2021 Jul 7.

Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon.

Background: Patients with cancer across the world have been impacted by the COVID-19 pandemic due to increased risk of infection and disruption to cancer diagnosis and treatment. Widening of healthcare disparities is expected as the gap between health systems with and without adequate resources to mitigate the pandemic become more apparent. We undertook a bibliometric analysis of research related to cancer and COVID-19 to understand (1) the type of research that has been conducted (e.g. patients, services and systems) and (2) whether the pandemic has impacted the state of global cancer research as measured by research outputs to date.

Methods: An existing filter for cancer research consisting of title words and the names of specialist cancer journals was used to identify cancer and COVID-19 related articles and reviews in the Web of Science (©Clarivate Analytics) between January 2019 and February 2021.

Results: One thousand five hundred and forty-five publications were identified. The majority (57%) were reviews, opinion pieces or concerned with modelling impact of delays to diagnosis and treatment. The main research domains focused on managing or estimating COVID-19 risk to cancer patients accounting for 384 papers (25%). High Income countries contributed the largest volume ( = 1,115; 72%), compared to Upper Middle ( = 302; 20%), Lower Middle ( = 122; 8%) and Low Income countries ( = 2.4; 0.2%). No evidence of a reduction in global cancer research output was observed in 2020.

Conclusions: We observed a shift in research focus rather than a decline in absolute output. However, there is variation based on national income and collaborations are minimal. There has been a focus on pan-cancer studies rather than cancer site-specific studies. Strengthening global multidisciplinary research partnerships with teams from diverse backgrounds with regard to gender, clinical expertise and resource setting is essential to prevent the widening of cancer inequalities.
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http://dx.doi.org/10.3332/ecancer.2021.1264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426029PMC
July 2021

Reply by Authors.

J Urol 2021 10 21;206(4):839. Epub 2021 Jul 21.

Translational Oncology and Urology Research (TOUR), King's College London, London, UK.

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http://dx.doi.org/10.1097/JU.0000000000001901.03DOI Listing
October 2021

Designing a Pragmatic Intervention to Help Improve the Bladder Cancer Patient Experience.

Inquiry 2021 Jan-Dec;58:469580211030217

King's College London, London, UK.

Bladder cancer (BC) is the 10 most common malignancy worldwide and the patient experience is found to be worse than that for patients diagnosed with other cancer types. We aimed to develop a wellbeing intervention to help improve the bladder cancer patient experience by ameliorating their health-related Quality of Life (HRQoL). We followed the 3 phases of the modified Medical Research Council (MRC) Framework for development of complex interventions. Following a systematic review of the literature on mental, sexual, and physical wellbeing, we conducted discussion groups with patients and healthcare professionals on these 3 themes. A consultation phase was then conducted with all relevant stakeholders to co-design a wellbeing intervention as part of a feasibility study. A pragmatic wellbeing feasibility trial was designed based on the hypothesis that a wellbeing program will increase patient awareness and attendance to services available to them and will better support their needs to improve HRQoL. The primary feasibility endpoints are patient attendance to the services offered and changes in HRQoL. The principle of patient centered care has strengthened the commitment to provide a holistic approach to support BC patients. In this study, we developed a wellbeing intervention in collaboration with patients and healthcare professionals to meet an unmet need in terms of the BC patient experience.
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http://dx.doi.org/10.1177/00469580211030217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287348PMC
October 2021

The importance of patient and public involvement in cancer research: time to create a new job profile.

Future Oncol 2021 Oct 2;17(28):3667-3670. Epub 2021 Jul 2.

Translational Oncology & Urology Research, Faculty of Life Sciences & Medicine, King's College London, London, SE1 9RT, UK.

Tweetable abstract Need to add #PPI coordinator to required job profiles in #research: improve research quality, enthuse research team and ensure #patients and their families are the center of our research activities.
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http://dx.doi.org/10.2217/fon-2021-0489DOI Listing
October 2021

The Current Evidence for Factors that Influence Treatment Decision Making in Localized Kidney Cancer: A Mixed Methods Systematic Review.

J Urol 2021 10 11;206(4):827-839. Epub 2021 Jun 11.

Translational Oncology and Urology Research (TOUR), King's College London, London, UK.

Purpose: With a growing number of treatment options for localized kidney cancer, patients and health care professionals have both the opportunity and the burden of selecting the most suitable management option. This mixed method systematic review aims to understand the barriers and facilitators of the treatment decision making process in localized kidney cancer.

Materials And Methods: We searched PubMed®, Embase® and Cochrane Central databases between January 1, 2004 and April 23, 2020 using the Joanna Briggs Manual for Evidence Synthesis and the Preferred Reporting Items for Systematic Review and Meta-analysis statement. We identified 553 unique citations; of these, 511 were excluded resulting in 42 articles included for synthesis. The Purpose, Respondents, Explanation, Findings and Significance and the Strengthening the Reporting of Observational Studies in Epidemiology checklist was applied.

Results: The key themes describing barriers and facilitators to treatment decision making were identified and categorized into 3 domains: 1) kidney cancer specific characteristics, 2) decision maker related criteria and 3) contextual factors. The main facilitators identified within these domains were size at diagnosis, age, comorbidities, body mass index, gender, nephrometry scoring systems, biopsy, socioeconomic status, family history of cancer, year of diagnosis, geographic region and practice pattern. The key barriers were race, gender, patient anxiety, low confidence in diagnostic and treatment options, cost of procedure, and practice patterns.

Conclusions: Future interventions designed to improve the decision making process for localized kidney cancer should consider these barriers and facilitators to ensure a better patient experience.
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http://dx.doi.org/10.1097/JU.0000000000001901DOI Listing
October 2021

Studying the Utility of Using Genetics to Predict Smoking-Related Outcomes in a Population-Based Study and a Selected Cohort.

Nicotine Tob Res 2021 Nov;23(12):2110-2116

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.

Introduction: The purpose of this study is to examine the predictive utility of polygenic risk scores (PRSs) for smoking behaviors.

Aims And Methods: Using summary statistics from the Sequencing Consortium of Alcohol and Nicotine use consortium, we generated PRSs of ever smoking, age of smoking initiation, cigarettes smoked per day, and smoking cessation for participants in the population-based Atherosclerosis Risk in Communities (ARIC) study (N = 8638), and the Collaborative Genetic Study of Nicotine Dependence (COGEND) (N = 1935). The outcomes were ever smoking, age of smoking initiation, heaviness of smoking, and smoking cessation.

Results: In the European ancestry cohorts, each PRS was significantly associated with the corresponding smoking behavior outcome. In the ARIC cohort, the PRS z-score for ever smoking predicted smoking (odds ratio [OR]: 1.37; 95% confidence interval [CI]: 1.31, 1.43); the PRS z-score for age of smoking initiation was associated with age of smoking initiation (OR: 0.87; 95% CI: 0.82, 0.92); the PRS z-score for cigarettes per day was associated with heavier smoking (OR: 1.17; 95% CI: 1.11, 1.25); and the PRS z-score for smoking cessation predicted successful cessation (OR: 1.24; 95% CI: 1.17, 1.32). In the African ancestry cohort, the PRSs did not predict smoking behaviors.

Conclusions: Smoking-related PRSs were associated with smoking-related behaviors in European ancestry populations. This improvement in prediction is greatest in the lowest and highest genetic risk categories. The lack of prediction in African ancestry populations highlights the urgent need to increase diversity in research so that scientific advances can be applied to populations other than those of European ancestry.

Implications: This study shows that including both genetic ancestry and PRSs in a single model increases the ability to predict smoking behaviors compared with the model including only demographic characteristics. This finding is observed for every smoking-related outcome. Even though adding genetics is more predictive, the demographics alone confer substantial and meaningful predictive power. However, with increasing work in PRSs, the predictive ability will continue to improve.
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http://dx.doi.org/10.1093/ntr/ntab100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570670PMC
November 2021

Is there a role for physical activity interventions in the treatment pathway of bladder cancer? A scoping review of the literature.

BMJ Open Sport Exerc Med 2021 10;7(1):e000951. Epub 2021 Mar 10.

Translational Oncology Urology Research, King's College London, London, UK.

Introduction: Physical activity (PA) interventions have been introduced in patients with cancer as they may contribute to better treatment outcomes and quality of life (QoL). However, little is known about the impact of PA on patients with bladder cancer (BC). This scoping review aimed to explore efficacy and feasibility of existing PA interventions in the BC care pathway.

Methods And Analysis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review guidelines and the Levac methodology framework were used; electronic databases were searched. Two independent reviewers screened all titles, abstracts and full-text publications for inclusion. The feasibility of integrating a PA intervention in the BC treatment pathway was discussed in a consultation phase with healthcare professionals and patient and public representatives.

Results: A total of 675 records were identified through database searching of which 14 studies were included in our scoping review. An additional 17 clinical trials were identified of which 12 were included for which no results have been published yet. The included studies looked at the feasibility of a PA intervention programme, the associations between PA, obesity and BC, but also the determinants of PA engagement for BC patients and the assessment of QoL.

Conclusion: This scoping review highlights that despite the general recognition on the role of PA in the BC treatment pathway, there is a gap regarding the understanding of the impact of PA interventions in BC care pathways as well as the limited understanding of factors underlying possible benefits of PA. No clear conclusions could be made regarding structure and processes of PA interventions that may lead to better outcomes. Further PA studies for patients with BC are needed to understand how to incorporate exercise guidelines recommendations.
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http://dx.doi.org/10.1136/bmjsem-2020-000951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949423PMC
March 2021

Gender Differences in Concerns About Participating in Cancer Research During the COVID-19 Pandemic.

Cancer Control 2021 Jan-Dec;28:1073274821989315

Translational Oncology and Urology Research (TOUR), School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom.

Introduction: The ongoing SARS-CoV-2 pandemic is having major effects on cancer research, including major reductions in participant accrual to cancer clinical trials. Existing research has indicated that these steep drops in accrual rates to cancer clinical trials may be disproportionately affecting women. We sought to determine if there were gender differences in a dataset collected to examine participants' concerns about taking part in cancer research during the pandemic.

Methods: Between 5-19 June 2020, we distributed a fully anonymized survey via social media. We contacted 85 UK cancer patient organizations/charities and asked them to share our questionnaire on their platforms, of which 26 obliged. Patients aged 18 with a cancer diagnosis were eligible to participate and asked about their clinical and demographic characteristics, concerns about research participation given the COVID-19 pandemic, anxiety levels measured using the Generalized Anxiety Disorder-7 (GAD-7) scale, amongst other questions. Anxiety levels and concerns about participating were compared between men and women using univariate and multivariate analyses.

Results: 93 individuals, comprising n = 37 women and n = 56 men of various cancer types, provided survey responses. Independent t-tests showed that women reported higher anxiety scores, and concerns about participating in cancer research during COVID-19, than men. Linear regression analyses showed that anxiety scores predicted concerns about research participation in women but not men (p = 0.002).

Conclusions: Cancer patients have concerns about participating in research during the COVID-19 pandemic that range from mild to serious. Furthermore, the relationship between general anxiety and concerns about research participation may be both more relevant and more pronounced in women than in men. Future work should examine the reasons why women are less likely to enrol in cancer trials during the COVID-19 pandemic.
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http://dx.doi.org/10.1177/1073274821989315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482716PMC
January 2021

Development of a pre- and postoperative physical activity promotion program integrated in the electronic health system of patients with bladder cancer (The POPEYE study): An intervention mapping approach.

Eur J Cancer Care (Engl) 2021 Mar 17;30(2):e13363. Epub 2020 Nov 17.

Department of Human Structure and Repair, Ghent University, Ghent, Belgium.

Introduction: Uptake of sufficient physical activity before and after radical cystectomy is important to improve physical and psychosocial outcomes in bladder cancer (BC) patients.

Methods: In this paper, we describe the development of an evidence-based and theory-informed intervention, guided by the steps of the Intervention Mapping approach, to promote physical activity before and after radical cystectomy in patients with BC.

Results: The intervention is a home-based physical activity program. The preoperative timeframe of the intervention is 4 or 12 weeks, depending on administration of neoadjuvant chemotherapy. Postoperatively, the intervention will last for 12 weeks. The intervention consists of a digital oncological platform (DOP), several consultations with healthcare professionals, personal booklet and follow-up phone calls. DOP includes information, diaries, visual representation of progress, mailbox, videos of peers and treating physician explaining the benefits of physical activity, photo material of exercises and a walking program with an activity tracker. Individual goals will be set and will be self-monitored by the patient through DOP. Patients will receive alerts and regular feedback.

Conclusions: Intervention Mapping ensures transparency of all intervention components and offers a useful approach for the development of behaviour change interventions for cancer patients and for translation of theories into practice.
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http://dx.doi.org/10.1111/ecc.13363DOI Listing
March 2021

A large-scale genome-wide association study meta-analysis of cannabis use disorder.

Lancet Psychiatry 2020 12 20;7(12):1032-1045. Epub 2020 Oct 20.

Stanford University Graduate School of Education, Stanford University, Stanford, CA, USA.

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.

Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10). Cannabis use disorder and cannabis use were genetically correlated (r 0·50, p=1·50 × 10), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.

Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.

Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.
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http://dx.doi.org/10.1016/S2215-0366(20)30339-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674631PMC
December 2020

Dissecting the genetic overlap of smoking behaviors, lung cancer, and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme.

Genet Epidemiol 2020 10 16;44(7):748-758. Epub 2020 Aug 16.

Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.

Smoking is a major contributor to lung cancer and chronic obstructive pulmonary disease (COPD). Two of the strongest genetic associations of smoking-related phenotypes are the chromosomal regions 15q25.1, encompassing the nicotinic acetylcholine receptor subunit genes CHRNA5-CHRNA3-CHRNB4, and 19q13.2, encompassing the nicotine metabolizing gene CYP2A6. In this study, we examined genetic relations between cigarettes smoked per day, smoking cessation, lung cancer, and COPD. Data consisted of genome-wide association study summary results. Genetic correlations were estimated using linkage disequilibrium score regression software. For each pair of outcomes, z-score-z-score (ZZ) plots were generated. Overall, heavier smoking and decreased smoking cessation showed positive genetic associations with increased lung cancer and COPD risk. The chromosomal region 19q13.2, however, showed a different correlational pattern. For example, the effect allele-C of the sentinel SNP (rs56113850) within CYP2A6 was associated with an increased risk of heavier smoking (z-score = 19.2; p = 1.10 × 10 ), lung cancer (z-score = 8.91; p = 5.02 × 10 ), and COPD (z-score = 4.04; p = 5.40 × 10 ). Surprisingly, this allele-C (rs56113850) was associated with increased smoking cessation (z-score = -8.17; p = 2.52 × 10 ). This inverse relationship highlights the need for additional investigation to determine how CYP2A6 variation could increase smoking cessation while also increasing the risk of lung cancer and COPD likely through increased cigarettes smoked per day.
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http://dx.doi.org/10.1002/gepi.22331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793026PMC
October 2020

Effect of a brief physical activity-based presentation by a former patient for men treated with radical prostatectomy for prostate cancer: a mixed methods pilot study.

Support Care Cancer 2021 Jan 22;29(1):145-154. Epub 2020 Apr 22.

Translational Oncology and Urology Research, King's College London, London, UK.

Purpose: Existing research indicates that physical activity (PA) is beneficial to men with prostate cancer (PCa). We examined the potential of a single-contact peer-support-based behavioural intervention to promote PA engagement in men treated for PCa.

Methods: A mixed methods design was employed, comprising a two-arm pragmatic trial and semi-structured interviews. The intervention was a 10-min PA-based presentation by a former patient, delivered in group seminars that are provided for patients as standard care. Seminars were alternately allocated to (a) cancer exercise specialist talk + patient speaker talk or (b) cancer exercise specialist talk only. Self-reported PA, exercise motivation, quality of life, fatigue and clinical and demographic characteristics were obtained from n = 148 (intervention: n = 69; control: n = 79) patients immediately prior to the seminar, and at follow-up ≈ 100 days later. Data were analysed using ANCOVA models and χ tests. Fourteen semi-structured interviews with intervention participants, which explored how the intervention was experienced, were analysed using a grounded theory-style approach.

Results: The intervention had no significant effect on quantitatively self-reported PA (p = 0.4). However, the intervention was statistically and clinically beneficial for fatigue (p = 0.04) and quality of life (p = 0.01). Qualitative analysis showed that the intervention was beneficial to psychological wellbeing and some participants had increased intention to engage in PA as a result of the intervention.

Conclusions: A brief one-off PA-based presentation for men with PCa, delivered by a former patient alongside cancer exercise specialist advice, may result in clinically significant benefits to quality of life and may influence PA intention in certain individuals.
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http://dx.doi.org/10.1007/s00520-020-05455-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686188PMC
January 2021

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

Mol Psychiatry 2020 08 26;25(8):1673-1687. Epub 2020 Feb 26.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.
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http://dx.doi.org/10.1038/s41380-020-0677-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392789PMC
August 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

Scoping review protocol: is there a role for physical activity interventions in the treatment pathway of bladder cancer?

BMJ Open 2019 11 12;9(11):e033518. Epub 2019 Nov 12.

Translational Oncology and Urology Research, King's College London, London, UK.

Introduction: Patients with bladder cancer (BC) have been found to have worse experiences than those with other cancers which may partly be due to impact on quality of life. Currently, little is known about the impact of physical activity (PA) on BC outcomes. This scoping review aims to identify what interventions are available, their reported efficacy and feasibility, and a description of potential underlying biological mechanisms for their effects.

Methods And Analysis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review (ScR) guidelines and the Levac methodology framework will be followed/used. Electronic databases will be searched (MEDLINE, EMBASE, the Cochrane Library, PsycInfo and Health, OpenGray). Two independent reviewers will screen all abstracts and titles and during a second stage and full-text publications for inclusion. All studies describing PA (as an existing lifestyle or as part of an intervention programme) during BC management will be included. Study characteristics will be recorded; qualitative data will be extracted and evaluated using the Donabedian framework. Quantitative data will be extracted and summarised. A further consultation step will be carried out with patients, their family members and healthcare professionals.

Ethics And Dissemination: Results will be disseminated through a peer-reviewed publication. Through the consultation step, we will ensure that findings will reach a wide audience and recommendations can be made for future development of PA interventions for patients with BC. Data used will be from publicly available secondary sources, and the consultation step will be carried out as part of patient and public involvement so this study does not require ethical review.
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http://dx.doi.org/10.1136/bmjopen-2019-033518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858121PMC
November 2019

Barriers and facilitators to physical activity in men with prostate cancer: A qualitative and quantitative systematic review.

Psychooncology 2019 12 6;28(12):2270-2285. Epub 2019 Nov 6.

Translational Oncology and Urology Research, King's College London, London, UK.

Objective: Existing research indicates that moderate-to-vigorous physical activity (PA) alleviates treatment side effects and is associated with survival in men with prostate cancer. We aimed to ascertain the state of research investigating barriers and facilitators to PA in men with prostate cancer and synthesise existing qualitative research on this topic.

Methods: A systematic review of qualitative and quantitative studies was conducted. MEDLINE, Embase, PsycINFO, Web of Knowledge, CINAHL, PEDro, OATD, and WorldCat were searched to June 2019 for quantitative studies investigating causes or predictors of PA or qualitative studies describing patient-reported barriers/facilitators to PA, amongst men with prostate cancer of any stage. Thirty-two studies (n = 17 quantitative; n = 15 qualitative) were included from 3698 screened articles.

Results: Heterogeneity and unsystematic reporting of quantitative study methods prohibited a quantitative data synthesis. Thematic synthesis of qualitative studies produced five analytical themes: individual needs by treatment pathway, self-determination and its relationship with prostate cancer-related events, co-ordination and support of the clinical care team, individual preferences in discrete aspects of PA engagement style, and the potential for a bidirectional facilitative relationship between structured group PA and spontaneous peer support. Both qualitative and quantitative studies indicated incontinence as a barrier.

Conclusions: Unsystematic reporting of interventions hinders a robust quantitative understanding of behavioural intervention research in this subject area. Good co-ordination of multidisciplinary care personnel could facilitate PA, by enabling a more comprehensive approach to targeting social cognitive processes. Well-timed intervention and access to highly individualised PA support, including optional group PA classes, seem to also be important facilitators.
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http://dx.doi.org/10.1002/pon.5240DOI Listing
December 2019

Brief behavioural intervention, delivered as standard care, to support physical activity engagement in men with prostate cancer: a pilot study protocol.

BMJ Open Sport Exerc Med 2018 17;4(1):e000469. Epub 2018 Dec 17.

Translational Oncology and Urology Research, King's College London, London, UK.

Introduction: Physical activity is beneficial to men with prostate cancer, but there remain barriers to fulfilling the potential of National Health Service trusts to support men with prostate cancer to be physically active. This article describes protocols for two pilot studies, each conducted in a different setting, designed to assess the potential of a behavioural intervention to affect patients' motivation to exercise. The intervention is theory based and inspired by recent empirical observations.

Methods And Analysis: The intervention consists of a 10 min talk, delivered to patients by a man with a history of prostate cancer treatment and a good experience of exercise, as part of their standard care. This talk either takes place in a preradical prostatectomy seminar (study one), or a post-treatment seminar designed to assist patients in adjusting to life after treatment (study two). Outcomes will be compared between patients attending the existing seminar format, and patients attending the novel seminar format. The two primary outcomes are: (1) differences in self-reported physical activity before and 90 days after the seminar and (2) the likelihood of the patient seeing an in-house exercise physiotherapist in those 90 days. Data on quality of life, fatigue and exercise behavioural regulations will also be captured at the same time points.

Ethics And Dissemination: These two projects have been approved by internal clinical audit committees due to their focus on service improvement. Findings from these pilot studies will be presented at oncology meetings and submitted for publication in academic journals.
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http://dx.doi.org/10.1136/bmjsem-2018-000469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350748PMC
December 2018

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders.

Nat Neurosci 2018 12 26;21(12):1656-1669. Epub 2018 Nov 26.

NIH/NIAAA, Laboratory of Neurogenetics, Bethesda, MD, USA.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10) and African ancestries (rs2066702; P = 2.2 × 10). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
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http://dx.doi.org/10.1038/s41593-018-0275-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430207PMC
December 2018

Tobacco Use Prevalence and Smoking Cessation Pharmacotherapy Prescription Patterns Among Hospitalized Patients by Medical Specialty.

Nicotine Tob Res 2019 04;21(5):631-637

Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO.

Introduction: Effective smoking cessation medications are readily available but may be underutilized in hospital settings. In our large, tertiary care hospital, we aimed to (1) characterize patient tobacco use prevalence across medical specialties, (2) determine smoking cessation pharmacotherapy prescription variation across specialties, and (3) identify opportunities for improvement in practice.

Methods: Using electronic health records at Barnes Jewish Hospital, we gathered demographic data, admitting service, admission route, length of stay, self-reported tobacco use, and smoking cessation prescriptions over a 6-year period, from 2010 to 2016. We then compared tobacco use prevalence and smoking cessation prescriptions across medical specialties using a cross-sectional, retrospective design.

Results: Past 12-month tobacco use was reported by patients in 27.9% of inpatient admissions; prescriptions for smoking cessation pharmacotherapy were provided during 21.5% of these hospitalizations. The proportion of patients reporting tobacco use was highest in psychiatry (55.3%) and lowest in orthopedic surgery (17.1%). Psychiatric patients who reported tobacco use were most likely to receive pharmacotherapy (71.8% of admissions), and plastic surgery patients were least likely (4.7% of admissions). Compared with Caucasian tobacco users, African American patients who used tobacco products were less likely to receive smoking cessation medications (adjusted odds ratio [aOR] = 0.65; 95% confidence interval [CI] = 0.62 to 0.68).

Conclusions: Among hospitalized tobacco users, safe and cost-effective pharmacotherapies are under-prescribed. We identified substantial variation in prescribing practices across different medical specialties and demographic groups, suggesting the need for an electronic medical record protocol that facilitates consistent tobacco use cessation pharmacotherapy treatment.

Implications: Tobacco use cessation pharmacotherapy is underutilized during hospitalization, and prescription rates vary greatly across medical specialties and patient characteristics. Hospitals may benefit from implementing policies and practices that standardize and automate the offer of smoking pharmacotherapy for all hospitalized patients who use tobacco.
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http://dx.doi.org/10.1093/ntr/nty031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468129PMC
April 2019

Epigenetic Effects of PTSD Remediation in Veterans Using Clinical Emotional Freedom Techniques: A Randomized Controlled Pilot Study.

Am J Health Promot 2018 Jan 12;32(1):112-122. Epub 2016 Aug 12.

5 Western Kentucky University, Bowling Green, KY, USA.

Purpose: To assess the feasibility of measuring changes in gene expression associated with post-traumatic stress disorder (PTSD) treatment using emotional freedom techniques (EFT).

Design: Participants were randomized into an EFT group receiving EFT and treatment as usual (TAU) throughout a 10-week intervention period and a group receiving only TAU during the intervention period and then receiving EFT.

Setting: A community clinic and a research institute in California.

Participants: Sixteen veterans with clinical levels of PTSD symptoms.

Intervention: Ten hour-long sessions of EFT.

Measures: Messenger RNA levels for a focused panel of 93 genes related to PTSD. The Symptom Assessment 45 questionnaire, Hospital Anxiety and Depression Scale, Insomnia Severity Scale, SF-12v2 for physical impairments, and Rivermead Postconcussion Symptoms Questionnaire.

Analysis: Pre-, posttreatment, and follow-up mean scores on questionnaires were assessed using repeated measures 1-way analysis of variance. A Student t test and post hoc analyses were performed on gene expression data.

Results: Post-traumatic stress disorder symptoms declined significantly in the EFT group (-53%, P < .0001). Participants maintained their gains on follow-up. Significant differential expression of 6 genes was found ( P < .05) when comparing the expression levels before and after the intervention period in participants receiving EFT.

Conclusion: Study results identify candidate gene expression correlates of successful PTSD treatment, providing guidelines for the design of further studies aimed at exploring the epigenetic effects of EFT.
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http://dx.doi.org/10.1177/0890117116661154DOI Listing
January 2018

Beyond cigarettes per day. A genome-wide association study of the biomarker carbon monoxide.

Ann Am Thorac Soc 2014 Sep;11(7):1003-10

1 Department of Psychiatry, and.

Rationale: The CHRNA5-CHRNA3-CHRNB4 locus is associated with self-reported smoking behavior and also harbors the strongest genetic associations with chronic obstructive pulmonary disease (COPD) and lung cancer. Because the associations with lung disease remain after adjustment for self-reported smoking behaviors, it has been asserted that CHRNA5-CHRNA3-CHRNB4 variants increase COPD and lung cancer susceptibility independently of their effects on smoking.

Objectives: To compare the genetic associations of exhaled carbon monoxide (CO), a biomarker of current cigarette exposure, with self-reported smoking behaviors.

Methods: A total of 1,521 European American and 247 African American current smokers recruited into smoking cessation studies were assessed for CO at intake before smoking cessation. DNA samples were genotyped using the Illumina Omni2.5 microarray. Genetic associations with CO and smoking behaviors (cigarettes smoked per day, Fagerstrom test for nicotine dependence) were studied.

Measurements And Main Results: Variants in the CHRNA5-CHRNA3-CHRNB4 locus, including rs16969968, a nonsynonymous variant in CHRNA5, are genomewide association study-significantly associated with CO (β = 2.66; 95% confidence interval [CI], 1.74-3.58; P = 1.65 × 10(-8)), and this association remains strong after adjusting for smoking behavior (β = 2.18; 95% CI, 1.32-3.04; P = 7.47 × 10(-7)). The correlation between CO and cigarettes per day is statistically significantly lower (z = 3.43; P = 6.07 × 10(-4)) in African Americans (r = 0.14; 95% CI, 0.02-0.26; P = 0.003) than in European-Americans (r = 0.36; 95% CI, 0.31-0.40; P = 0.0001).

Conclusions: Exhaled CO, a biomarker that is simple to measure, captures aspects of cigarette smoke exposure in current smokers beyond the number of cigarettes smoked per day. Behavioral measures of smoking are therefore insufficient indices of cigarette smoke exposure, suggesting that genetic associations with COPD or lung cancer that persist after adjusting for self-reported smoking behavior may still reflect genetic effects on smoking exposure.
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http://dx.doi.org/10.1513/AnnalsATS.201401-010OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214060PMC
September 2014

A genome-wide association study of DSM-IV cannabis dependence.

Addict Biol 2011 Jul 4;16(3):514-8. Epub 2010 Nov 4.

Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid, Saint Louis, MO 63110, USA.

Despite twin studies showing that 50-70% of variation in DSM-IV cannabis dependence is attributable to heritable influences, little is known of specific genotypes that influence vulnerability to cannabis dependence. We conducted a genome-wide association study of DSM-IV cannabis dependence. Association analyses of 708 DSM-IV cannabis-dependent cases with 2346 cannabis-exposed non-dependent controls was conducted using logistic regression in PLINK. None of the 948 142 single nucleotide polymorphisms met genome-wide significance (P at E-8). The lowest P values were obtained for polymorphisms on chromosome 17 (rs1019238 and rs1431318, P values at E-7) in the ANKFN1 gene. While replication is required, this study represents an important first step toward clarifying the biological underpinnings of cannabis dependence.
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http://dx.doi.org/10.1111/j.1369-1600.2010.00255.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117436PMC
July 2011

Interplay of Genetic Risk Factors and Parent Monitoring in Risk for Nicotine Dependence.

Addiction 2009 Oct;104(10):1731-1740

Department of Psychiatry, Washington University, St. Louis, Missouri.

BACKGROUND: Several studies have found replicable associations between nicotine dependence and specific variants in the nicotinic receptor genes CHRNA5(rs16969968) and CHRNA3(rs3743078). How these newly identified genetic risks combine with known environmental risks is unknown. This study examined whether the level of parent monitoring during early adolescence modified the risk of nicotine dependence associated with these genetic variants. METHODS: In a cross-sectional case control study of US-based community sample of 2027 subjects, we use a systematic series of regression models to examine the effect of parent monitoring on risk associated with two distinct variants in the nicotinic receptor genes CHRNA5(rs16969968) and CHRNA3(rs3743078). RESULTS: Low parent monitoring as well as the previously identified genetic variants were associated with an increased risk of nicotine dependence. An interaction was found between the SNP(rs16969968) and parent monitoring (p=0.034). The risk for nicotine dependence increased significantly with the risk genotype of SNP(rs16969968) when combined with lowest quartile parent monitoring. In contrast, there was no evidence of an interaction between SNP(rs3743078) and parent monitoring (p=0.80). CONCLUSIONS: The genetic risk of nicotine dependent associated with rs16969968 was modified by level of parent monitoring, while the genetic risk associated with rs3743078 was not, suggesting that the increased risk due to some genes may be mitigated by environmental factors such as parent monitoring.
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http://dx.doi.org/10.1111/j.1360-0443.2009.02697.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943646PMC
October 2009

Effects of child maltreatment and inherited liability on antisocial development: an official records study.

J Am Acad Child Adolesc Psychiatry 2010 Apr;49(4):321-32; quiz 431

George Warren Brown School of Social Work, Washington University, Saint Louis, MO, USA.

Objective: Evidence is steadily accumulating that a preventable environmental hazard, child maltreatment, exerts causal influences on the development of long-standing patterns of antisocial behavior in humans. The relationship between child maltreatment and antisocial outcome, however, has never previously been tested in a large-scale study in which official reports (rather than family member reports) of child abuse and neglect were incorporated, and genetic influences comprehensively controlled for.

Method: We cross-referenced official report data on child maltreatment from the Missouri Division of Social Services (DSS) with behavioral data from 4,432 epidemiologically ascertained Missouri twins from the Missouri Twin Registry (MOTWIN). We performed a similar procedure for a clinically ascertained sample of singleton children ascertained from families affected by alcohol dependence participating in the Collaborative Study on the Genetics of Alcoholism (COGA; n = 428) to determine whether associations observed in the general population held true in an "enriched" sample at combined inherited and environmental risk for antisocial development.

Results: For both the twin and clinical samples, the additive effects (not interactive effects) of maltreatment and inherited liability on antisocial development were confirmed and were highly statistically significant.

Conclusions: Child maltreatment exhibited causal influence on antisocial outcome when controlling for inherited liability in both the general population and in a clinically ascertained sample. Official report maltreatment data represents a critical resource for resolving competing hypotheses on genetic and environmental causation of child psychopathology, and for assessing intervention outcomes in efforts to prevent antisocial development.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878182PMC
April 2010

A genome-wide association study of alcohol dependence.

Proc Natl Acad Sci U S A 2010 Mar 2;107(11):5082-7. Epub 2010 Mar 2.

Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.

Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10(-5), but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor alpha2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.
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http://dx.doi.org/10.1073/pnas.0911109107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841942PMC
March 2010

Pandemic influenza planning by videoconference.

J Telemed Telecare 2009 ;15(7):368-72

Department of Epidemiology and Health Services, School of Public Health, University of Washington, Seattle, Washington 98195, USA.

Collaboration between nations and sectors is crucial to improve regional preparedness against pandemic influenza. In 2008, a Virtual Symposium was organized in the Asia-Pacific region by the Asia-Pacific Economic Cooperation Emerging Infections Network (APEC EINet) to discuss pandemic preparedness. The multipoint videoconference lasted approximately 4.5 hours and was attended by 16 APEC members who shared best practices in public-private partnerships for pandemic influenza preparedness planning. Twelve of the 16 APEC members who participated responded to a post-event survey. The overall experience of the event was rated highly. Partnering public health, technology and business communities to discuss best practices in preparedness using videoconferencing may be an effective way to improve regional preparedness. Utilization of videoconferencing on a routine basis should be considered to improve preparedness among APEC members and enhance its usability during a pandemic.
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http://dx.doi.org/10.1258/jtt.2009.090311DOI Listing
March 2010

The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans.

Cancer Res 2009 Sep 25;69(17):6848-56. Epub 2009 Aug 25.

Department of Genetics, Washington University, St. Louis, Missouri 63110, UA.

Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample (N = 710) and in a European-American sample (N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [P = 4.49 x 10(-8); odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25-1.61] as well as in African-Americans only (P = 0.015; OR, 2.04; 1.15-3.62) and in European-Americans only (P = 4.14 x 10(-7); OR, 1.40; 1.23-1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency
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http://dx.doi.org/10.1158/0008-5472.CAN-09-0786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874321PMC
September 2009

Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5.

Hum Mol Genet 2009 Aug 14;18(16):3125-35. Epub 2009 May 14.

Department of Psychiatry, Washington University, 660 South Euclid, PO Box 8134, St Louis, MO 63110, USA.

Nicotine dependence risk and lung cancer risk are associated with variants in a region of chromosome 15 encompassing genes encoding the nicotinic receptor subunits CHRNA5, CHRNA3 and CHRNB4. To identify potential biological mechanisms that underlie this risk, we tested for cis-acting eQTLs for CHRNA5, CHRNA3 and CHRNB4 in human brain. Using gene expression and disease association studies, we provide evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. We demonstrated that the risk allele of rs16969968 primarily occurs on the low mRNA expression allele of CHRNA5. The non-risk allele at rs16969968 occurs on both high and low expression alleles tagged by rs588765 within CHRNA5. When the non-risk allele occurs on the background of low mRNA expression of CHRNA5, the risk for nicotine dependence and lung cancer is significantly lower compared to those with the higher mRNA expression. Together, these variants identify three levels of risk associated with CHRNA5. We conclude that there are at least two distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by a D398N amino acid variant in CHRNA5 (rs16969968) and variability in CHRNA5 mRNA expression.
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http://dx.doi.org/10.1093/hmg/ddp231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714722PMC
August 2009
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