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1. Client experiences with “Dynamic Choice Prevention,” a model for flexible patient‐centred HIV prevention delivery in rural Eastern Africa

Author

Camlin, Carol S, Arunga, Titus, Johnson‐Peretz, Jason, Akatukwasa, Cecilia, Atwine, Fredrick, Onyango, Angeline, Owino, Lawrence, Kamya, Moses R, Petersen, Maya L, Chamie, Gabriel, Kakande, Elijah, Kabami, Jane, Balzer, Laura B, Havlir, Diane V, and Ayieko, James

Subjects
Biomedical and Clinical Sciences, Health Services and Systems, Public Health, Clinical Sciences, Health Sciences, Mental Health, Infectious Diseases, Sexually Transmitted Infections, Clinical Research, HIV/AIDS, Prevention, Women's Health, Health Disparities, Behavioral and Social Science, 7.1 Individual care needs, 8.1 Organisation and delivery of services, Generic health relevance, Infection, Good Health and Well Being, Humans, HIV Infections, Female, Male, Adult, Rural Population, Pre-Exposure Prophylaxis, Qualitative Research, Interviews as Topic, Africa, Eastern, Young Adult, Patient-Centered Care, Middle Aged, Anti-HIV Agents, pre-exposure prophylaxis, post-exposure prophylaxis, HIV self-testing, differentiated care, HIV stigma, sub-Saharan Africa, HIV self‐testing, post‐exposure prophylaxis, pre‐exposure prophylaxis, sub‐Saharan Africa, Public Health and Health Services, Other Medical and Health Sciences, Clinical sciences, Epidemiology, Public health
Abstract

IntroductionIdentifying the optimal approaches to offering HIV prevention to meet the needs of those at risk is a high priority, particularly given the expanding toolkit of biomedical HIV prevention options. An ongoing study in rural East African communities evaluated the uptake of choices in product, testing mode and location of care delivery through a structured patient-centred HIV prevention delivery model. In this qualitative study, we sought to understand clients' experiences of this "dynamic choice prevention model" (DCP) and highlight pathways of action to inform HIV prevention delivery models.MethodsIn-depth semi-structured interviews were conducted from November 2021 through March 2022 with a purposively selected sample of n = 56 participants in DCP trials (across outpatient departments, antenatal clinics and community settings), and n = 21 healthcare providers (total n = 77). A seven-person multi-regional team translated and inductively coded transcript data. We used a framework analysis approach to identify emergent themes.ResultsIndividuals taking up HIV pre-exposure prophylaxis (PrEP) reported feelings of relief, liberation from fears of acquiring HIV and satisfaction with being able to take action despite partners' behaviours. Couples used a range of approaches afforded by the study to persuade partners to get tested and opt for PrEP. Post-exposure prophylaxis (PEP) use was less common, although women welcomed it in the event of sexual coercion or assault. Participants discussed switching from PEP to PrEP after familiarizing themselves with usage and ascertaining ongoing risk. Participants felt respected by providers, trusted them and appreciated being able to contact them directly for telephone support. Prevention uptake was hindered by stigma, limited experience with and knowledge of prevention methods, gendered and generational power dynamics within intimate partnerships and families, and negative perceptions of methods due to the products themselves. Participants anticipated long-acting injectable PrEP could solve their challenges regarding pill size, daily pill burden and the likelihood of unwanted disclosure.ConclusionsDiverse preferences and barriers to uptake of prevention require a choice of HIV prevention options, locations and delivery modalities-but in addition, flexible, competent and friendly care provision is crucial to promote uptake. Helping clients feel valued, and addressing their unique needs and challenges, enables their agency to prioritize their health.

Published
2024

2. Correlates of supportive care needs among Asian Americans with colorectal, liver, or lung cancer from a web‐based patient navigation portal intervention: The Patient COUNTS study

Author

Wang, Katarina, Chu, Janet N, Oh, Debora L, Shariff‐Marco, Salma, Allen, Laura, Kuo, Mei‐Chin, Wong, Ching, Bui, Hoan, Chen, Junlin, Li, Feng Ming, Ma, Carmen, Truong, Angeline, Gomez, Scarlett L, Nguyen, Tung T, and Tsoh, Janice Y

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Rehabilitation, Aging, Digestive Diseases, Behavioral and Social Science, Colo-Rectal Cancer, Cancer, Management of diseases and conditions, 7.1 Individual care needs, Good Health and Well Being, Adult, Female, Humans, Male, Middle Aged, Asian, Colorectal Neoplasms, Internet, Lung Neoplasms, Patient Navigation, Quality of Life, Liver Neoplasms, Patient Portals, Asian American, cancer, cultural competence, cultural humility, multilingual, patient navigation, supportive care needs, Oncology and carcinogenesis
Abstract

BackgroundCancer is the leading cause of death among Asian Americans, who often face barriers to cancer care. Cancer supportive care needs among Asian Americans remain understudied.AimsWe examined cancer supportive care needs and participant factors correlated with these needs, identified profiles of supportive care needs, and examined whether needs profiles are associated with quality of life among Asian American adults.Methods and resultsWe recruited 47 Asian American adults with colorectal, liver, or lung cancer who spoke Chinese, English, or Vietnamese, and were starting or undergoing cancer treatment. We assessed cancer supportive care needs in four domains: cancer information, daily living, behavioral health, and language assistance. Hierarchical cluster analysis was used to identify clusters of participants based on their supportive need profiles to further examine the association between need profiles and quality of life (QoL) assessed by the Functional Assessment of Cancer Therapy. Participants (mean age = 57.6) included 72% males and 62% spoke English less than very well. Older participants (age ≥ 65) and those with annual income

Published
2024

3. Matched Analysis of Detailed Peripheral Blood and Tumor Immune Microenvironment Profiles in Bladder Cancer

Author

Chen, Ji-Qing, Salas, Lucas A, Wiencke, John K, Koestler, Devin C, Molinaro, Annette M, Andrew, Angeline S, Seigne, John D, Karagas, Margaret R, Kelsey, Karl T, and Christensen, Brock C

Subjects
Biological Sciences, Genetics, Urologic Diseases, Clinical Research, Cancer, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Humans, Tumor Microenvironment, Urinary Bladder Neoplasms, Cluster Analysis, DNA Methylation, Protein Processing, Post-Translational, Prognosis, bladder cancer, circulating immune profiles, DNA methylation, immune profiles, methylation cytometry, tumor microenvironment, Clinical Sciences
Abstract

Background: Bladder cancer and therapy responses hinge on immune profiles in the tumor microenvironment (TME) and blood, yet studies linking tumor-infiltrating immune cells to peripheral immune profiles are limited. Methods: DNA methylation cytometry quantified TME and matched peripheral blood immune cell proportions. With tumor immune profile data as the input, subjects were grouped by immune infiltration status and consensus clustering. Results: Immune hot and cold groups had different immune compositions in the TME but not in circulating blood. Two clusters of patients identified with consensus clustering had different immune compositions not only in the TME but also in blood. Conclusion: Detailed immune profiling via methylation cytometry reveals the significance of understanding tumor and systemic immune relationships in cancer patients.

Published
2024

4. Genome-scale methylation analysis identifies immune profiles and age acceleration associations with bladder cancer outcomes

Author

Chen, Ji-Qing, Salas, Lucas A, Wiencke, John K, Koestler, Devin C, Molinaro, Annette M, Andrew, Angeline S, Seigne, John D, Karagas, Margaret R, Kelsey, Karl T, and Christensen, Brock C

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Urologic Diseases, Prevention, Clinical Research, Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Humans, Neoplasm Recurrence, Local, Urinary Bladder Neoplasms, DNA Methylation, Lymphocytes, Proportional Hazards Models, Prognosis, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundImmune profiles have been associated with bladder cancer outcomes and may have clinical applications for prognosis. However, associations of detailed immune cell subtypes with patient outcomes remain underexplored and may contribute crucial prognostic information for better managing bladder cancer recurrence and survival.MethodsBladder cancer case peripheral blood DNA methylation was measured using the Illumina HumanMethylationEPIC array. Extended cell-type deconvolution quantified 12 immune cell-type proportions, including memory, naïve T and B cells, and granulocyte subtypes. DNA methylation clocks determined biological age. Cox proportional hazards models tested associations of immune cell profiles and age acceleration with bladder cancer outcomes. The partDSA algorithm discriminated 10-year overall survival groups from clinical variables and immune cell profiles, and a semi-supervised recursively partitioned mixture model (SS-RPMM) with DNA methylation data was applied to identify a classifier for 10-year overall survival.ResultsHigher CD8T memory cell proportions were associated with better overall survival [HR = 0.95, 95% confidence interval (CI) = 0.93-0.98], while higher neutrophil-to-lymphocyte ratio (HR = 1.36, 95% CI = 1.23-1.50), CD8T naïve (HR = 1.21, 95% CI = 1.04-1.41), neutrophil (HR = 1.04, 95% CI = 1.03-1.06) proportions, and age acceleration (HR = 1.06, 95% CI = 1.03-1.08) were associated with worse overall survival in patient with bladder cancer. partDSA and SS-RPMM classified five groups of subjects with significant differences in overall survival.ConclusionsWe identified associations between immune cell subtypes and age acceleration with bladder cancer outcomes.ImpactThe findings of this study suggest that bladder cancer outcomes are associated with specific methylation-derived immune cell-type proportions and age acceleration, and these factors could be potential prognostic biomarkers.

Published
2023

5. Clinical Reasoning: A 67-Year-Old Man With Multiple Intracranial Lesions.

Author

Ngo, Angeline, McGehrin, Kevin, Di Loreto, Christina, Arora, Rajan, and Labuzetta, Jamie

Subjects
Humans, Male, Aged, Hemianopsia, Magnetic Resonance Imaging, Brain, Central Nervous System Protozoal Infections, Naegleria fowleri, Anti-Bacterial Agents, Treatment Outcome
Abstract

A wide variety of diseases present with intracranial lesions. In this case report, a 67-year-old man initially presented to an outside hospital with nausea, headache, and ataxia and was found to have multiple intracranial lesions. Diagnostic workup was ultimately unrevealing, and his condition improved after a course of steroids and antibiotics. Unfortunately, symptoms returned 3 months later. MRI of the brain revealed progression of his intracranial lesions. This case highlights a diagnostic approach and general management strategy for patients presenting with undifferentiated intracranial pathology. A final diagnosis is ultimately reached and raises further discussion.

Published
2023

6. Deriving Schwann cells from hPSCs enables disease modeling and drug discovery for diabetic peripheral neuropathy.

Author

Chemel, Angeline, Okoye, Mesomachukwu, Scantlen, Megan, Tchieu, Jason, Calder, Elizabeth, Le Rouzic, Valerie, Shibata, Bradley, Arab, Abolfazl, Goodarzi, Hani, Pasternak, Gavril, Kocsis, Jeffery, Chen, Shuibing, Studer, Lorenz, Fattahi, Faranak, Amin, Sadaf, Ghazizadeh, Zaniar, Arroyo, Edgardo, Lankford, Karen, Majd, Homa, Farahvashi, Sina, Cesiulis, Andrius, and Majd, Alireza

Subjects
demyelination, drug repurposing, metabolic stress, myelination disorders, nerve repair, Mice, Animals, Humans, Diabetic Neuropathies, Bupropion, Retrospective Studies, Sciatic Nerve, Schwann Cells, Drug Discovery, Diabetes Mellitus
Abstract

Schwann cells (SCs) are the primary glia of the peripheral nervous system. SCs are involved in many debilitating disorders, including diabetic peripheral neuropathy (DPN). Here, we present a strategy for deriving SCs from human pluripotent stem cells (hPSCs) that enables comprehensive studies of SC development, physiology, and disease. hPSC-derived SCs recapitulate the molecular features of primary SCs and are capable of in vitro and in vivo myelination. We established a model of DPN that revealed the selective vulnerability of SCs to high glucose. We performed a high-throughput screen and found that an antidepressant drug, bupropion, counteracts glucotoxicity in SCs. Treatment of hyperglycemic mice with bupropion prevents their sensory dysfunction, SC death, and myelin damage. Further, our retrospective analysis of health records revealed that bupropion treatment is associated with a lower incidence of neuropathy among diabetic patients. These results highlight the power of this approach for identifying therapeutic candidates for DPN.

Published
2023

7. EPIREGULIN creates a developmental niche for spatially organized human intestinal enteroids

Author

Childs, Charlie J, Holloway, Emily M, Sweet, Caden W, Tsai, Yu-Hwai, Wu, Angeline, Vallie, Abigail, Eiken, Madeline K, Capeling, Meghan M, Zwick, Rachel K, Palikuqi, Brisa, Trentesaux, Coralie, Wu, Joshua H, Pellon-Cardenas, Oscar, Zhang, Charles J, Glass, Ian A, Loebel, Claudia, Yu, Qianhui, Camp, J Gray, Sexton, Jonathan Z, Klein, Ophir D, Verzi, Michael P, and Spence, Jason R

Subjects
Biomedical and Clinical Sciences, Stem Cell Research, Regenerative Medicine, Digestive Diseases, Stem Cell Research - Embryonic - Human, Biotechnology, Clinical Research, Stem Cell Research - Nonembryonic - Human, Stem Cell Research - Nonembryonic - Non-Human, 1.1 Normal biological development and functioning, Underpinning research, Humans, Epidermal Growth Factor, Epiregulin, Intestines, Intestinal Mucosa, Cell Differentiation, Development, Human stem cells, Organogenesis, Stem cells, Biomedical and clinical sciences, Health sciences
Abstract

Epithelial organoids derived from intestinal tissue, called enteroids, recapitulate many aspects of the organ in vitro and can be used for biological discovery, personalized medicine, and drug development. Here, we interrogated the cell signaling environment within the developing human intestine to identify niche cues that may be important for epithelial development and homeostasis. We identified an EGF family member, EPIREGULIN (EREG), which is robustly expressed in the developing human crypt. Enteroids generated from the developing human intestine grown in standard culture conditions, which contain EGF, are dominated by stem and progenitor cells and feature little differentiation and no spatial organization. Our results demonstrate that EREG can replace EGF in vitro, and EREG leads to spatially resolved enteroids that feature budded and proliferative crypt domains and a differentiated villus-like central lumen. Multiomic (transcriptome plus epigenome) profiling of native crypts, EGF-grown enteroids, and EREG-grown enteroids showed that EGF enteroids have an altered chromatin landscape that is dependent on EGF concentration, downregulate the master intestinal transcription factor CDX2, and ectopically express stomach genes, a phenomenon that is reversible. This is in contrast to EREG-grown enteroids, which remain intestine like in culture. Thus, EREG creates a homeostatic intestinal niche in vitro, enabling interrogation of stem cell function, cellular differentiation, and disease modeling.

Published
2023

8. SMALL-GAUGE TECHNIQUES FOR REMOVING A FLUOCINOLONE ACETONIDE IMPLANT

Author

Knight, Darren K, Wang, Angeline L, Tsao, Sean W, Carter, Steven L, and Mehta, Mitul C

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Bioengineering, Eye Disease and Disorders of Vision, Humans, Fluocinolone Acetonide, Vitrectomy, Sclera, Device Removal, Opthalmology and Optometry, Ophthalmology and optometry
Abstract

PurposeLong-acting injectable fluocinolone releasing implants are used in clinical practice. Although limited in scope, situations may arise where removal of the implant is warranted. We set out to describe possible explantation techniques and to determine whether these implants can be safely removed from a standard sclerotomy or eliminated using a vitrectomy system.MethodsA vitreoretinal surgery system was designed using a porcine eye model. A fluocinolone implant was injected into the vitreous cavity. Pars plana vitrectomy was performed and the vitreous cavity was infused with balanced salt solution. The injected implants were removed from 23-Gauge (G) and 25-Gauge (G) vitrectomy cannulas with 27-G forceps. The implants were examined under the microscope for induced defects. Implants were injected into the eye model and eliminated using a 23-G and 25-G vitrector system.ResultsThe implant was removed from both the 23-G and 25-G vitrectomy cannulas with only mild structural damage to the implant. During implant extraction through the 25-G sclerotomy, the cannula was dislodged from the incision along with the implant. The most technically challenging portion involved aligning the implant coaxially to allow for removal en bloc through the sclerotomy site. Implants could be eliminated using both the 23-G and 25-G vitrector using a low-cut rate.ConclusionThe fluocinolone implant was removed safely via standard 23-G or 25-G vitrectomy systems. It is unknown whether intraocular manipulation will affect pharmacokinetics of drug delivery if the implant is not explanted.

Published
2023

9. Impaired belief updating and devaluation in adult women with bulimia nervosa

Author

Berner, Laura A, Fiore, Vincenzo G, Chen, Joanna Y, Krueger, Angeline, Kaye, Walter H, Viranda, Thalia, and de Wit, Sanne

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Mental Health, Behavioral and Social Science, Nutrition, Brain Disorders, Clinical Research, Eating Disorders, Adult, Female, Humans, Bulimia Nervosa, Bayes Theorem, Bulimia, Binge-Eating Disorder, Feeding and Eating Disorders, Clinical Sciences, Public Health and Health Services, Clinical sciences, Neurosciences, Biological psychology
Abstract

Recent models of bulimia nervosa (BN) propose that binge-purge episodes ultimately become automatic in response to cues and insensitive to negative outcomes. Here, we examined whether women with BN show alterations in instrumental learning and devaluation sensitivity using traditional and computational modeling analyses of behavioral data. Adult women with BN (n = 30) and group-matched healthy controls (n = 31) completed a task in which they first learned stimulus-response-outcome associations. Then, participants were required to repeatedly adjust their responses in a "baseline test", when different sets of stimuli were explicitly devalued, and in a "slips-of-action test", when outcomes instead of stimuli were devalued. The BN group showed intact behavioral sensitivity to outcome devaluation during the slips-of-action test, but showed difficulty overriding previously learned stimulus-response associations on the baseline test. Results from a Bayesian learner model indicated that this impaired performance could be accounted for by a slower pace of belief updating when a new set of previously learned responses had to be inhibited (p = 0.036). Worse performance and a slower belief update in the baseline test were each associated with more frequent binge eating (p = 0.012) and purging (p = 0.002). Our findings suggest that BN diagnosis and severity are associated with deficits in flexibly updating beliefs to withhold previously learned responses to cues. Additional research is needed to determine whether this impaired ability to adjust behavior is responsible for maintaining automatic and persistent binge eating and purging in response to internal and environmental cues.

Published
2023

10. Immune profiles and DNA methylation alterations related with non-muscle-invasive bladder cancer outcomes

Author

Chen, Ji-Qing, Salas, Lucas A, Wiencke, John K, Koestler, Devin C, Molinaro, Annette M, Andrew, Angeline S, Seigne, John D, Karagas, Margaret R, Kelsey, Karl T, and Christensen, Brock C

Subjects
Biological Sciences, Genetics, Clinical Research, Cancer, Urologic Diseases, Aged, Biomarkers, Tumor, Cohort Studies, DNA Methylation, Female, Humans, Male, Middle Aged, Outcome Assessment, Health Care, Proportional Hazards Models, Urinary Bladder Neoplasms, DNA methylation, Non-muscle-invasive bladder cancer, Immune profile, Immunomethylomic, Recurrence, Survival, Clinical Sciences, Paediatrics and Reproductive Medicine
Abstract

BackgroundNon-muscle-invasive bladder cancer (NMIBC) patients receive frequent monitoring because ≥ 70% will have recurrent disease. However, screening is invasive, expensive, and associated with significant morbidity making bladder cancer the most expensive cancer to treat per capita. There is an urgent need to expand the understanding of markers related to recurrence and survival outcomes of NMIBC.Methods and resultsWe used the Illumina HumanMethylationEPIC array to measure peripheral blood DNA methylation profiles of NMIBC patients (N = 603) enrolled in a population-based cohort study in New Hampshire and applied cell type deconvolution to estimate immune cell-type proportions. Using Cox proportional hazard models, we identified that increasing CD4T and CD8T cell proportions were associated with a statistically significant decreased hazard of tumor recurrence or death (CD4T: HR = 0.98, 95% CI = 0.97-1.00; CD8T: HR = 0.97, 95% CI = 0.95-1.00), whereas increasing monocyte proportion and methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) were associated with the increased hazard of tumor recurrence or death (monocyte: HR = 1.04, 95% CI = 1.00-1.07; mdNLR: HR = 1.12, 95% CI = 1.04-1.20). Then, using an epigenome-wide association study (EWAS) approach adjusting for age, sex, smoking status, BCG treatment status, and immune cell profiles, we identified 2528 CpGs associated with the hazard of tumor recurrence or death (P

Published
2022

11. Patient-reported supportive care needs among Asian American cancer patients

Author

Wang, Katarina, Ma, Carmen, Li, Feng Ming, Truong, Angeline, Shariff-Marco, Salma, Chu, Janet N, Oh, Debora L, Allen, Laura, Kuo, Mei-Chin, Wong, Ching, Bui, Hoan, Chen, Junlin, Gomez, Scarlett L, Nguyen, Tung T, and Tsoh, Janice Y

Subjects
Health Services and Systems, Nursing, Health Sciences, Aging, Clinical Research, Digestive Diseases, Cancer, Colo-Rectal Cancer, Good Health and Well Being, Humans, Young Adult, Adult, Asian, Pilot Projects, Health Services Accessibility, Lung Neoplasms, Patient Reported Outcome Measures, Asian American, Patient navigation, Multilingual, Cultural humility, Cultural competence, Supportive care needs, Medical and Health Sciences, Psychology and Cognitive Sciences, Oncology & Carcinogenesis, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

PurposeCancer is the leading cause of death for Asian Americans. However, few studies have documented supportive care needs from the perspective of Asian American cancer patients. This study describes the needs reported by Asian American patients with colorectal, liver, or lung cancer over a 6-month period during their treatment.MethodsParticipants were recruited through the Greater Bay Area Cancer Registry and from cancer care providers in San Francisco. Participants self-identified as Asian or Asian American; were age 21 or older; spoke English, Chinese, or Vietnamese; and had stage I-III colon, rectum, liver, or lung cancer. Participants were matched with a language concordant patient navigator who provided support during a 6-month period. Needs were assessed by surveys at baseline, 3, and 6 months.ResultsAmong 24 participants, 58% were 65 years or older, 42% did not complete high school, and 75% had limited English proficiency (LEP). At baseline, the most prevalent needs were cancer information (79%), nutrition and physical activity (67%), language assistance (54%), and daily living (50%). At the 3- and 6-month follow-up surveys, there was a higher reported need for mental health resources and healthcare access among participants.ConclusionIn this pilot study of Asian American cancer patients who predominantly had LEP, participants reported many needs, with cancer information and language assistance as the most prominent. The findings highlight the importance of culturally and linguistically appropriate patient navigators in addressing supportive care needs among cancer patients with LEP.Trial registrationClinicalTrials.gov identifier: NCT03867916.

Published
2022

12. Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer.

Author

Byun, Jinyoung, Han, Younghun, Li, Yafang, Xia, Jun, Long, Erping, Choi, Jiyeon, Xiao, Xiangjun, Zhu, Meng, Zhou, Wen, Sun, Ryan, Bossé, Yohan, Song, Zhuoyi, Schwartz, Ann, Lusk, Christine, Rafnar, Thorunn, Stefansson, Kari, Zhang, Tongwu, Zhao, Wei, Pettit, Rowland W, Liu, Yanhong, Li, Xihao, Zhou, Hufeng, Walsh, Kyle M, Gorlov, Ivan, Gorlova, Olga, Zhu, Dakai, Rosenberg, Susan M, Pinney, Susan, Bailey-Wilson, Joan E, Mandal, Diptasri, de Andrade, Mariza, Gaba, Colette, Willey, James C, You, Ming, Anderson, Marshall, Wiencke, John K, Albanes, Demetrius, Lam, Stephan, Tardon, Adonina, Chen, Chu, Goodman, Gary, Bojeson, Stig, Brenner, Hermann, Landi, Maria Teresa, Chanock, Stephen J, Johansson, Mattias, Muley, Thomas, Risch, Angela, Wichmann, H-Erich, Bickeböller, Heike, Christiani, David C, Rennert, Gad, Arnold, Susanne, Field, John K, Shete, Sanjay, Le Marchand, Loic, Melander, Olle, Brunnstrom, Hans, Liu, Geoffrey, Andrew, Angeline S, Kiemeney, Lambertus A, Shen, Hongbing, Zienolddiny, Shanbeh, Grankvist, Kjell, Johansson, Mikael, Caporaso, Neil, Cox, Angela, Hong, Yun-Chul, Yuan, Jian-Min, Lazarus, Philip, Schabath, Matthew B, Aldrich, Melinda C, Patel, Alpa, Lan, Qing, Rothman, Nathaniel, Taylor, Fiona, Kachuri, Linda, Witte, John S, Sakoda, Lori C, Spitz, Margaret, Brennan, Paul, Lin, Xihong, McKay, James, Hung, Rayjean J, and Amos, Christopher I

Subjects
Humans, Lung Neoplasms, Genetic Predisposition to Disease, RNA-Binding Proteins, DNA-Binding Proteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Human Genome, Cancer, Genetics, Lung, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

Published
2022

13. Assessment and Counseling Gaps Among Former Smokers Eligible for Lung Cancer Screening in US Adults

Author

Hood-Medland, Eve Angeline, Dove, Melanie S, and Tong, Elisa K

Subjects
Biomedical and Clinical Sciences, Public Health, Health Sciences, Tobacco Smoke and Health, Prevention, Lung, Substance Misuse, Tobacco, Cancer, Behavioral and Social Science, Lung Cancer, Women's Health, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, Respiratory, Good Health and Well Being, Adult, Cotinine, Counseling, Cross-Sectional Studies, Early Detection of Cancer, Electronic Nicotine Delivery Systems, Humans, Lung Neoplasms, Nutrition Surveys, Smokers, tobacco, preventative medicine, lung cancer screening, Clinical Sciences, General & Internal Medicine, Clinical sciences, Health services and systems, Public health
Abstract

BackgroundLung cancer screening (LCS) for former and current smokers requires that current smokers are counseled on tobacco treatment. In the USA, over 4 million former smokers are estimated to be eligible for LCS based on self-report for "not smoking now." Tobacco use and exposure can be measured with the biomarker cotinine, a nicotine metabolite reflecting recent exposure.ObjectiveTo examine predictors of tobacco use and exposure among self-reported former smokers eligible for LCS.DesignCross-sectional study using the 2013-2018 National Health and Nutrition Examination Survey.ParticipantsFormer smokers eligible for LCS (n = 472).Main measuresRecent tobacco use was defined as reported tobacco use in the past 5 days or a cotinine level above the race/ethnic cut points for tobacco use. Recent tobacco exposure was measured among former smokers without recent tobacco use and defined as having a cotinine level above 0.05 ng/mL.Key resultsOne in five former smokers eligible for LCS, totaling 1,416,485 adults, had recent tobacco use (21.4%, 95% confidence interval (CI) 15.8%, 27.0%), with about a third each using cigarettes, e-cigarettes, or other tobacco products. Among former smokers without recent tobacco use, over half (53.0%, 95% CI: 44.6%, 61.4%) had cotinine levels indicating recent tobacco exposure. Certain subgroups had higher percentages for tobacco use or exposure, especially those having quit within the past 3 years or living with a household smoker.ConclusionsFormer smokers eligible for LCS should be asked about recent tobacco use and exposure and considered for cotinine testing. Nearly 1.5 million "former smokers" eligible for LCS may be current tobacco users who have been missed for counseling. The high percentage of "passive smokers" is at least double that of the general nonsmoking population. Counseling about the harms of tobacco use and exposure and resources is needed.

Published
2022

14. Evaluating the use of lamotrigine to reduce mood lability and impulsive behaviors in adults with chronic and severe eating disorders

Author

Reilly, Erin E, Berner, Laura A, Trunko, Mary Ellen, Schwartz, Terry, Anderson, Leslie K, Krueger, Angeline, Yu, Xinze, Chen, Joanna Y, Cusack, Anne, Nakamura, Tiffany, and Kaye, Walter H

Subjects
Clinical and Health Psychology, Social and Personality Psychology, Psychology, Mind and Body, Behavioral and Social Science, Brain Disorders, Basic Behavioral and Social Science, Mental Health, Depression, Clinical Research, Mental health, Adult, Affective Symptoms, Borderline Personality Disorder, Feeding and Eating Disorders, Female, Humans, Impulsive Behavior, Lamotrigine, Bulimia nervosa, Anorexia nervosa, Emotion dysregulation, Impulsivity, Clinical Sciences, Clinical Psychology, Clinical sciences, Nutrition and dietetics, Clinical and health psychology
Abstract

BackgroundGold-standard psychological and pharmacological treatments for bulimic-spectrum eating disorders only result in remission for around 50% of patients; patients with affective lability and impulsivity represent a subgroup with particularly poor outcomes. Both dialectical behavior therapy (DBT), a treatment for emotion dysregulation, and lamotrigine, a mood stabilizer, have demonstrated promise for targeting affective lability and impulsivity; however, data exploring the combination of these interventions remain limited.ObjectiveWe followed a group of women with recurrent dysregulated eating behaviors (N = 62) throughout intensive DBT treatment and compared the symptom trajectory of those prescribed lamotrigine (n = 28) and those who were not (n = 34).MethodParticipants completed surveys every 2 weeks throughout treatment.ResultsGroup analyses suggested that all participants self-reported decreases in emotional reactivity, negative urgency, and symptoms of borderline personality disorder (BPD). The lamotrigine group reported greater elevations in BPD symptoms at baseline, but demonstrated steeper decreases in emotion and behavioral dysregulation than the non-matched comparison group. Within-subject analyses suggested that within the lamotrigine group, subjects reported greater decreases in symptoms following prescription of lamotrigine.ConclusionsFindings provide initial data suggesting that lamotrigine could be useful as an adjunctive treatment for patients with affective lability and impulsivity.Level of evidenceIV, time series without randomization.

Published
2022

15. Changes in cognitive and behavioral control after lamotrigine and intensive dialectical behavioral therapy for severe, multi-impulsive bulimia nervosa: an fMRI case study

Author

Berner, Laura A, Reilly, Erin E, Yu, Xinze, Krueger, Angeline, Trunko, Mary Ellen, Anderson, Leslie K, Chen, Joanna, Simmons, Alan N, and Kaye, Walter H

Subjects
Biological Psychology, Psychology, Clinical Trials and Supportive Activities, Brain Disorders, Neurosciences, Mind and Body, Mental Health, Behavioral and Social Science, Biomedical Imaging, Clinical Research, Nutrition, Eating Disorders, Adult, Behavior Control, Behavior Therapy, Bulimia Nervosa, Cognition, Female, Humans, Impulsive Behavior, Lamotrigine, Magnetic Resonance Imaging, Binge eating, Purging, Bulimia nervosa, Cognitive control, Dialectical behavior therapy, Clinical Sciences, Clinical Psychology, Clinical sciences, Nutrition and dietetics, Clinical and health psychology
Abstract

PurposeAdults with bulimia nervosa (BN) and co-occurring emotional dysregulation and multiple impulsive behaviors are less responsive to existing interventions. Initial data suggest that the combination of Dialectical Behavior Therapy (DBT) and a mood stabilizer, lamotrigine, significantly reduces symptoms of affective and behavioral dysregulation in these patients. Identifying candidate neurobiological mechanisms of change for this novel treatment combination may help guide future randomized controlled trials and inform new and targeted treatment development. Here, we examined neurocognitive and symptom changes in a female patient with BN and severe affective and behavioral dysregulation who received DBT and lamotrigine.MethodsGo/no-go task performance data and resting-state functional MRI scans were acquired before the initiation of lamotrigine (after 6 weeks in an intensive DBT program), and again after reaching and maintaining a stable dose of lamotrigine. The patient completed a battery of symptom measures biweekly for 18 weeks over the course of treatment.ResultsAfter lamotrigine initiation, the patient made fewer errors on a response inhibition task and showed increased and new connectivity within frontoparietal and frontolimbic networks involved in behavioral and affective control. Accompanying this symptom improvement, the patient reported marked reductions in bulimic symptoms, behavioral dysregulation, and reactivity to negative affect, along with increases in DBT skills use.ConclusionImproved response inhibition and cognitive control network connectivity should be further investigated as neurocognitive mechanisms of change with combined DBT and lamotrigine for eating disorders. Longitudinal, controlled trials integrating neuroimaging and symptom measures are needed to fully evaluate the effects of this treatment.Level of evidenceIV: Evidence obtained from multiple time series with or without the intervention, such as case studies.

Published
2022

16. Accounting for EGFR mutations in epidemiological analyses of non-small cell lung cancers: Examples based on the International Lung Cancer Consortium data

Author

Schmid, Sabine, Jiang, Mei, Brown, M Catherine, Fares, Aline, Garcia, Miguel, Soriano, Joelle, Dong, Mei, Thomas, Sera, Kohno, Takashi, Leal, Leticia Ferro, Diao, Nancy, Xie, Juntao, Wang, Zhichao, Zaridze, David, Holcatova, Ivana, Lissowska, Jolanta, Świątkowska, Beata, Mates, Dana, Savic, Milan, Wenzlaff, Angela S, Harris, Curtis C, Caporaso, Neil E, Ma, Hongxia, Fernandez-Tardon, Guillermo, Barnett, Matthew J, Goodman, Gary, Davies, Michael PA, Pérez-Ríos, Mónica, Taylor, Fiona, Duell, Eric J, Schoettker, Ben, Brenner, Hermann, Andrew, Angeline, Cox, Angela, Ruano-Ravina, Alberto, Field, John K, Marchand, Loic Le, Wang, Ying, Chen, Chu, Tardon, Adonina, Shete, Sanjay, Schabath, Matthew B, Shen, Hongbing, Landi, Maria Teresa, Ryan, Brid M, Schwartz, Ann G, Qi, Lihong, Sakoda, Lori C, Brennan, Paul, Yang, Ping, Zhang, Jie, Christiani, David C, Reis, Rui Manuel, Shiraishi, Kouya, Hung, Rayjean J, Xu, Wei, and Liu, Geoffrey

Subjects
Lung, Lung Cancer, Cancer, Prevention, Carcinoma, Non-Small-Cell Lung, ErbB Receptors, Humans, Lung Neoplasms, Mutation, Survival Analysis, Medical and Health Sciences, Epidemiology
Abstract

BackgroundSomatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches.MethodsThrough analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status.ResultsOf 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74-0.77) in the training and 0.77 (95% CI, 0.74-0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients.ConclusionsWe introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC.ImpactThe proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

Published
2022

17. Comparative cellular analysis of motor cortex in human, marmoset and mouse

Author

Bakken, Trygve E, Jorstad, Nikolas L, Hu, Qiwen, Lake, Blue B, Tian, Wei, Kalmbach, Brian E, Crow, Megan, Hodge, Rebecca D, Krienen, Fenna M, Sorensen, Staci A, Eggermont, Jeroen, Yao, Zizhen, Aevermann, Brian D, Aldridge, Andrew I, Bartlett, Anna, Bertagnolli, Darren, Casper, Tamara, Castanon, Rosa G, Crichton, Kirsten, Daigle, Tanya L, Dalley, Rachel, Dee, Nick, Dembrow, Nikolai, Diep, Dinh, Ding, Song-Lin, Dong, Weixiu, Fang, Rongxin, Fischer, Stephan, Goldman, Melissa, Goldy, Jeff, Graybuck, Lucas T, Herb, Brian R, Hou, Xiaomeng, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, van Lew, Baldur, Li, Yang Eric, Liu, Christine S, Liu, Hanqing, Lucero, Jacinta D, Mahurkar, Anup, McMillen, Delissa, Miller, Jeremy A, Moussa, Marmar, Nery, Joseph R, Nicovich, Philip R, Niu, Sheng-Yong, Orvis, Joshua, Osteen, Julia K, Owen, Scott, Palmer, Carter R, Pham, Thanh, Plongthongkum, Nongluk, Poirion, Olivier, Reed, Nora M, Rimorin, Christine, Rivkin, Angeline, Romanow, William J, Sedeño-Cortés, Adriana E, Siletti, Kimberly, Somasundaram, Saroja, Sulc, Josef, Tieu, Michael, Torkelson, Amy, Tung, Herman, Wang, Xinxin, Xie, Fangming, Yanny, Anna Marie, Zhang, Renee, Ament, Seth A, Behrens, M Margarita, Bravo, Hector Corrada, Chun, Jerold, Dobin, Alexander, Gillis, Jesse, Hertzano, Ronna, Hof, Patrick R, Höllt, Thomas, Horwitz, Gregory D, Keene, C Dirk, Kharchenko, Peter V, Ko, Andrew L, Lelieveldt, Boudewijn P, Luo, Chongyuan, Mukamel, Eran A, Pinto-Duarte, António, Preissl, Sebastian, Regev, Aviv, Ren, Bing, Scheuermann, Richard H, Smith, Kimberly, Spain, William J, White, Owen R, Koch, Christof, Hawrylycz, Michael, Tasic, Bosiljka, Macosko, Evan Z, McCarroll, Steven A, and Ting, Jonathan T

Subjects
Human Genome, Neurosciences, Genetics, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Animals, Atlases as Topic, Callithrix, Epigenesis, Genetic, Epigenomics, Female, GABAergic Neurons, Gene Expression Profiling, Glutamates, Humans, In Situ Hybridization, Fluorescence, Male, Mice, Middle Aged, Motor Cortex, Neurons, Organ Specificity, Phylogeny, Single-Cell Analysis, Species Specificity, Transcriptome, General Science & Technology
Abstract

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

Published
2021

18. Severities in persistent mild traumatic brain injury related headache is associated with changes in supraspinal pain modulatory functions

Author

Flowers, Matthew, Leung, Albert, Schiehser, Dawn M, Metzger-Smith, Valerie, Delano-Wood, Lisa, Sorg, Scott, Kunnel, Alphonsa, Wong, Angeline, Vaninetti, Michael, Golshan, Shahrokh, and Lee, Roland

Subjects
Neurosciences, Brain Disorders, Traumatic Head and Spine Injury, Chronic Pain, Clinical Research, Traumatic Brain Injury (TBI), Behavioral and Social Science, Headaches, Pain Research, Physical Injury - Accidents and Adverse Effects, Basic Behavioral and Social Science, Neurological, Brain Concussion, Headache, Humans, Magnetic Resonance Imaging, Neuralgia, Pain Perception, MTBI, traumatic brain injury, chronic post-traumatic headache, pain modulation, functional magnetic resonance imaging, resting state functional activity, Biochemistry and Cell Biology, Neurology & Neurosurgery
Abstract

Emerging evidence suggests mild traumatic brain injury related headache (MTBI-HA) is a form of neuropathic pain state. Previous supraspinal mechanistic studies indicate patients with MTBI-HA demonstrate a dissociative state with diminished levels of supraspinal prefrontal pain modulatory functions and enhanced supraspinal sensory response to pain in comparison to healthy controls. However, the relationship between supraspinal pain modulatory functional deficit and severity of MTBI-HA is largely unknown. Understanding this relationship may provide enhanced levels of insight about MTBI-HA and facilitate the development of treatments. This study assessed pain related supraspinal resting states among MTBI-HA patients with various headache intensity phenotypes with comparisons to controls via functional magnetic resonance imaging (fMRI). Resting state fMRI data was analyzed with self-organizing-group-independent-component-analysis in three MTBI-HA intensity groups (mild, moderate, and severe) and one control group (n = 16 per group) within a pre-defined supraspinal pain network based on prior studies. In the mild-headache group, significant increases in supraspinal function were observed in the right premotor cortex (T = 3.53, p

Published
2021

19. Adolescent Cannabinoid and Nicotine Exposure Differentially Alters Adult Nicotine Self-Administration in Males and Females

Author

Dukes, Angeline J, Fowler, James P, Lallai, Valeria, Pushkin, Anna N, and Fowler, Christie D

Subjects
Epidemiology, Public Health, Health Sciences, Cannabinoid Research, Substance Misuse, Tobacco Smoke and Health, Basic Behavioral and Social Science, Pediatric, Behavioral and Social Science, Drug Abuse (NIDA only), Tobacco, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Mental health, Good Health and Well Being, Adolescent, Adult, Animals, Cannabinoids, Electronic Nicotine Delivery Systems, Female, Humans, Male, Mice, Mice, Inbred C57BL, Nicotine, Reinforcement, Psychology, Reward, Self Administration, Clinical Sciences, Public Health and Health Services, Marketing, Public health
Abstract

IntroductionDuring adolescence, exposure to nicotine or cannabis independently induces effects on neuromaturation and later cognitive function. However, the potential effect of both drugs under co-use conditions has become of increasing concern given the prevalence of e-cigarettes, legalization of cannabis, and availability of synthetic "spice" cannabinoid agonists.Aims and methodsThe current studies investigated the effects of exposure to a cannabinoid receptor agonist (WIN55,212-2) and/or nicotine over a discrete time period in mid-adolescence on later intravenous nicotine self-administration in adult male and female mice. We further examined whether cannabinoid agonist administration in adulthood would alter nicotine reinforcement, with either acute or chronic pairing across 7 days.ResultsWe found that adult males exhibited increased nicotine self-administration at a lower, rewarding nicotine dose following adolescent cannabinoid exposure, either alone or with nicotine coadministration. In contrast, adult females demonstrated an opposing effect in which adolescent cannabinoid and nicotine coexposure resulted in decreased nicotine intake compared with the nicotine only and control groups. Furthermore, after maintaining nicotine self-administration across sessions, pretreatment with a low dose of the cannabinoid agonist decreased nicotine intake in both male and female control mice, and this lowering effect was evidenced after both acute and chronic treatment. However, the cannabinoid agonist was ineffective in altering nicotine intake in mice previously exposed to nicotine, cannabinoid agonist, or both during adolescence.ConclusionsThese data provide evidence that adolescent drug exposure can alter later nicotine reinforcement in a sex-specific manner and can further modulate the effectiveness of interventions in reducing nicotine intake during adulthood.ImplicationsThese studies demonstrate a significant impact of nicotine, cannabinoids, or coexposure on developmental processes during adolescence. Differential effects were observed within each sex, with opposing results found for cannabinoid exposure on nicotine intake in males and females. Intriguingly, we also evidenced resistance to the lowering effects of a cannabinoid agonist on nicotine intake in adulthood based on adolescent drug exposure. Thus, these findings have important implications for our understanding of the impact of nicotine and cannabinoids (eg, Δ9-tetrahydrocannabinol (THC) and synthetic "spice" cannabinoids) during development, with further implications for the effectiveness of therapeutic interventions based on prior drug exposure in youth.

Published
2020

20. Body Mistrust Bridges Interoceptive Awareness and Eating Disorder Symptoms

Author

Brown, Tiffany A, Vanzhula, Irina A, Reilly, Erin E, Levinson, Cheri A, Berner, Laura A, Krueger, Angeline, Lavender, Jason M, Kaye, Walter H, and Wierenga, Christina E

Subjects
Biological Psychology, Psychology, Mental Health, Nutrition, Eating Disorders, Adolescent, Adult, Age Factors, Awareness, Emotions, Feeding and Eating Disorders, Female, Humans, Interoception, Male, Young Adult, network analysis, interoceptive awareness, eating disorder, comorbidity, Cognitive Sciences, Clinical Psychology, Applied and developmental psychology, Clinical and health psychology, Cognitive and computational psychology
Abstract

Interoceptive awareness (IA), or the awareness of internal body states, is known to be impaired in individuals with eating disorders (EDs); however, little is understood about how IA and ED symptoms are connected. Network analysis is a statistical approach useful for examining how symptoms interrelate and how comorbidities may be maintained. The present study used network analysis to (1) test central symptoms within an IA-ED network, (2) identify symptoms that may bridge the association between IA and ED symptoms, and (3) explore whether central and bridge symptoms predict ED remission at discharge from intensive treatment. A regularized partial correlation network was estimated in a sample of 428 adolescent (n = 187) and adult (n = 241) ED patients in a partial hospital program. IA was assessed using items from the Multidimensional Assessment of Interoceptive Awareness, and ED symptoms were assessed using items from the Eating Disorder Examination-Questionnaire. Central symptoms within the network were strong desire to lose weight, feeling guilty, and listening for information from the body about emotional state. The most central symptom bridging IA and ED symptoms was (not) feeling safe in one's body. Of the central symptoms, greater desire to lose weight predicted lower likelihood of remission at treatment discharge. Bridge symptoms did not significantly predict remission. Body mistrust may be a mechanism by which associations between IA and EDs are maintained. Findings suggest targeting central and bridge symptoms may be helpful to improve IA and ED symptoms. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Published
2020

21. Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility.

Author

Kachuri, Linda, Johansson, Mattias, Rashkin, Sara R, Graff, Rebecca E, Bossé, Yohan, Manem, Venkata, Caporaso, Neil E, Landi, Maria Teresa, Christiani, David C, Vineis, Paolo, Liu, Geoffrey, Scelo, Ghislaine, Zaridze, David, Shete, Sanjay S, Albanes, Demetrius, Aldrich, Melinda C, Tardón, Adonina, Rennert, Gad, Chen, Chu, Goodman, Gary E, Doherty, Jennifer A, Bickeböller, Heike, Field, John K, Davies, Michael P, Dawn Teare, M, Kiemeney, Lambertus A, Bojesen, Stig E, Haugen, Aage, Zienolddiny, Shanbeh, Lam, Stephen, Le Marchand, Loïc, Cheng, Iona, Schabath, Matthew B, Duell, Eric J, Andrew, Angeline S, Manjer, Jonas, Lazarus, Philip, Arnold, Susanne, McKay, James D, Emami, Nima C, Warkentin, Matthew T, Brhane, Yonathan, Obeidat, Ma'en, Martin, Richard M, Relton, Caroline, Davey Smith, George, Haycock, Philip C, Amos, Christopher I, Brennan, Paul, Witte, John S, and Hung, Rayjean J

Subjects
Lung, Humans, Lung Neoplasms, Genetic Predisposition to Disease, Respiratory Function Tests, Vital Capacity, Forced Expiratory Volume, Prospective Studies, Phenotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide
Abstract

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

Published
2020

22. A 2019 reproductive update from the Midwest Reproductive Symposium International

Author

Zolton, Jessica R, Collins, Gretchen G, Greenwood, Eleni A, Hobeika, Elie, Jeelani, Roohi, Beltsos, Angeline, and Kearns, William G

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Contraception/Reproduction, Infertility, Reproductive health and childbirth, Good Health and Well Being, Congresses as Topic, Humans, Physicians, Reproduction, infertility, genetics, reproductive endocrinology, continuing medical education, medical conference, Genetics, Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine, Reproductive medicine
Abstract

"Mystery, Medicine, and the Magnificent Mile," the theme for the annual Midwest Reproductive Symposium International (MRSi) in Chicago, IL, captured the attention of reproductive professionals all over the world. Each year, the conference agenda encompasses emerging technologies in assisted reproduction, updates in the management of reproductive diseases, and common challenges encountered in clinical practice. The structure of the meeting, offering a mixture of lectures, panel discussions, and interactive workshops, creates a collaborative environment for physicians, geneticists, embryologists, nurses, mental health professionals, basic scientists, business administrative professionals, reproductive endocrinology and infertility fellows, and obstetrics and gynecology residents. The goal of the MRSi meeting is to provide all reproductive professionals the opportunity to exchange ideas, foster relationships, and deliver quality patient care. As the field continues to evolve, MRSi provides an exciting venue to uncover the mysteries of reproductive medicine with enthusiasm and collaboration.

Published
2019

23. Perspectives on Patient-Centered Family Planning Care from Incarcerated Girls: A Qualitative Study

Author

Ti, Angeline, Burns, Roshan, Barnert, Elizabeth S, Sufrin, Carolyn, and Dehlendorf, Christine

Subjects
Paediatrics, Reproductive Medicine, Biomedical and Clinical Sciences, Behavioral and Social Science, Clinical Research, Pediatric, Health and social care services research, 8.1 Organisation and delivery of services, Good Health and Well Being, Adolescent, California, Contraception Behavior, Family Planning Services, Female, Health Services Accessibility, Humans, Patient-Centered Care, Prisoners, Prisons, Qualitative Research, Juvenile justice, Reproductive health, Family planning, Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine, Reproductive medicine
Abstract

Study objectiveWe applied a patient-centered care (PCC) framework to explore incarcerated girls' experiences of and preferences for family planning (FP) care.DesignWe conducted qualitative semistructured interviews with incarcerated girls to explore domains of PCC: access to care, patient preferences, information and education, emotional support, family and friends, physical comfort, coordination of care, and continuity and transition.SettingA juvenile detention center (JDC) in an urban California county.ParticipantsGirls incarcerated during the study period.Interventions and main outcome measuresTranscripts were analyzed using directed content analysis to identify themes related to PCC and additional overarching themes.ResultsTwenty-two participants completed interviews. Overarching themes of stigma and autonomy emerged as influential in girls' experiences and preferences for FP care. Participants described stigma related to incarceration, sexual activity, and lack of contraception use. Participants' desire for autonomy contributed to concerns around FP care. Despite this, most desired access to FP care while incarcerated. Many valued relationships they had with JDC providers, reporting more trust and familiarity with JDC providers than those in the community. Constraints of incarceration decreased availability of emotional supports and decreased involvement of family in health-related decision-making, which worsened girls' experiences with FP care and enhanced their sense of autonomy. Difficulties with care coordination and transitions between the JDC and community often resulted in fragmented care.ConclusionProviding patient-centered FP care in JDCs is desirable but complex, and requires prioritizing patient preferences while recognizing the strengths and limitations of providing FP care within JDCs.

Published
2019

24. Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

Author

Hung, Rayjean J, Spitz, Margaret R, Houlston, Richard S, Schwartz, Ann G, Field, John K, Ying, Jun, Li, Yafang, Han, Younghun, Ji, Xuemei, Chen, Wei, Wu, Xifeng, Gorlov, Ivan P, Na, Jie, de Andrade, Mariza, Liu, Geoffrey, Brhane, Yonathan, Diao, Nancy, Wenzlaff, Angela, Davies, Michael PA, Liloglou, Triantafillos, Timofeeva, Maria, Muley, Thomas, Rennert, Hedy, Saliba, Walid, Ryan, Bríd M, Bowman, Elise, Barros-Dios, Juan-Miguel, Pérez-Ríos, Mónica, Morgenstern, Hal, Zienolddiny, Shanbeh, Skaug, Vidar, Ugolini, Donatella, Bonassi, Stefano, van der Heijden, Erik HFM, Tardon, Adonina, Bojesen, Stig E, Landi, Maria Teresa, Johansson, Mattias, Bickeböller, Heike, Arnold, Susanne, Le Marchand, Loic, Melander, Olle, Andrew, Angeline, Grankvist, Kjell, Caporaso, Neil, Teare, M Dawn, Schabath, Matthew B, Aldrich, Melinda C, Kiemeney, Lambertus A, Wichmann, H-Erich, Lazarus, Philip, Mayordomo, Jose, Neri, Monica, Haugen, Aage, Zhang, Zuo-Feng, Ruano-Raviña, Alberto, Brenner, Hermann, Harris, Curtis C, Orlow, Irene, Rennert, Gadi, Risch, Angela, Brennan, Paul, Christiani, David C, Amos, Christopher I, Yang, Ping, and Gorlova, Olga Y

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Lung Cancer, Tobacco, Prevention, Cancer, Genetics, Clinical Research, Tobacco Smoke and Health, Lung, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Case-Control Studies, Chromosomes, Human, Pair 5, Europe, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, Humans, Lung Neoplasms, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Telomerase, Lung cancer, Never smokers, Genome-wide association study, Genetic susceptibility, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

IntroductionInherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer.MethodsWe conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer.ResultsWe detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate.ConclusionsWe found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

Published
2019

25. Health System Implementation of a Tobacco Quitline eReferral

Author

Hood-Medland, Eve Angeline, Stewart, Susan L, Nguyen, Hien, Avdalovic, Mark, MacDonald, Scott, Zhu, Shu-Hong, Mayoral, Antonio, and Tong, Elisa K

Subjects
Health Services and Systems, Public Health, Health Sciences, Clinical Research, Tobacco, Prevention, Tobacco Smoke and Health, Health Services, Good Health and Well Being, Electronic Health Records, Humans, Referral and Consultation, Smoking Cessation, Telecommunications, specific condition, tobacco use cessation, electronic health record, implementation science, preventive medicine, adoption, Nicotiana, Information Systems, Clinical Sciences, Health services and systems
Abstract

BackgroundProactive referrals through electronic orders (eReferrals) can increase patient connection with tobacco quitlines. More information is needed on "real-world" implementation of electronic health record tools to promote tobacco cessation while minimizing provider burden.ObjectivesThis paper examines the health system implementation of an eReferral to a tobacco quitline without best practice alerts in primary care, specialty, and hospital settings in an academic health system.MethodsThis is a prospective implementation study of a health system tobacco eReferral to a state quitline that was completed with an approach to minimize provider cognitive burden. Data are drawn from electronic health record data at University of California, Davis Health Systems (March 2013-February 2016).ResultsOver 3 years, 16,083 encounters with smokers resulted in 1,137 eReferral orders (7.1%). Treatment reach was 1.6% for quitline services and 2.3% for outpatient group classes. While the group classes were offered to outpatient smokers, the eReferral order was included in an outpatient order set and eventually an automated inpatient discharge order set; no provider alerts were implemented. Referrals were sustained and doubled after inpatient order set implementation. Among all first time eReferral patients, 12.2% had a 6 to 12 month follow-up visit at which they were documented as nonsmoking.ConclusionThis study demonstrates a quitline eReferral order can be successfully implemented and sustained with minimal promotion, without provider alerts and in conjunction with group classes. Reach and effectiveness were similar to previously described literature.

Published
2019

26. IL-26 contributes to host defense against intracellular bacteria

Author

Dang, Angeline Tilly, Teles, Rosane MB, Weiss, David I, Parvatiyar, Kislay, Sarno, Euzenir N, Ochoa, Maria T, Cheng, Genhong, Gilliet, Michel, Bloom, Barry R, and Modlin, Robert L

Subjects
Infectious Diseases, Genetics, 2.2 Factors relating to the physical environment, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Autophagy, Cytokines, Gene Expression Profiling, Humans, Interleukins, Leprosy, Lepromatous, Leprosy, Tuberculoid, Lysosomes, Macrophages, Monocytes, Mycobacterium leprae, Mycobacterium tuberculosis, Phagosomes, Recombinant Proteins, Signal Transduction, Th17 Cells, Cellular immune response, Immunology, Infectious disease, Medical and Health Sciences
Abstract

IL-26 is an antimicrobial protein secreted by Th17 cells that has the ability to directly kill extracellular bacteria. To ascertain whether IL-26 contributes to host defense against intracellular bacteria, we studied leprosy, caused by the obligate intracellular pathogen Mycobacterium leprae, as a model. Analysis of leprosy skin lesions by gene expression profiling and immunohistology revealed that IL-26 was more strongly expressed in lesions from the self-limited tuberculoid compared with expression in progressive lepromatous patients. IL-26 directly bound to M. leprae in axenic culture and reduced bacteria viability. Furthermore, IL-26, when added to human monocyte-derived macrophages infected with M. leprae, entered the infected cell, colocalized with the bacterium, and reduced bacteria viability. In addition, IL-26 induced autophagy via the cytoplasmic DNA receptor stimulator of IFN genes (STING), as well as fusion of phagosomes containing bacilli with lysosomal compartments. Altogether, our data suggest that the Th17 cytokine IL-26 contributes to host defense against intracellular bacteria.

Published
2019

27. Autophagy links antimicrobial activity with antigen presentation in Langerhans cells.

Author

Dang, Angeline Tilly, Teles, Rosane Mb, Liu, Phillip T, Choi, Aaron, Legaspi, Annalisa, Sarno, Euzenir N, Ochoa, Maria T, Parvatiyar, Kislay, Cheng, Genhong, Gilliet, Michel, Bloom, Barry R, and Modlin, Robert L

Subjects
Epidermis, Langerhans Cells, T-Lymphocytes, Cells, Cultured, Lysosomes, Humans, Mycobacterium leprae, Leprosy, Antimicrobial Cationic Peptides, Recombinant Proteins, Antigens, Bacterial, Microscopy, Electron, Transmission, Biopsy, Antigen Presentation, Up-Regulation, Autophagy, Interferon-gamma, Primary Cell Culture, Autophagosomes, Antigen presentation, Immunology, Infectious disease, Infectious Diseases, 2.1 Biological and endogenous factors, Infection
Abstract

DC, through the uptake, processing, and presentation of antigen, are responsible for activation of T cell responses to defend the host against infection, yet it is not known if they can directly kill invading bacteria. Here, we studied in human leprosy, how Langerhans cells (LC), specialized DC, contribute to host defense against bacterial infection. IFN-γ treatment of LC isolated from human epidermis and infected with Mycobacterium leprae (M. leprae) activated an antimicrobial activity, which was dependent on the upregulation of the antimicrobial peptide cathelicidin and induction of autophagy. IFN-γ induction of autophagy promoted fusion of phagosomes containing M. leprae with lysosomes and the delivery of cathelicidin to the intracellular compartment containing the pathogen. Autophagy enhanced the ability of M. leprae-infected LC to present antigen to CD1a-restricted T cells. The frequency of IFN-γ labeling and LC containing both cathelicidin and autophagic vesicles was greater in the self-healing lesions vs. progressive lesions, thus correlating with the effectiveness of host defense against the pathogen. These data indicate that autophagy links the ability of DC to kill and degrade an invading pathogen, ensuring cell survival from the infection while facilitating presentation of microbial antigens to resident T cells.

Published
2019

28. Alcohol consumption and lung cancer risk: A pooled analysis from the International Lung Cancer Consortium and the SYNERGY study

Author

Brenner, Darren R, Fehringer, Gord, Zhang, Zuo-Feng, Lee, Yuan-Chin Amy, Meyers, Travis, Matsuo, Keitaro, Ito, Hidemi, Vineis, Paolo, Stucker, Isabelle, Boffetta, Paolo, Brennan, Paul, Christiani, David C, Diao, Nancy, Hong, Yun-Chul, Landi, Maria T, Morgenstern, Hal, Schwartz, Ann G, Rennert, Gad, Saliba, Walid, McLaughlin, John R, Harris, Curtis C, Orlow, Irene, Dios, Juan M Barros, Raviña, Alberto Ruano, Siemiatycki, Jack, Koushik, Anita, Cote, Michele, Lazarus, Philip, Fernandez-Tardon, Guillermo, Tardon, Adonina, Le Marchand, Loïc, Brenner, Hermann, Saum, Kai-Uwe, Duell, Eric J, Andrew, Angeline S, Consonni, Dario, Olsson, Ann, Hung, Rayjean J, and Straif, Kurt

Subjects
Biomedical and Clinical Sciences, Epidemiology, Health Sciences, Public Health, Oncology and Carcinogenesis, Cancer, Alcoholism, Alcohol Use and Health, Lung Cancer, Lung, Prevention, Substance Misuse, 2.2 Factors relating to the physical environment, Aetiology, Stroke, Good Health and Well Being, Adenocarcinoma, Aged, Alcohol Drinking, Alcoholic Beverages, Carcinoma, Squamous Cell, Case-Control Studies, Cohort Studies, Female, Humans, Lung Neoplasms, Male, Middle Aged, Odds Ratio, Risk Factors, Surveys and Questionnaires, Alcohol, Lung cancer, Pooled analysis, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThere is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders.MethodsTwenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type.ResultsWe observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10-19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12-15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for ≥20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90).ConclusionsWhether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms.

Published
2019

29. Cannabinoid and nicotine exposure during adolescence induces sex-specific effects on anxiety- and reward-related behaviors during adulthood.

Author

Pushkin, Anna N, Eugene, Angeline J, Lallai, Valeria, Torres-Mendoza, Alan, Fowler, JP, Chen, Edison, and Fowler, Christie D

Subjects
Animals, Humans, Mice, Disease Models, Animal, Nicotine, Benzoxazines, Morpholines, Naphthalenes, Sucrose, Anxiety, Conditioning, Operant, Reward, Sex Characteristics, Locomotion, Female, Male, Disease Models, Animal, Conditioning, Operant, MD Multidisciplinary, General Science & Technology
Abstract

Nicotine and cannabis use during adolescence has the potential to induce long lasting changes on affective and cognitive function. Here, we examined whether adolescent exposure to nicotine, the cannabinoid agonist WIN55-212,2 (WIN), or co-exposure to both would alter operant learning, locomotion, and anxiety- and reward-related behaviors in male and female mice during adulthood. Males exposed to a moderate dose of WIN (2 mg/kg) or co-exposed to nicotine and the moderate dose of WIN exhibited decreased anxiety-associated behaviors and increased cognitive flexibility, but did not differ in operant learning or generalized locomotion. In contrast, differences were not found among the females in these measures at the moderate WIN dose or in both sexes with exposure to a low WIN dose (0.2 mg/kg). Furthermore, a sex-dependent dissociative effect was found in natural reward consumption. Males exposed to the moderate dose of WIN or co-exposed to nicotine and the moderate dose of WIN demonstrated increased sucrose consumption. In contrast, females exposed to the moderate dose of WIN exhibited a decrease in sucrose consumption, which was ameliorated with co-administration of nicotine. Together, these novel findings demonstrate that adolescent exposure to cannabinoids in the presence or absence of nicotine results in altered affective and reward-related behaviors during adulthood.

Published
2019

30. Shared heritability and functional enrichment across six solid cancers.

Author

Jiang, Xia, Finucane, Hilary K, Schumacher, Fredrick R, Schmit, Stephanie L, Tyrer, Jonathan P, Han, Younghun, Michailidou, Kyriaki, Lesseur, Corina, Kuchenbaecker, Karoline B, Dennis, Joe, Conti, David V, Casey, Graham, Gaudet, Mia M, Huyghe, Jeroen R, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline S, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Antonenkova, Natalia N, Arnold, Susanne M, Aronson, Kristan J, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Batra, Jyotsna, Beckmann, Matthias W, Benitez, Javier, Benlloch, Sara, Berchuck, Andrew, Berndt, Sonja I, Bickeböller, Heike, Bien, Stephanie A, Blomqvist, Carl, Boccia, Stefania, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brenton, James D, Brook, Mark N, Brunet, Joan, Brunnström, Hans, Buchanan, Daniel D, Burwinkel, Barbara, Butzow, Ralf, Cadoni, Gabriella, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Campbell, Peter T, Cancel-Tassin, Géraldine, Cannon-Albright, Lisa, Campa, Daniele, Caporaso, Neil, Carvalho, André L, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Christiani, David C, Claes, Kathleen BM, Claessens, Frank, Clements, Judith, Collée, J Margriet, Correa, Marcia Cruz, Couch, Fergus J, Cox, Angela, Cunningham, Julie M, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, deFazio, Anna, Devilee, Peter, Diez, Orland, Gago-Dominguez, Manuela, Donovan, Jenny L, Dörk, Thilo, Duell, Eric J, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Edlund, Christopher K, Edwards, Digna R Velez, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Ferris, Robert L, Liloglou, Triantafillos, Figueiredo, Jane C, Fletcher, Olivia, Fortner, Renée T, Fostira, Florentia, Franceschi, Silvia, Friedman, Eitan, Gallinger, Steven J, and Ganz, Patricia A

Subjects
Humans, Breast Neoplasms, Colorectal Neoplasms, Ovarian Neoplasms, Head and Neck Neoplasms, Lung Neoplasms, Prostatic Neoplasms, Genetic Predisposition to Disease, Neoplasm Proteins, Case-Control Studies, Smoking, Mental Disorders, Inheritance Patterns, Phenotype, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Prevention, Cancer, Breast Cancer, Genetics, Rare Diseases, Lung Cancer, Human Genome, Colo-Rectal Cancer, Digestive Diseases, Lung, MD Multidisciplinary
Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Published
2019

31. Synaptotagmin 4 Regulates Pancreatic β Cell Maturation by Modulating the Ca2+ Sensitivity of Insulin Secretion Vesicles

Author

Huang, Chen, Walker, Emily M, Dadi, Prasanna K, Hu, Ruiying, Xu, Yanwen, Zhang, Wenjian, Sanavia, Tiziana, Mun, Jisoo, Liu, Jennifer, Nair, Gopika G, Tan, Hwee Yim Angeline, Wang, Sui, Magnuson, Mark A, Stoeckert, Christian J, Hebrok, Matthias, Gannon, Maureen, Han, Weiping, Stein, Roland, Jacobson, David A, and Gu, Guoqiang

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Diabetes, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Animals, Biological Transport, Calcium, Cell Differentiation, Female, Gene Expression Regulation, Glucose, Humans, Hypoglycemic Agents, Insulin, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Sweetening Agents, Synaptotagmins, Ca(2+), Myt1, Syt4, diabetes, docking, insulin, maturation, membrane fusion, secretion, vesicle, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology
Abstract

Islet β cells from newborn mammals exhibit high basal insulin secretion and poor glucose-stimulated insulin secretion (GSIS). Here we show that β cells of newborns secrete more insulin than adults in response to similar intracellular Ca2+ concentrations, suggesting differences in the Ca2+ sensitivity of insulin secretion. Synaptotagmin 4 (Syt4), a non-Ca2+ binding paralog of the β cell Ca2+ sensor Syt7, increased by ∼8-fold during β cell maturation. Syt4 ablation increased basal insulin secretion and compromised GSIS. Precocious Syt4 expression repressed basal insulin secretion but also impaired islet morphogenesis and GSIS. Syt4 was localized on insulin granules and Syt4 levels inversely related to the number of readily releasable vesicles. Thus, transcriptional regulation of Syt4 affects insulin secretion; Syt4 expression is regulated in part by Myt transcription factors, which repress Syt4 transcription. Finally, human SYT4 regulated GSIS in EndoC-βH1 cells, a human β cell line. These findings reveal the role that altered Ca2+ sensing plays in regulating β cell maturation.

Published
2018

32. HIV status and treatment influence on fertility desires among women newly becoming eligible for antiretroviral therapy in western Kenya: insights from a qualitative study

Author

Ayieko, James, Ti, Angeline, Hagey, Jill, Akama, Eliud, Bukusi, Elizabeth A, Cohen, Craig R, and Patel, Rena C

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Basic Behavioral and Social Science, Contraception/Reproduction, Behavioral and Social Science, Pediatric, Clinical Research, HIV/AIDS, Infection, Good Health and Well Being, Adult, Anti-Retroviral Agents, Attitude of Health Personnel, Family Planning Services, Female, HIV Infections, Humans, Male, Middle Aged, Qualitative Research, Socioeconomic Factors, Women, HIV-infected women, ART-naive, Fertility desires, Kenya, ART-naïve, Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine, Reproductive medicine, Public health
Abstract

BackgroundFactors influencing fertility desires among HIV-infected individuals remain poorly understood. With new recommendations for universal HIV treatment and increasing antiretroviral therapy (ART) access, we sought to evaluate how access to early ART influences fertility desires among HIV-infected ART-naïve women.MethodsSemi-structured in-depth interviews were conducted with a select subgroup of 20 HIV-infected ART-naïve women attending one of 13 HIV facilities in western Kenya between July and August 2014 who would soon newly become eligible to initiate ART based on the latest national policy recommendations. The interviews covered four major themes: 1) definitions of family and children's role in community; 2) personal, interpersonal, institutional, and societal factors influencing fertility desires; 3) influence of HIV-positive status on fertility desires; and 4) influence of future ART initiation on fertility desires. An iterative process of reading transcripts, applying inductive codes, and comparing and contrasting codes was used to identify convergent and divergent themes.ResultsThe women indicated their HIV-positive status did influence-largely negatively-their fertility desires. Furthermore, initiating ART and anticipating improved health status did not necessarily translate to increased fertility desires. Instead, individual factors, such as age, parity, current health status, financial resources and number of surviving or HIV-infected children, played a crucial role in decisions about future fertility. In addition, societal influences, such as community norms and health providers' expectations of their fertility desires, played an equally important role in determining fertility desires.ConclusionsInitiating ART may not be the leading factor influencing fertility desires among previously ART-naïve HIV-infected women. Instead, individual and societal factors appear to be the major determinants of fertility desires among these women.

Published
2017

33. Pubertal development in girls by breast cancer family history: the LEGACY girls cohort

Author

Terry, Mary Beth, Keegan, Theresa HM, Houghton, Lauren C, Goldberg, Mandy, Andrulis, Irene L, Daly, Mary B, Buys, Saundra S, Wei, Ying, Whittemore, Alice S, Protacio, Angeline, Bradbury, Angela R, Chung, Wendy K, Knight, Julia A, and John, Esther M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, Body Mass Index, Breast Neoplasms, Canada, Child, Child, Preschool, Cohort Studies, Female, Humans, Incidence, Kaplan-Meier Estimate, Menarche, Odds Ratio, Population Surveillance, Puberty, Risk, United States, BMI, Breast cancer, Breast cancer family history, Pubertal development, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundPubertal milestones, such as onset of breast development and menstruation, play an important role in breast cancer etiology. It is unclear if these milestones are different in girls with a first- or second-degree breast cancer family history (BCFH).MethodsIn the LEGACY Girls Study (n = 1040), we examined whether three mother/guardian-reported pubertal milestones (having reached Tanner Stage 2 or higher (T2+) for breast and pubic hair development, and having started menstruation) differed by BCFH. We also examined whether associations between body size and race/ethnicity and pubertal milestones were modified by BCFH. We used mother/guardian reports as the primary measure of pubertal milestones, but also conducted sensitivity analyses using clinical Tanner measurements available for a subcohort (n = 204). We analyzed cross-sectional baseline data with logistic regression models for the entire cohort, and longitudinal data with Weibull survival models for the subcohort of girls that were aged 5-7 years at baseline (n = 258).ResultsBCFH was modestly, but not statistically significantly, associated with Breast T2+ (odds ratio (OR) = 1.36, 95% confidence interval (CI) = 0.88-2.10), with a stronger association seen in the subcohort of girls with clinical breast Tanner staging (OR = 2.20, 95% CI = 0.91-5.32). In a longitudinal analysis of girls who were aged 5-7 years at baseline, BCFH was associated with a 50% increased rate of having early breast development (hazard ratio (HR) = 1.49, 95% CI = 1.0-2.21). This association increased to twofold in girls who were not overweight at baseline (HR = 2.04, 95% CI = 1.29-3.21). BCFH was not associated with pubic hair development and post-menarche status. The median interval between onset of breast development and menarche was longer for BCFH+ than BCFH- girls (2.3 versus 1.7 years), suggesting a slower developmental tempo for BCFH+ girls. Associations between pubertal milestones and body size and race/ethnicity were similar in girls with or without a BCFH. For example, weight was positively associated with Breast T2+ in both girls with (OR = 1.06 per 1 kg, 95% CI = 1.03-1.10) and without (OR = 1.14 per 1 kg, 95% CI = 1.04-1.24) a BCFH.ConclusionsThese results suggest that BCFH may be related to earlier breast development and slower pubertal tempo independent of body size and race/ethnicity.

Published
2017

34. Early life socioeconomic environment and mammographic breast density

Author

Tehranifar, Parisa, Cohn, Barbara A, Flom, Julie D, Protacio, Angeline, Cirillo, Piera, Lumey, LH, Michels, Karin B, and Terry, Mary Beth

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Pediatric, Aging, Cancer, Prevention, Breast Cancer, Clinical Research, Aetiology, 2.3 Psychological, social and economic factors, Adult, Body Mass Index, Breast, Breast Density, Breast Neoplasms, Female, Humans, Life Style, Mammography, Models, Statistical, Prognosis, Risk Factors, Social Class, United States, Life-course, Socioeconomic status, Mammographic breast density, Reproductive factors, Lifestyles, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Epidemiology
Abstract

BackgroundEarly life social environment may influence breast cancer through shaping risk factors operating in early life, adolescence and adulthood, or may be associated with breast cancer risk independent of known risk factors. We investigated the associations between early life socioeconomic status (SES) and mammographic density, a strong risk factor for breast cancer, and the extent to which these associations were independent of risk factors across the lifecourse.MethodsWe used data from an adult follow-up study of two U.S. birth cohorts of women (average age = 43 years) with prospectively collected data starting during the pregnancy of the mother and continuing through early childhood of the offspring. We collected data on factors in later life periods through computer-assisted interviews with the offspring as adults, and obtained routine clinical mammograms for measurement of percent density and dense and nondense breast areas using a computer assisted method. We used generalized estimating equation models for multivariable analysis to account for correlated data for sibling sets within the study sample (n = 700 composed of 441 individuals and 127 sibling sets).ResultsHighest vs. lowest family income level around the time of birth was associated with smaller dense breast area after adjustment for early life factors (e.g., birthweight, maternal smoking during pregnancy) and risk factors in later life periods, including adult body mass index (BMI) and adult SES (β = -8.2 cm2, 95% confidence interval [CI]: -13.3, -3.2). Highest vs. lowest parental educational attainment was associated with higher percent density in models that adjusted for age at mammogram and adult BMI (e.g., β = 4.8, 95% CI = 0.6, 9.1 for maternal education of college or higher degree vs. less than high school), but the association was attenuated and no longer statistically significant after further adjustment for early life factors. There were no associations between early life SES indicators and non-dense area after adjustment for adult BMI. Neither adult education nor adult income was statistically significantly associated with any measure of mammographic density after adjusting for age and adult BMI.ConclusionsWe did not observe consistent associations between different measures of early life SES and mammographic density in adulthood.

Published
2017

35. The WNT target SP5 negatively regulates WNT transcriptional programs in human pluripotent stem cells.

Author

Huggins, Ian J, Bos, Tomas, Gaylord, Olivia, Jessen, Christina, Lonquich, Brianna, Puranen, Angeline, Richter, Jenna, Rossdam, Charlotte, Brafman, David, Gaasterland, Terry, and Willert, Karl

Subjects
Cell Line, Pluripotent Stem Cells, Humans, DNA-Binding Proteins, Transcription Factors, Gene Expression Regulation, beta Catenin, Wnt3A Protein, Wnt Signaling Pathway
Abstract

The WNT/β-catenin signaling pathway is a prominent player in many developmental processes, including gastrulation, anterior-posterior axis specification, organ and tissue development, and homeostasis. Here, we use human pluripotent stem cells (hPSCs) to study the dynamics of the transcriptional response to exogenous activation of the WNT pathway. We describe a mechanism involving the WNT target gene SP5 that leads to termination of the transcriptional program initiated by WNT signaling. Integration of gene expression profiles of wild-type and SP5 mutant cells with genome-wide SP5 binding events reveals that SP5 acts to diminish expression of genes previously activated by the WNT pathway. Furthermore, we show that activation of SP5 by WNT signaling is most robust in cells with developmental potential, such as stem cells. These findings indicate a mechanism by which the developmental WNT signaling pathway reins in expression of transcriptional programs.

Published
2017

36. Do Emotions Spark Interest in Alternative Tobacco Products?

Author

Popova, Lucy, So, Jiyeon, Sangalang, Angeline, Neilands, Torsten B, and Ling, Pamela M

Subjects
Public Health, Health Sciences, Clinical Research, Tobacco Smoke and Health, Tobacco, Prevention, Cancer, Good Health and Well Being, Adult, Age Factors, Electronic Nicotine Delivery Systems, Emotions, Female, Humans, Male, Sex Factors, Smoking Cessation, Tobacco Products, electronic cigarettes, emotions, hope, smokeless, tobacco, tobacco products, Medical and Health Sciences, Education, Psychology and Cognitive Sciences, Public health, Applied and developmental psychology
Abstract

BackgroundExposure to advertisements for tobacco products and tobacco warning labels evokes emotions. This study evaluated the association of discrete positive and negative emotions with interest in alternative tobacco products.MethodIn 2013, 1,226 U.S. adult nonsmokers and current smokers viewed advertisements for moist snuff, snus, and electronic cigarettes (e-cigarettes) with various warning labels and then indicated their emotional responses in terms of anger, anxiety, sadness, guilt, disgust, discouragement, hope, and contentment. Outcomes were openness to using moist snuff, snus, and e-cigarettes in the future and interest in a free sample of each product. Data were analyzed in 2016.ResultsHope was positively associated with openness and interest across all alternative tobacco products as was contentment for moist snuff and snus. Anger was negatively associated with openness to moist snuff and e-cigarettes, disgust negatively to moist snuff and snus, and anxiety negatively to e-cigarettes. Being a current smoker, ever trying a corresponding product, being male, and younger age were associated with greater openness to and interest in moist snuff and snus. For e-cigarettes, being a current smoker, ever trying e-cigarettes, and being female were associated with greater openness, and being a current smoker was associated with greater odds of selecting a free sample.ConclusionsPositive emotions, particularly hope, were consistently positively associated with interest in alternative tobacco products. Hope is widely used by tobacco and e-cigarette companies to advertise their products. Antitobacco messages should aim to lower hope associated with tobacco products but increase hope for cessation or life without tobacco.

Published
2017

37. Alcohol and lung cancer risk among never smokers: A pooled analysis from the international lung cancer consortium and the SYNERGY study

Author

Fehringer, Gordon, Brenner, Darren R, Zhang, Zuo‐Feng, Lee, Yuan‐Chin Amy, Matsuo, Keitaro, Ito, Hidemi, Lan, Qing, Vineis, Paolo, Johansson, Mattias, Overvad, Kim, Riboli, Elio, Trichopoulou, Antonia, Sacerdote, Carlotta, Stucker, Isabelle, Boffetta, Paolo, Brennan, Paul, Christiani, David C, Hong, Yun‐Chul, Landi, Maria Teresa, Morgenstern, Hal, Schwartz, Ann G, Wenzlaff, Angela S, Rennert, Gad, McLaughlin, John R, Harris, Curtis C, Olivo‐Marston, Susan, Orlow, Irene, Park, Bernard J, Zauderer, Marjorie, Dios, Juan M Barros, Raviña, Alberto Ruano, Siemiatycki, Jack, Koushik, Anita, Lazarus, Philip, Fernández‐Somoano, Ana, Tardon, Adonina, Le Marchand, Loic, Brenner, Hermann, Saum, Kai‐Uwe, Duell, Eric J, Andrew, Angeline S, Szeszenia‐Dabrowska, Neonila, Lissowska, Jolanta, Zaridze, David, Rudnai, Peter, Fabianova, Eleonora, Mates, Dana, Foretova, Lenka, Janout, Vladimir, Bencko, Vladimir, Holcatova, Ivana, Pesatori, Angela Cecilia, Consonni, Dario, Olsson, Ann, Straif, Kurt, and Hung, Rayjean J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Lung, Cancer, Substance Misuse, Tobacco, Alcoholism, Alcohol Use and Health, Tobacco Smoke and Health, Prevention, Lung Cancer, Cardiovascular, Stroke, Respiratory, Good Health and Well Being, Aged, Alcohol Drinking, Alcoholic Beverages, Asia, Case-Control Studies, Cohort Studies, Europe, Female, Humans, Lung Neoplasms, Male, Middle Aged, North America, Risk Factors, Smoking, alcohol, lung cancer, wine, beer, liquor, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship is likely confounded by smoking, complicating the interpretation of previous studies. We examined the association of alcohol consumption and lung cancer risk in a large pooled international sample, minimizing potential confounding of tobacco consumption by restricting analyses to never smokers. Our study included 22 case-control and cohort studies with a total of 2548 never-smoking lung cancer patients and 9362 never-smoking controls from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. Alcohol consumption was categorized into amounts consumed (grams per day) and also modelled as a continuous variable using restricted cubic splines for potential non-linearity. Analyses by histologic sub-type were included. Associations by type of alcohol consumed (wine, beer and liquor) were also investigated. Alcohol consumption was inversely associated with lung cancer risk with evidence most strongly supporting lower risk for light and moderate drinkers relative to non-drinkers (>0-4.9 g per day: OR = 0.80, 95% CI = 0.70-0.90; 5-9.9 g per day: OR = 0.82, 95% CI = 0.69-0.99; 10-19.9 g per day: OR = 0.79, 95% CI = 0.65-0.96). Inverse associations were found for consumption of wine and liquor, but not beer. The results indicate that alcohol consumption is inversely associated with lung cancer risk, particularly among subjects with low to moderate consumption levels, and among wine and liquor drinkers, but not beer drinkers. Although our results should have no relevant bias from the confounding effect of smoking we cannot preclude that confounding by other factors contributed to the observed associations. Confounding in relation to the non-drinker reference category may be of particular importance.

Published
2017

38. Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

Author

Carreras-Torres, Robert, Johansson, Mattias, Haycock, Philip C, Wade, Kaitlin H, Relton, Caroline L, Martin, Richard M, Smith, George Davey, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline, Arnold, Susanne M, Bickeböller, Heike, Bojesen, Stig E, Brunnström, Hans, Manjer, Jonas, Brüske, Irene, Caporaso, Neil E, Chen, Chu, Christiani, David C, Christian, W Jay, Doherty, Jennifer A, Duell, Eric J, Field, John K, Davies, Michael PA, Marcus, Michael W, Goodman, Gary E, Grankvist, Kjell, Haugen, Aage, Hong, Yun-Chul, Kiemeney, Lambertus A, van der Heijden, Erik HFM, Kraft, Peter, Johansson, Mikael B, Lam, Stephen, Landi, Maria Teresa, Lazarus, Philip, Le Marchand, Loïc, Liu, Geoffrey, Melander, Olle, Park, Sungshim L, Rennert, Gad, Risch, Angela, Haura, Eric B, Scelo, Ghislaine, Zaridze, David, Mukeriya, Anush, Savić, Milan, Lissowska, Jolanta, Swiatkowska, Beata, Janout, Vladimir, Holcatova, Ivana, Mates, Dana, Schabath, Matthew B, Shen, Hongbing, Tardon, Adonina, Teare, M Dawn, Woll, Penella, Tsao, Ming-Sound, Wu, Xifeng, Yuan, Jian-Min, Hung, Rayjean J, Amos, Christopher I, McKay, James, and Brennan, Paul

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Genetics, Lung, Nutrition, Tobacco Smoke and Health, Prevention, Cancer, Tobacco, Obesity, Clinical Research, Lung Cancer, Aetiology, 2.1 Biological and endogenous factors, Body Mass Index, Fasting, Humans, Insulin, Insulin Resistance, Likelihood Functions, Lipids, Lung Neoplasms, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, General Science & Technology
Abstract

BackgroundAssessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer.Methods and findingsWe identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results.ConclusionsOur results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

Published
2017

39. S100A12 Is Part of the Antimicrobial Network against Mycobacterium leprae in Human Macrophages.

Author

Realegeno, Susan, Kelly-Scumpia, Kindra M, Dang, Angeline Tilly, Lu, Jing, Teles, Rosane, Liu, Philip T, Schenk, Mirjam, Lee, Ernest Y, Schmidt, Nathan W, Wong, Gerard CL, Sarno, Euzenir N, Rea, Thomas H, Ochoa, Maria T, Pellegrini, Matteo, and Modlin, Robert L

Subjects
Macrophages, Humans, Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium Infections, Leprosy, Fluorescent Antibody Technique, Flow Cytometry, Gene Expression Profiling, Real-Time Polymerase Chain Reaction, Transcriptome, S100A12 Protein, Virology, Microbiology, Immunology, Medical Microbiology
Abstract

Triggering antimicrobial mechanisms in macrophages infected with intracellular pathogens, such as mycobacteria, is critical to host defense against the infection. To uncover the unique and shared antimicrobial networks induced by the innate and adaptive immune systems, gene expression profiles generated by RNA sequencing (RNAseq) from human monocyte-derived macrophages (MDMs) activated with TLR2/1 ligand (TLR2/1L) or IFN-γ were analyzed. Weighed gene correlation network analysis identified modules of genes strongly correlated with TLR2/1L or IFN-γ that were linked by the "defense response" gene ontology term. The common TLR2/1L and IFN-γ inducible human macrophage host defense network contained 16 antimicrobial response genes, including S100A12, which was one of the most highly induced genes by TLR2/1L. There is limited information on the role of S100A12 in infectious disease, leading us to test the hypothesis that S100A12 contributes to host defense against mycobacterial infection in humans. We show that S100A12 is sufficient to directly kill Mycobacterium tuberculosis and Mycobacterium leprae. We also demonstrate that S100A12 is required for TLR2/1L and IFN-γ induced antimicrobial activity against M. leprae in infected macrophages. At the site of disease in leprosy, we found that S100A12 was more strongly expressed in skin lesions from tuberculoid leprosy (T-lep), the self-limiting form of the disease, compared to lepromatous leprosy (L-lep), the progressive form of the disease. These data suggest that S100A12 is part of an innate and adaptive inducible antimicrobial network that contributes to host defense against mycobacteria in infected macrophages.

Published
2016

40. CHRNA5 Risk Variant Predicts Delayed Smoking Cessation and Earlier Lung Cancer Diagnosis—A Meta-Analysis

Author

Chen, Li-Shiun, Hung, Rayjean J, Baker, Timothy, Horton, Amy, Culverhouse, Rob, Saccone, Nancy, Cheng, Iona, Deng, Bo, Han, Younghun, Hansen, Helen M, Horsman, Janet, Kim, Claire, Lutz, Sharon, Rosenberger, Albert, Aben, Katja K, Andrew, Angeline S, Breslau, Naomi, Chang, Shen-Chih, Dieffenbach, Aida Karina, Dienemann, Hendrik, Frederiksen, Brittni, Han, Jiali, Hatsukami, Dorothy K, Johnson, Eric O, Pande, Mala, Wrensch, Margaret R, McLaughlin, John, Skaug, Vidar, van der Heijden, Henricus F, Wampfler, Jason, Wenzlaff, Angela, Woll, Penella, Zienolddiny, Shanbeh, Bickeböller, Heike, Brenner, Hermann, Duell, Eric J, Haugen, Aage, Heinrich, Joachim, Hokanson, John E, Hunter, David J, Kiemeney, Lambertus A, Lazarus, Philip, Le Marchand, Loic, Liu, Geoffrey, Mayordomo, Jose, Risch, Angela, Schwartz, Ann G, Teare, Dawn, Wu, Xifeng, Wiencke, John K, Yang, Ping, Zhang, Zuo-Feng, Spitz, Margaret R, Kraft, Peter, Amos, Christopher I, and Bierut, Laura J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Lung, Lung Cancer, Cancer, Human Genome, Tobacco, Prevention, Genetics, Tobacco Smoke and Health, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Respiratory, Good Health and Well Being, Genetic Variation, Humans, Lung Neoplasms, Middle Aged, Nerve Tissue Proteins, Phenotype, Receptors, Nicotinic, Risk Factors, Smoking, Smoking Cessation, Time Factors, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundRecent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis.MethodsMeta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided.ResultsThe rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)).ConclusionThese data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.

Published
2015

41. Intestinal Epithelial Barrier Disruption through Altered Mucosal MicroRNA Expression in Human Immunodeficiency Virus and Simian Immunodeficiency Virus Infections

Author

Gaulke, Christopher A, Porter, Matthew, Han, Yan-Hong, Sankaran-Walters, Sumathi, Grishina, Irina, George, Michael D, Dang, Angeline T, Ding, Shou-Wei, Jiang, Guochun, Korf, Ian, and Dandekar, Satya

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Biotechnology, Genetics, HIV/AIDS, Infectious Diseases, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Infection, Adult, Animals, Base Sequence, CD4-Positive T-Lymphocytes, Computational Biology, Densitometry, Flow Cytometry, HIV, Humans, Intestinal Mucosa, Laser Capture Microdissection, Lentivirus Infections, Macaca mulatta, Male, MicroRNAs, Microarray Analysis, Middle Aged, Molecular Sequence Data, Real-Time Polymerase Chain Reaction, Sequence Analysis, RNA, Simian Immunodeficiency Virus, Viral Load, Simian immunodeficiency virus, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Virology, Agricultural, veterinary and food sciences, Biological sciences, Biomedical and clinical sciences
Abstract

UnlabelledEpithelial barrier dysfunction during human immunodeficiency virus (HIV) infection has largely been attributed to the rapid and severe depletion of CD4(+) T cells in the gastrointestinal (GI) tract. Although it is known that changes in mucosal gene expression contribute to intestinal enteropathy, the role of small noncoding RNAs, specifically microRNA (miRNA), has not been investigated. Using the simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV pathogenesis, we investigated the effect of viral infection on miRNA expression in intestinal mucosa. SIV infection led to a striking decrease in the expression of mucosal miRNA compared to that in uninfected controls. This decrease coincided with an increase in 5'-3'-exoribonuclease 2 protein and alterations in DICER1 and Argonaute 2 expression. Targets of depleted miRNA belonged to molecular pathways involved in epithelial proliferation, differentiation, and immune response. Decreased expression of several miRNA involved in maintaining epithelial homeostasis in the gut was localized to the proliferative crypt region of the intestinal epithelium. Our findings suggest that SIV-induced decreased expression of miRNA involved in epithelial homeostasis, disrupted expression of miRNA biogenesis machinery, and increased expression of XRN2 are involved in the development of epithelial barrier dysfunction and gastroenteropathy.ImportanceMicroRNA (miRNA) regulate the development and function of intestinal epithelial cells, and many viruses disrupt normal host miRNA expression. In this study, we demonstrate that SIV and HIV disrupt expression of miRNA in the small intestine during infection. The depletion of several key miRNA is localized to the proliferative crypt region of the gut epithelium. These miRNA are known to control expression of genes involved in inflammation, cell death, and epithelial maturation. Our data indicate that this disruption might be caused by altered expression of miRNA biogenesis machinery during infection. These findings suggest that the disruption of miRNA in the small intestine likely plays a role in intestinal enteropathy during HIV infection.

Published
2014

42. Enhanced Innate Antiviral Gene Expression, IFN-α, and Cytolytic Responses Are Predictive of Mucosal Immune Recovery during Simian Immunodeficiency Virus Infection

Author

Verhoeven, David, George, Michael D, Hu, William, Dang, Angeline T, Smit-McBride, Zeljka, Reay, Elizabeth, Macal, Monica, Fenton, Anne, Sankaran-Walters, Sumathi, and Dandekar, Satya

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, HIV/AIDS, Infectious Diseases, Lung, 2.1 Biological and endogenous factors, Aetiology, Respiratory, Inflammatory and immune system, Infection, Good Health and Well Being, Acquired Immunodeficiency Syndrome, Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytotoxicity, Immunologic, Disease Models, Animal, Flow Cytometry, Gene Expression, Host-Pathogen Interactions, Humans, Immunity, Mucosal, Immunologic Memory, Intestinal Mucosa, Macaca mulatta, Male, Oligonucleotide Array Sequence Analysis, Predictive Value of Tests, Prognosis, Recovery of Function, Respiratory Mucosa, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus, Transcriptome, Tumor Necrosis Factor-alpha, Simian immunodeficiency virus, Biochemistry and cell biology
Abstract

The mucosa that lines the respiratory and gastrointestinal (GI) tracts is an important portal of entry for pathogens and provides the first line of innate immune defense against infections. Although an abundance of memory CD4(+) T cells at mucosal sites render them highly susceptible to HIV infection, the gut and not the lung experiences severe and sustained CD4(+) T cell depletion and tissue disruption. We hypothesized that distinct immune responses in the lung and gut during the primary and chronic stages of viral infection contribute to these differences. Using the SIV model of AIDS, we performed a comparative analysis of the molecular and cellular characteristics of host responses in the gut and lung. Our findings showed that both mucosal compartments harbor similar percentages of memory CD4(+) T cells and displayed comparable cytokine (IL-2, IFN-γ, and TNF-α) responses to mitogenic stimulations prior to infection. However, despite similar viral replication and CD4(+) T cell depletion during primary SIV infection, CD4(+) T cell restoration kinetics in the lung and gut diverged during acute viral infection. The CD4(+) T cells rebounded or were preserved in the lung mucosa during chronic viral infection, which correlated with heightened induction of type I IFN signaling molecules and innate viral restriction factors. In contrast, the lack of CD4(+) T cell restoration in the gut was associated with dampened immune responses and diminished expression of viral restriction factors. Thus, unique immune mechanisms contribute to the differential response and protection of pulmonary versus GI mucosa and can be leveraged to enhance mucosal recovery.

Published
2014

43. Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel.

Author

Brett, Maggie, McPherson, John, Zang, Zhi Jiang, Lai, Angeline, Tan, Ee-Shien, Ng, Ivy, Ong, Lai-Choo, Cham, Breana, Tan, Patrick, Rozen, Steve, and Tan, Ene-Choo

Subjects
Humans, RNA Splice Sites, Gene Expression Profiling, DNA Mutational Analysis, Phenotype, Mutation, Polymorphism, Single Nucleotide, Female, Male, Congenital Abnormalities, Genetic Variation, Genome-Wide Association Study, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Intellectual Disability, Autism Spectrum Disorder, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

Developmental delay and/or intellectual disability (DD/ID) affects 1-3% of all children. At least half of these are thought to have a genetic etiology. Recent studies have shown that massively parallel sequencing (MPS) using a targeted gene panel is particularly suited for diagnostic testing for genetically heterogeneous conditions. We report on our experiences with using massively parallel sequencing of a targeted gene panel of 355 genes for investigating the genetic etiology of eight patients with a wide range of phenotypes including DD/ID, congenital anomalies and/or autism spectrum disorder. Targeted sequence enrichment was performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the Illumina HiSeq2000 using paired-end reads. For all eight patients, 81-84% of the targeted regions achieved read depths of at least 20×, with average read depths overlapping targets ranging from 322× to 798×. Causative variants were successfully identified in two of the eight patients: a nonsense mutation in the ATRX gene and a canonical splice site mutation in the L1CAM gene. In a third patient, a canonical splice site variant in the USP9X gene could likely explain all or some of her clinical phenotypes. These results confirm the value of targeted MPS for investigating DD/ID in children for diagnostic purposes. However, targeted gene MPS was less likely to provide a genetic diagnosis for children whose phenotype includes autism.

Published
2014

44. Higher dose corticosteroids in patients admitted to hospital with COVID-19 who are hypoxic but not requiring ventilatory support (RECOVERY)

Author

Obbina Abani, Ali Abbas, Fatima Abbas, Joshua Abbas, Kasim Abbas, Mustafa Abbas, Sadia Abbasi, Hakam Abbass, Alfie Abbott, Alison Abbott, Nabeel Abdallah, Ammar Abdelaziz, Ashraf Abdelaziz, Mohamed Abdelfattah, Bushra Abdelqader, Audrey Abdul, Basir Abdul, Siddiqui Abdul, Althaf Abdul Rasheed, Ajibode Abdulakeem, Rezan Abdul-Kadir, Abdullah Abdullah, Abdulfatahi Abdulmumeen, Rasheed Abdul-Raheem, Niyaz Abdulshukkoor, Kula Abdusamad, Yazeed Abed El Khaleq, Mai Abedalla, Abeer Abeer Ul Amna, Lynn Abel, Katrina Abernethy, Movin Abeywickrema, Chandra Abhinaya, Affyarsyah Abidin, Adebanke Aboaba, Abigail Aboagye-Odei, Christopher Aboah, Heba Aboelela, Hani Abo-Leyah, Karim Abouelela, Ahmed Abou-Haggar, Mahmoud Abouibrahim, Ahmed Abousamra, Mona Abouzaid, Miriam Abraham, Tizzy Abraham, Abraheem Abraheem, Judith Abrams, Rebecca Abrams, Hyacinth-John Abu, Ahmed Abu-Arafeh, Syed M Abubacker, Akata Abung, Yousuf Abusamra, Yaa Aceampong, Amaka Achara, Devikumar Acharya, Faustina Acheampong, Prince Acheampong, Sarah Acheampong, Janet Acheson, Shiella Achieng, Andres Acosta, Rebecca Acquah, Catherine Acton, Jacqueline Adabie-Ankrah, Paul Adair, Fiona Adam, Matthew Adam, Huzaifa Adamali, Marta Adamczyk, Carol Adams, Charlotte Adams, Daniel Adams, Kate Adams, Laura Adams, Nikkita Adams, Richard Adams, Tim Adams, Laura Adamu-Ikeme, Krishma Adatia, Kirsty Adcock, Lawrence Addai-Boampong, Afua Addo, Oluwatobi Adeagbo, Ade Adebiyi, Ogunlana Adedeji, Yewande Adegeye, Ken Adegoke, Vicki Adell, Sherna Adenwalla, Femi W Adeoye, Oluwasegun A Adesemoye, Emmanuel O Adewunmi, Adedamola Adeyanju, Joyce Adeyemi, Tenifayo Adeyemo, Binay Adhikari, Shanti A Adhikari, Rina Adhikary, Adhikarla Aditya, Patience Adjepong, Gabrielle Adkins, Adnan Adnan, Marguerite Adriaanse, John Aeron-Thomas, Debbie Affleck, Carmel Afnan, Muhammad Afridi, Patricia Afrim, Felicia Akua Afriyie, Zainab A Aftab, Meenakshi Agarwal, Rachel Agbeko, Chris Agbo, Sunil Aggarwal, Arameh Aghababaie, Laura Aguilar Jimenez, Jacqueline Afrakomah Agyekum, Kwame Agyen, Shafana Ahamed Sadiq, Mohamed H Ahammed Nazeer, Mohammad Ahmad, Syed Ahmad, Afshan Ahmed, Ashar Ahmed, Asim Ahmed, Basheer A R Ahmed, Bilal Ahmed, Forizuddin Ahmed, Hamze Ahmed, Hanad Ahmed, Irshad Ahmed, Khaled Ahmed, Khalil Ahmed, Liban Ahmed, Mahin Ahmed, Maria C Ahmed, Muhammad S Ahmed, Naseer Ahmed, Nausheen Ahmed, Osama Ahmed, Rajia A Ahmed, Rawya Ahmed, Rizwan Ahmed, Saif Ahmed, Sammiya Ahmed, Sana G Ahmed, Syed Ahmed, Syed H Ahmed, Roa Ahmed Ali, Bilal Ahmed Mohamud, Sana Ahmed, Sana Ahmer, Augustine Ahonia, Christine Aiken, Dhiraj Ail, Mark Ainsworth, Myriam Aissa, Lindianne Aitken, Bini Ajay, Abdulakeem Ajibode, Ayesha Ajmi, Nasim Akhtar, Nauman Akhtar, Suha Akili, Bolutito Akinbiyi, Oludoyinsola Akindolie, Yinka Akinfenwa, Olugbenga Akinkugbe, Ibrahim Akinpelu, Mohammad Akram, Olugbenro Aktinade, Uzayr Akudi, Ahmad S A R Al Aaraj, Asma Al Balushi, Majd Al Dakhola, Aladdin Al Swaifi, Eslam Al-Abadi, Adegoke Alabi, Narendra Aladangady, Mohamed Alafifi, Ayaz Alam, Sajid Alam, Abbas Al-Asadi, Kyriaki Alatzoglou, Paul Albert, Albertus Albertus, Lorraine Albon, Angela Alcala, Gemma Alcorn, Stephen Alcorn, Aggie Aldana, David Alderdice, Abdullah Aldesouki, Rayan Aldouri, Jonathan Aldridge, Nicolas Aldridge, Ram Maya Ale, Ana Alegria, Alison Alexander, Courtney Alexander, John Alexander, Peter D G Alexander, Julyan Al-fori, Laith Alghazawi, Osama Alhabsha, Bahij Al-Hakim, Rafil Alhameed, Mohammed Al-Hayali, Shams Al-Hity, Ali Ali, Amanda Ali, Asad Ali, Fawzia R Ali, Jawad Ali, Mariam Ali, Mohamed Ali, Mohammad Ali, Muhammad S Ali, Nayab Ali, Oudai Ali, Ramla Ali, Sakina Ali, Syed Ali, Emilio Aliberti, Jade Alin, Abid Alina, Analyn Alipustain, Bachti Alisjahbana, Fine Aliyuda, Katrin Alizadeh, Maithem Al-Jibury, Saba Al-Juboori, Majid Al-Khalil, Abdullah Alkhudhayri, Moutaz Alkhusheh, Fiona Allan, Nataliya Allan, Alison Allanson, Robert Allcock, Eireann Allen, Jade Allen, Kerry Allen, Louise Allen, Poppy Allen, Rebecca Allen, Sam Allen, Sharon Allen, Simon Allen, Tania Allen, Abiola Alli, Kathryn Allison, Bethan Allman, Helen K Allsop, Lynne Allsop, David Allsup, Amal F T Almahroos, Hassan Al-Moasseb, Magda Al-Obaidi, Lina Alomari, Akram Al-Rabahi, Bahar Al-Ramadhani, Zayneb Al-Saadi, Riyam Al-Sammarraie, Inji Alshaer, Rustam Al-Shahi Salman, Warkaq Al-Shamkhani, Fadia Alsheikh, Bashar Al-Sheklly, Sara Altaf, Amanda Alty, Mary Alvarez, Maria Alvarez Corral, Edward Alveyn, Maysaa Alzetani, Susan Amamou, Noor Amar, Sakkarai Ambalavanan, Robert Ambrogetti, Chris Ambrose, Amir Ameen, Amel Amelia Ganefianty, Katharine Ames, Maria R Amezaga, Allison Amin, Amina Amin, Kanish Amin, Syed Amin, Tara Amin, Badshah Amit, Amjad Amjad, Neelma Amjad, James Amoah-Dankwa, Victoria Amosun, Muhammad Amsal, Khaled Amsha, John Amuasi, Noelia Amutio Martin, Pugh Amy, Ann Anada, Atul Anand, Samantha Anandappa, Satya D Anantapatnaikuni, Ellen Anderson, Julie Anderson, Laura Anderson, Marina Anderson, Michelle Anderson, Nicola Anderson, Rachel Anderson, Rebecca Anderson, Rory Anderson, Samantha Anderson, Wendy Anderson, Prematie Andreou, Angela Andrews, Antonette Andrews, Jill Andrews, Joyann Andrews, Kanayochukwu Aneke, Andrew Ang, Wan Wei Ang, Tammy Angel, Aramburo Angela, Paola Angelini, Lazarus Anguvaa, Oleg Anichtchik, Millicent Anim-Somuah, Krishnan Aniruddhan, Jessica Annett, Louise Anning, Maldwyn Ansah, Patrick J Anstey, Rebekah Anstey, Alpha Anthony, Aaron Anthony-Pillai, Philip Antill, Zhelyazkova Antonina, Varghese Anu, Muhammad Anwar, Elena Apetri, Aristeidis Apostolopoulos, Sarah Appleby, Diane Appleyard, Maia F Aquino, Bianca Araba, Samuel Aransiola, Mariana Araujo, Ann Archer, Denise Archer, Samuel Archer, Simon Archer, Daniele Arcoria, Christian Ardley, Ana-Maria Arias, Oluwatoyin Aribike, Ryoki Arimoto, Charlotte Arkley, Charlotte Armah, Ilianna Armata, Jennifer Armistead, Adam Armitage, Ceri Armstrong, Maureen Armstrong, Sonia Armstrong, Wendy Armstrong, Philippa Armtrong, Heike Arndt, Clare Arnison-Newgass, David Arnold, Rachael Arnold, Andrew Arnott, Dhawal Arora, Kavan Arora, Pardeep Arora, Rishi Arora, Arslam Arter, Armena Arumaithurai, Ayush Arya, Rita Arya, Diptesh Aryal, Denisa Asandei, Adeeba Asghar, Malik Asghar, Arif Ashab, Catherine Ashbrook-Raby, Helen Ashby, Jan Ashcroft, John Ashcroft, Samuel Ashcroft, Georgia Asher, Zakariya Ashfak, Ayesha Ashfaq, Abdul Ashish, Dawn Ashley, Sally Ashman-Flavell, Sundar Ashok, Abd-El-Aziz Ashour, Muhammad Z Ashraf, Saima Ashraf, Mohammad B Ashraq, Deborah Ashton, Susan Ashton, Andrew Ashworth, Fiona J Ashworth, Rebecca Ashworth, Arshia Aslam, I Aslam, Suhail Aslam, Laura Aslett, Harshini Asogan, Atif Asrar, Omar Assaf, Raine Astin-Chamberlain, Deborah Athorne, Billie Atkins, Christopher Atkins, Stacey Atkins, John Atkinson, Vicki Atkinson, Abolaji Atomode, Brygitta Atraskiewicz, Abdul A Attia, Eva Attubato, Marie Attwood, Paula Aubrey, Zoltan Auer, Avinash Aujayeb, Aye Chan Thar Aung, Hnin Aung, Hnin Wint Wint Aung, Ko Ko Aung, Kyaw Thu Aung, Nwe Aung, Yin Aung, Zaw Myo Aung, Emily Austin, Karen Austin, Abdusshakur Auwal, Malcolm Avari, Miriam Avery, Nicholas Aveyard, Joanne Avis, Georgina Aviss, Cristina Avram, Paula Avram, Abuzar Awadelkareem, Gabriel Awadzi, Mahmoud Awaly, Atia Awan, Aszad Aya, Eman Ayaz, John Maximilian Ayerh, Amanda Ayers, Jawwad Azam, Ahmed Azeem, Mohammed Azharuddin, Ammar Aziz, Ghazala Aziz, Imran Aziz, N Aziz, Ali Azkoul, Ashaari Azman Shah, Giada Azzopardi, Hocine Azzoug, Fiyinfoluwa Babatunde, Melvin Babi, Babiker Babiker, Gayna Babington, Matthew Babirecki, Marta Babores, Adetona O Babs-Osibodu, Sammy Bacciarelli, Roudi Bachar, Michel-Elie Bachour, Alisjahbana Bachti, Gina Bacon, Jenny Bacon, Bibi Badal, Aysha Badat, Maryuma Bader, Gurpreet R Badhan, Shreya Badhrinarayanan, Joseph P Bae, Alice Baggaley, Amy Baggott, Graham Bagley, Dinesh Bagmane, Lynsey Bagshaw, Kasra Bahadori, Angela Bailey, James Bailey, Katie Bailey, Lindsey Bailey, Liz Bailey, Lucy Bailey, Maria A Bailey, Morgan Bailey, Pippa Bailey, Sarah Bailey, Hamish Baillie, J Kenneth Baillie, Jennifer Bain, Vikram Bains, David Baird, Eilidh Baird, Kevin Baird, Susan Baird, Tracy Baird, Yolanda Baird, Aiysha Bajandouh, Danielle C Baker, Evelyn Baker, Johanne Baker, Josephine Baker, Kenneth Baker, Mark Baker, Rebecca Baker, Terri-Anne Baker, Victoria Baker, Hugh Bakere, Nawar Bakerly, Michelle Baker-Moffatt, Ameet Bakhai, Nauman Bakhtiar, Panos Bakoulas, Dhanalakshmi Bakthavatsalam, Niranjan Balachandran, Andrea Balan, Prasath Balasingam, Theodosios Balaskas, Madhu Balasubramaniam, Nicola Balatoni, Alison Balcombe, Alexander Baldwin, Ashley Baldwin, Caron Baldwin, Danielle Baldwin, Fiona Baldwin, Rebekah Baldwin-Jones, Nichola Bale, James Balfour, Matthew Ball, Robert Ball, K Ballard, Ismael Balluz, Craig Balmforth, Emese Balogh, Abeir Baltmr, Amir Baluwala, Gabby Bambridge, Alasdair Bamford, Amy Bamford, Peter Bamford, Adefunke Bamgboye, Elizabeth Bancroft, Hollie Bancroft, Joyce Banda, Krishna Bandaru, Srini Bandi, Nageswar Bandla, Somaditya Bandyopadhyam, Amit Banerjee, Ritwik Banerjee, Santosh Baniya, Omar Bani-Saad, Harrison Banks, Luke Banks, Paul Banks, Claudia Bann, Helen Bannister, Oliver Bannister, Laura Banton, Tran Bao, Mariamma Baptist, Tanya Baqai, Ananya M Baral, Sharad Chandra Baral, Desislava Baramova, Russel Barber, Emma Barbon, Monica Barbosa, Jamie Barbour, Alexander Barclay, Amanda Barclay, Claire Barclay, George Bardsley, Stephanie Bareford, Shahedal Bari, Morris Barimbing, Amy Barker, Debbie Barker, Erandi Barker, Helen Barker, Joseph Barker, Leon Barker, Lesley Barker, Oliver Barker, Kerry Barker-Williams, Sinha Barkha, Juliana Barla, Gavin Barlow, Richard Barlow, Valerie Barlow, James Barnacle, Alex Barnard, Debi Barnes, Nicky Barnes, Rory Barnes, Theresa Barnes, Calum Barnetson, Amy Barnett, Ashton Barnett-Vanes, Prince Gyenti Barning, William Barnsley, Andrew Barr, David Barr, James Barr, Charlotte Barr, Nina Barratt, Shaney Barratt, Manuella Barrera, Amy Barrett, Fiona Barrett, Jessica Barrett, Sue Barrett, Esther Barrow, Jazz Bartholomew, Claire Bartlett, Georgina Bartlett, James Bartlett, Louise Bartlett, Shauna Bartley, Sandra Bartolmeu-Pires, Anna Barton, Greg Barton, Jill Barton, Lorna Barton, Rachael Barton, Rosaleen Baruah, Sonia Baryschpolec, Hannah Bashir, Archana Bashyal, Betsy Basker, Sudha Basnet, Buddha Basnyat, Ayten Basoglu, Alexander Basran, John Bassett, G Bassett, Chris Bassford, Bengisu Bassoy, Victoria Bastion, Anup Bastola, Anupam Basumatary, Precious Basvi, Jireh A Batac, Vipula R Bataduwaarachchi, Tristan Bate, Harry J Bateman, Kathryn Bateman, Vhairi Bateman, Eleanor Bates, Hayley Bates, Michelle Bates, Simon Bates, Sally Batham, Ana Batista, Amit Batla, Dushyant Batra, Harry Batty, Thomas Batty, Alice Batty, Miranda Baum, Rachel Baumber, Carina Bautista, Fareha Bawa, Tanveer Bawa, Fatima S Bawani, Simon Bax, Matt Baxter, Nicola Baxter, Zachary Baxter, Hannah Bayes, Lee-Ann Bayo, Farid Bazari, Rohit Bazaz, Ahmad Bazli, Laura Beacham, Wendy Beadles, Kirsten Beadon, Philip Beak, Andy Beale, Kathy Beard, Jack Bearpark, Alanna Beasley, Sandee Beattie, Karen Beaumont, Dawn Beaumont-Jewell, Theresa Beaver, Sarah Beavis, Christy Beazley, Sarah Beck, Virginia Beckett, Rosie Beckitt, Sarah Beckley, Heidi Beddall, Seonaid Beddows, Deborah Beeby, Sophia Beeby, Gail Beech, Michelle Beecroft, Nigel Beer, Sally Beer, Jane Beety, Gabriela Bega, Alison Begg, Susan Begg, Sara Beghini, Ayesha Begum, Salman Begum, Selina Begum, Teresa Behan, Roya Behrouzi, Jon Beishon, Claire Beith, James Belcher, Holly Belfield, Katherine Belfield, Ajay Belgaumkar, Dina Bell, Gareth Bell, Gillian Bell, Jessica Bell, Lauren Bell, Louise Bell, Nicholas Bell, Pippa Bell, Stephanie Bell, Jennifer Bellamu, Mary Bellamy, Tammy Bellamy, Arianna Bellini, Amanda Bellis, Fionn Bellis, Lesley Bendall, Naveena Benesh, Nicola Benetti, Leonie Benham, Guy Benison-Horner, Sarah Benkenstein, Tracey Benn, Ann 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Flanagan, Charles Flanders, Nikolaos Flaris, Gail Fleming, Julie Fleming, Lucy Fleming, Paul Fleming, William Flesher, Alison Fletcher, Anna Fletcher, Jonathan Fletcher, Lucy Fletcher, Simon Fletcher, Sophie Fletcher, Fiona Flett, Karen Flewitt, Sarah Flockhart, Christopher Flood, Ian Floodgate, Jonathan Flor, Vincent Florence, Mary Flowerdew, Sharon Floyd, Margaret J Flynn, Rachel Flynn, Claire Foden, Adama Fofana, Georgina Fogarty, Paul Foley, Linda Folkes, Tracey Fong, Daniela M Font, Aiwyne Foo, Jane Foo, Andrew Foot, Helen R Foot, Jayne Foot, Jane Forbes, Amber Ford, Jamie Ford, Imogen Fordham, Jennifer Foreman, Matthew Forester, Mohammad Forkan, Caroline Fornolles, Adam Forrest, Ellie Forsey, Miranda Forsey, Thomas Forshall, Elliot Forster, Abigail Forsyth, Julian Forton, Conrad Foster, Emily Foster, Joseph Foster, Rachel A Foster, Tracy Foster, Angela Foulds, Ian Foulds, Folakemi Fowe, Natasha Fowkes, Emily Fowler, Robert Fowler, Stephen Fowler, Amy Fox, Claire Fox, Heather Fox, 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Giokanini-Royal, Anna Gipson, Barbie Giri, Joanna Girling, Rhian Gisby, Angelena Gkioni, Aikaterini Gkoritsa, Effrossyni Gkrania-Klotsas, Amy Gladwell, James Glanville, Jessica Glasgow, Susannah Glasgow, Jon Glass, Lynn Glass, Sharon Glaysher, Lisa Gledhill, Eleanor Glenday, Ana Glennon, Jodie Glossop, John Glover, Kyle Glover, Michelle Glover, Jan Glover Bengtsson, Deborah Glowski, Sharon Glynn, Chevanthy Gnanalingam, Julie Goddard, Wendy Goddard, Emily Godden, Jo Godden, Sarah Godlee, Emma Godson, Gillian Godwin, Sukanya Gogoi, Aiky Goh, Manjinder Gohel, Rebeca Goiriz, Sriya Gokaraju, Raphael Goldacre, Arthur Goldsmith, Portia Goldsmith, Darren Gomersall, Lucia Gomez, Raquel Gomez-Marcos, Ali Gondal, Celia Gonzalez, Jack Goodall, Vicky Goodall, Bob Goodenough, Anna Goodfellow, Laura Goodfellow, James Goodlife, Camelia Goodwin, Elizabeth Goodwin, Jayne Goodwin, Paula Goodyear, Rajiv Gooentilleke, Michelle Goonasekara, Sheila Gooseman, Shameer Gopal, Chris Gordon, Sally Gordon, Robin 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Hale, Jennie Hale, Carmel Halevy, Paul Halford, William Halford, Alaina Halim, Alistair Hall, Anthony Hall, Claire Hall, Elizabeth Hall, Fiona Hall, Helen Hall, Jennifer Hall, Kathryn Hall, Laura Hall, Jan Hallas, Kyle Hallas, Charles Hallett, Jackie Halliday, Akmal Hallman, Heather Halls, Maryam Hamdollah-Zadeh, Ifedadepo A Hamed-Adekale, Bilal Hameed, Mohammed Hameed, Raph L Hamers, Imran Hamid, Mohamad Hamie, Raymond Hamill, Bethany Hamilton, Fergus Hamilton, Gus Hamilton, Leigh Hamilton, Melanie Hamilton, Nicola Hamilton, Sara Hamilton, Ruth Hamlin, Eleanor Hamlyn, Beatrice Hammans, Shirley Hammersley, Kate Hammerton, Bev Hammond, Emily Hammond, Leah Hammond, Sally Hammond, Fiona Hammonds, Ibrahim Hamoodi, Karen Hampshire, James A Hampson, Jude Hampson, Lucy Hampson, Lisa Hamzah, Jenny Han, Ozan Hanci, Sadiyah Hand, Lala Handayani, Jasmine Handford, Soran Handrean, Nina K Handzewniak, Sarah Haney, Vu Thi Kim Hang, Sheharyar Hanif, E Hanison, Esther Hanison, Jennifer Hannah, Amy 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Ruth Hartley, Tom Hartley, William Hartrey, Phillipa Hartridge, Stuart Hartshorn, Alice Harvey, Angela Harvey, Anna Harvey, Max Harvey, Catherine Harwood, Helen Harwood, Zoe Harzeli, Brigitte Haselden, Kazi Hashem, Mohammed Hashimm, Tadaaki Hashimoto, Imranullah Hashmi, Jack Haslam, Zena Haslam, Grace Hasnip, Adil Hassan, Ali Hassan, Amro Hassan, Awab Hassan, Zeinab Hassan, Sapna Hassasing, Jane Hassell, Philip Hassell, Alex Hastings, Bethany Hastings, Janice Hastings, Sarah Hathaway-Lees, Jonathan Hatton, Jennifer Hau, May Havinden-Williams, Stefan Havlik, Daniel B Hawcutt, Kadean Hawes, Liz Hawes, Nicola Hawes, Lydia Hawker, Annie Hawkins, Joe Hawkins, Nancy Hawkins, W John Hawkins, Dan Hawley, Ed Hawley-Jones, Edward Haworth, Alasdair W Hay, Cathy Hay, Amna Hayat, Jamal Hayat, Mohamed-Riyal Hayathu, Anne Hayes, Jonas Hayes, Kate Hayes, Melony Hayes, Fiona Hayes, Patrick Hayle, Chloe Haylett, Antara Hayman, Melanie Hayman, Matthew Haynes, Richard Haynes, Rachel Hayre, Carole Hays, Sarah Haysom, James Hayward, Patrick Haywood, Hazel Haywood Hasford, Tracy Hazelton, Phoebe Hazenberg, Zhengmai He, Elizabeth Headon, Carrie Heal, Brendan Healy, Jessica L Healy, Amy Hearn, David Heasman, Angela Heath, Debbie Heath, Rowan Heath, Diane Heaton, Adam Heavens, Kerry Hebbron, Catherine Heckman, Gemma Hector, Sadie Heddon, Andy Hedges, Katrine Hedges, Cheryl Heeley, Elaine Heeney, Richard Heinink, Rajdeep Heire, Ingvild Helgesen, Joanne Hemingway, Ulla Hemmila, Beth Hemmings, Scott Hemphill, Deborah Hemsley, Abigail Henderson, Eilidh Henderson, Jennifer Henderson, Steven Henderson, Joanne Henry, Karol Henry, Lavinia Henry, Margo Henry, Natalie Henry, David Henshall, Gillian Herdman, Rosaleen Herdman-Grant, Morag Herkes, Lucas E Hermans, Fe Marie Hernandez, Emma Heron, Lisa Heron, William Herrington, Emilia Heselden, Peta Heslop, Tracey Heslop, Simon Hester, Emily Hetherington, Joseph Hetherington, Chamila Hettiarachchi, Pramodh Hettiarachchi, Hayley Hewer, John Hewertson, Anna Hewetson, Sue Hewins, Nicola Hewitson, Claire Hewitt, Davina Hewitt, Richard Hewitt, Samuel Hey, Robert S Heyderman, Mathis Heydtmann, Joseph Heys, Jonathan Heywood, Meg Hibbert, John Hickey, Naomi Hickey, Peter Hickey, Nicky Hickman, Alex Hicks, Jenny Hicks, Scott R Hicks, Phan Thi Thu Hien, Daniel Higbee, Lucy Higgins, Andrew Higham, Martin Highcock, Judith Highgate, Mondy Hikmat, Amanda Hill, Helen Hill, Joanne Hill, Lisa Hill, Lucy Hill, Phoebe Hill, Uta Hill, Annette Hilldrith, Catherine Hillman-Cooper, Jon Hilton, Zoe Hilton, Sarah Hinch, Andrew Hindle, Esther Hindley, Alice Hindmarsh, Paul Hine, Kim Hinshaw, Clare Hird, Claire Hirst, Lindsay Hirst, Jemma Hives, Htet M Hlaing, Benson Ho, David K K Ho, Rosemary Ho, Michaela Hoare, David Hobden, Gill Hobden, Maria Hobrok, Simon Hobson, Christopher Hodge, Simon Hodge, Lesley Hodgen, George Hodgetts, Holly Hodgkins, Sally Hodgkinson, David Hodgson, Helen Hodgson, Luke Hodgson, Sheila Hodgson, Gemma Hodkinson, Kenneth Hodson, 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Elizabeth Horsley, Sarah Horton, Jane Hosea, Toby Hoskins, Muhammad S Hossain, Rashed Hossain, Maxine Hough, Sarah Hough, Catherine Houghton, Kathryn Houghton, Rebecca Houlihan, Kay Housely, Hamish Houston, Roseanna Hovvels, Lee How, Laura Howaniec, Joanne Howard, Kate Howard, Laura Howard, Linda Howard, Lucy Howard, Megan Howard, Sarah Howard, Stuart Howard, Richard Howard-Griffin, Louise Howard-Sandy, Serena Howe, Alice Howell, Mark Howells, Lyn Howie, Kerry Howlett, Sophie Howlett, Ruth Howman, Josh Hrycaiczuk, Hein Htet, Naing Z Htoon, Su Htwe, Ying Hu, Chiang O H Huah, Sylvia Huang, Kelly Hubbard, Abby Huckle, Shahzya Huda, Alison Hudak, Lisa Hudig, Heather Hudson, Suzanne Hudson, Oli Hudson, Alison Hufton, Connor Huggins, Alistair Hughes, Caitlin Hughes, Emma Hughes, Gareth Hughes, Heather Hughes, Luke Hughes, Martin Hughes, Rachel Hughes, Rebecca Hughes, Samantha Hughes, Stephen Hughes, Vikki Hughes, Wesley Hughes, Lukas Huhn, Ching Hui, Ruth Hulbert, Diana Hull, Grace Hull, Robert Hull, Amanda Hulme, Peter Hulme, Wendy Hulse, George Hulston, Ryan Hum, Megan Hume, Charlotte Humphrey, Alasdair Humphries, Amy Humphries, Joanne Humphries, Charlotte Hunt, Fiona Hunt, Jane Hunt, Jonquil Hunt, Kristen Hunt, Luke Hunt, Molly Hunt, Sophie Hunt, Alexandra Hunter, Catherine Hunter, Ewan Hunter, Karl Hunter, Neil Hunter, Ross Hunter, Sophie Hunter, George Huntington, Fuad Huq, Elizabeth Hurditch, Judith Hurdman, Cian Hurley, Katrina Hurley, Mohammed A Husain, Syeda Y Husaini, Coralie Huson, Afreen Hussain, Chreif Hussain, Ibraar Hussain, Ifza Hussain, Mohammad Hussain, Mohammed Hussain, Muhammad Hussain, Reda Hussain, Rizwana Hussain, Samia Hussain, Sanniah Hussain, Yasmin Hussain, Mohammed Hussam El-Din, Samahir F E M Hussein, Ziad Hussein, Rebecca Hussey, Adiel Haqiq Hussien, Anja Hutchinson, Camille Hutchinson, Dorothy Hutchinson, Elizabeth Hutchinson, John Hutchinson, Claire Hutsby, Paula Hutton, Nguyen Quang Huy, Thuong Huyen, Tran Bang Huyen, Nguyen Thi Huyen Thuong, Hieu Huynh, Daniella Hydes, Jamie Hyde-Wyatt, Niamh Hynes, Megan Hyslop, Angeliki Iakovou, Katherine Ibison, Mazen Ibraheim, Abdalla Ibrahim, Ahmed Ibrahim, Asil Ibrahim, Javed Ibrahim, Mamoun Ibrahim, Mohamed Ibrahim, Wadah Ibrahim, Becky Icke, Adetokunbo Idowu Idowu, Muhammad Idrees, Nauman Idrees, Hina Iftikhar, Mawara Iftikhar, Chukwuemeka Igwe, Ogechukwu Igwe, Mohammad Ijaz, Amaju Ikomi, Clare Iles, Stamatina Iliodromiti, Mary Ilsley, Lorna Ilves, Fatima Mariam Ilyas, La'ali Imam-Gutierrez, Mohamed Iman, Christopher Imray, Haider Imtiaz, Jack Ingham, Jo Ingham, Julie Ingham, Rory Ingham, Tejas Ingle, Jennifer Inglis, Samantha Inglis-Hawkes, Anne Ingram, Luke Ingram, Tanya Ingram, Nicholas Innes, Peter Inns, Vithusha Inpadhas, Ken Inweregbu, Andreea A Ionescu, Ana Ionita, Ilian Petkov Iordanov, Anil Ipe, Javaid Iqbal, Madiha Iqbal, Mishal Iqbal, Mohammed Iqbal, Faisal Iqbal Sait, Iziegbe Irabor, Jane Ireland, Jamie Irisari, Robert Irons, Mohannad Irshad, Muhammad S Irshad, 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Jennings, Jacqui Jennings, Louise Jennings, Virginia Jennings, Ellen Jerome, Douglas Jerry, Greame Jervis, Ellen Jessup-Dunton, Jorge A Jesus Silva, Champa Jetha, Kishan Jethwa, Roshan Kumar Jha, Shaman Jhanji, Khoo Jian, Zhixin Jiao, Laura Jimenez, Ana Jimenez Gil, Jithin Jith, Teishel Joefield, Navraj Johal, Simran Johal, Karine Johannessen, Aisyah Johari, Annie John, Anu John, Maya John, Navin John, Emma Johns, Margaret Johns, Antoinette Johnson, Emma Johnson, Gillian Johnson, Kathryn Johnson, Katie Johnson, Luke Johnson, Mark Johnson, Nelsonseelan Johnson, Oliver Johnson, Rachel Johnson, Brogan Johnston, Claire Johnston, Janet Johnston, Susan Johnston, Victoria Johnston, Dawn Johnstone, Ed Johnstone, Janet Johnstone, Manohar Joishy, Adam Jones, Alistair Jones, Amy Jones, Angela Jones, Annabel Jones, Ben Jones, Bryony Jones, Carys Jones, Ceri Jones, Charlotte Jones, Christine E Jones, Debra Jones, Emily Jones, Gareth Jones, Geraldine Jones, Jac Jones, James Jones, Jonathon Jones, Julie Jones, Kate E Jones, Kimberly Jones, Laura Jones, Laura M Jones, Louise Jones, Mathew Jones, Nancy Jones, Nicola Jones, Olivia Jones, Paul Jones, Philip H Jones, Rhianna Jones, Ruth E Jones, Samantha Jones, Sophie Jones, Stefanie Jones, Steve Jones, Susan Jones, Taya Jones, Thomas Jones, Tim Jones, Tracey Jones, Ramya Jonnalagadda, Rebecca Jordache, Michele Jordan, Sarah Jordan, Abi Jose, Litty Jose, Louise Jose, Sanal Jose, Anna Joseph, Gigee Joseph, P Aiden Joseph, Rosane Joseph, Sibet Joseph, Dhaara Joshi, Mehul Joshi, Pratichi Joshi, Tushar Joshi, Benz Josiah, Lijo Joy, Tiffany Joyce, Hong Ju, Adriel Ju Wen Kwek, Andrew Judd, Edward Jude, Parminder Judge, Jessica Juhl, Sirisha Jujjavarapu, Mark Juniper, Edmund Juszczak, Deepthi Jyothish, Kasamu Kabiru Dawa, Mark Kacar, Nikhil Kadam, Nicole Kader, Ajai Kailey, Matthew Kain, Gail Kakoullis, Azad Kala Bhushan, Richard J K Kalayi, Roobala Kaliannan Periyasami, Efthymia Kallistrou, Thomas Kalmus Eliasz, Seika Kalsoom, Elisa Kam, 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Infection and Global Health Division, University of St Andrews. School of Medicine, and Group, RECOVERY Collaborative

Subjects
Adult, Male, Hypoxia/etiology, SARS-CoV-2, COVID-19, 3rd-DAS, General Medicine, Adrenal Cortex Hormones/therapeutic use, AC, Dexamethasone/therapeutic use, Hospitals, Oxygen, Treatment Outcome, SDG 3 - Good Health and Well-being, MCP, Humans, Female
Abstract

Background Low-dose corticosteroids have been shown to reduce mortality for patients with COVID-19 requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group. Methods This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (ie, receiving oxygen or with oxygen saturation Findings Between May 25, 2021, and May 13, 2022, 1272 patients with COVID-19 and hypoxia receiving no oxygen (eight [1%]) or simple oxygen only (1264 [99%]) were randomly allocated to receive usual care plus higher dose corticosteroids (659 patients) versus usual care alone (613 patients, of whom 87% received low-dose corticosteroids during the follow-up period). Of those randomly assigned, 745 (59%) were in Asia, 512 (40%) in the UK, and 15 (1%) in Africa. 248 (19%) had diabetes and 769 (60%) were male. Overall, 123 (19%) of 659 patients allocated to higher dose corticosteroids versus 75 (12%) of 613 patients allocated to usual care died within 28 days (rate ratio 1·59 [95% CI 1·20–2·10]; p=0·0012). There was also an excess of pneumonia reported to be due to non-COVID infection (64 cases [10%] vs 37 cases [6%]; absolute difference 3·7% [95% CI 0·7–6·6]) and an increase in hyperglycaemia requiring increased insulin dose (142 [22%] vs 87 [14%]; absolute difference 7·4% [95% CI 3·2–11·5]). Interpretation In patients hospitalised for COVID-19 with clinical hypoxia who required either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared with usual care, which included low-dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalised with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Funding UK Research and Innovation (Medical Research Council), National Institute of Health and Care Research, and Wellcome Trust.

Published
2023
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46. Previous Lung Diseases and Lung Cancer Risk: A Pooled Analysis From the International Lung Cancer Consortium

Author

Brenner, Darren R, Boffetta, Paolo, Duell, Eric J, Bickeböller, Heike, Rosenberger, Albert, McCormack, Valerie, Muscat, Joshua E, Yang, Ping, Wichmann, H-Erich, Brueske-Hohlfeld, Irene, Schwartz, Ann G, Cote, Michele L, Tjønneland, Anne, Friis, Søren, Le Marchand, Loic, Zhang, Zuo-Feng, Morgenstern, Hal, Szeszenia-Dabrowska, Neonila, Lissowska, Jolanta, Zaridze, David, Rudnai, Peter, Fabianova, Eleonora, Foretova, Lenka, Janout, Vladimir, Bencko, Vladimir, Schejbalova, Miriam, Brennan, Paul, Mates, Ioan N, Lazarus, Philip, Field, John K, Raji, Olaide, McLaughlin, John R, Liu, Geoffrey, Wiencke, John, Neri, Monica, Ugolini, Donatella, Andrew, Angeline S, Lan, Qing, Hu, Wei, Orlow, Irene, Park, Bernard J, and Hung, Rayjean J

Subjects
Epidemiology, Health Services and Systems, Health Sciences, Chronic Obstructive Pulmonary Disease, Pneumonia, Prevention, Lung, Tobacco Smoke and Health, Cancer, Tobacco, Rare Diseases, Pneumonia & Influenza, Lung Cancer, Infectious Diseases, Respiratory, Good Health and Well Being, Bronchitis, Chronic, Humans, Logistic Models, Lung Neoplasms, Proportional Hazards Models, Pulmonary Emphysema, Risk, Risk Factors, Self Report, Tuberculosis, Pulmonary, bronchitis, chronic, emphysema, lung diseases, lung neoplasms, meta-analysis, pneumonia, pulmonary disease, chronic obstructive, tuberculosis, Mathematical Sciences, Medical and Health Sciences
Abstract

To clarify the role of previous lung diseases (chronic bronchitis, emphysema, pneumonia, and tuberculosis) in the development of lung cancer, the authors conducted a pooled analysis of studies in the International Lung Cancer Consortium. Seventeen studies including 24,607 cases and 81,829 controls (noncases), mainly conducted in Europe and North America, were included (1984-2011). Using self-reported data on previous diagnoses of lung diseases, the authors derived study-specific effect estimates by means of logistic regression models or Cox proportional hazards models adjusted for age, sex, and cumulative tobacco smoking. Estimates were pooled using random-effects models. Analyses stratified by smoking status and histology were also conducted. A history of emphysema conferred a 2.44-fold increased risk of lung cancer (95% confidence interval (CI): 1.64, 3.62 (16 studies)). A history of chronic bronchitis conferred a relative risk of 1.47 (95% CI: 1.29, 1.68 (13 studies)). Tuberculosis (relative risk = 1.48, 95% CI: 1.17, 1.87 (16 studies)) and pneumonia (relative risk = 1.57, 95% CI: 1.22, 2.01 (12 studies)) were also associated with lung cancer risk. Among never smokers, elevated risks were observed for emphysema, pneumonia, and tuberculosis. These results suggest that previous lung diseases influence lung cancer risk independently of tobacco use and that these diseases are important for assessing individual risk.

Published
2012

47. In-Home Coal and Wood Use and Lung Cancer Risk: A Pooled Analysis of the International Lung Cancer Consortium

Author

Hosgood, H Dean, Boffetta, Paolo, Greenland, Sander, Lee, Yuan-Chin Amy, McLaughlin, John, Seow, Adeline, Duell, Eric J, Andrew, Angeline S, Zaridze, David, Szeszenia-Dabrowska, Neonila, Rudnai, Peter, Lissowska, Jolanta, Fabiánová, Eleonóra, Mates, Dana, Bencko, Vladimir, Foretova, Lenka, Janout, Vladimir, Morgenstern, Hal, Rothman, Nathaniel, Hung, Rayjean J, Brennan, Paul, and Lan, Qing

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Lung, Clinical Research, Cancer, Prevention, Lung Cancer, Respiratory, Aged, Air Pollution, Indoor, Coal, Cooking, Female, Heating, Humans, International Agencies, Lung Neoplasms, Male, Middle Aged, Risk Factors, Wood, coal, lung cancer, pooled, risk factor, wood, Environmental Sciences, Medical and Health Sciences, Toxicology, Biomedical and clinical sciences, Environmental sciences, Health sciences
Abstract

BackgroundDomestic fuel combustion from cooking and heating is an important public health issue because roughly 3 billion people are exposed worldwide. Recently, the International Agency for Research on Cancer classified indoor emissions from household coal combustion as a human carcinogen (group 1) and from biomass fuel (primarily wood) as a probable human carcinogen (group 2A).ObjectivesWe pooled seven studies from the International Lung Cancer Consortium (5,105 cases and 6,535 controls) to provide further epidemiological evaluation of the association between in-home solid-fuel use, particularly wood, and lung cancer risk.MethodsUsing questionnaire data, we classified subjects as predominant solid-fuel users (e.g., coal, wood) or nonsolid-fuel users (e.g., oil, gas, electricity). Unconditional logistic regression was used to estimate the odds ratios (ORs) and to compute 95% confidence intervals (CIs), adjusting for age, sex, education, smoking status, race/ethnicity, and study center.ResultsCompared with nonsolid-fuel users, predominant coal users (OR = 1.64; 95% CI, 1.49-1.81), particularly coal users in Asia (OR = 4.93; 95% CI, 3.73-6.52), and predominant wood users in North American and European countries (OR = 1.21; 95% CI, 1.06-1.38) experienced higher risk of lung cancer. The results were similar in never-smoking women and other subgroups.ConclusionsOur results are consistent with previous observations pertaining to in-home coal use and lung cancer risk, support the hypothesis of a carcinogenic potential of in-home wood use, and point to the need for more detailed study of factors affecting these associations.

Published
2010

48. Identification of methylated genes associated with aggressive bladder cancer.

Author

Marsit, Carmen J, Houseman, E Andres, Christensen, Brock C, Gagne, Luc, Wrensch, Margaret R, Nelson, Heather H, Wiemels, Joseph, Zheng, Shichun, Wiencke, John K, Andrew, Angeline S, Schned, Alan R, Karagas, Margaret R, and Kelsey, Karl T

Subjects
Cell Line, Tumor, Humans, Carcinoma, Transitional Cell, Neoplasm Invasiveness, Glycoproteins, Intracellular Signaling Peptides and Proteins, Homeodomain Proteins, Transcription Factors, DNA, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, DNA Methylation, Gene Expression Regulation, Neoplastic, CpG Islands, Middle Aged, Female, Male, Genes, Neoplasm, Urinary Bladder Neoplasms, Keratin-13, Genetic Loci, Cell Line, Tumor, Carcinoma, Transitional Cell, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, General Science & Technology
Abstract

Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment.

Published
2010

49. Lung Cancer in a U.S. Population with Low to Moderate Arsenic Exposure

Author

Heck, Julia E, Andrew, Angeline S, Onega, Tracy, Rigas, James R, Jackson, Brian P, Karagas, Margaret R, and Duell, Eric J

Subjects
Epidemiology, Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Foodborne Illness, Cancer, Lung Cancer, Prevention, Lung, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Respiratory, Adult, Aged, Arsenic, Carcinoma, Squamous Cell, Case-Control Studies, Environmental Exposure, Female, Humans, Logistic Models, Lung Diseases, Lung Neoplasms, Male, Middle Aged, Nails, New Hampshire, Retrospective Studies, Risk Factors, Selenium, Small Cell Lung Carcinoma, Spectrophotometry, Atomic, Vermont, Water Pollutants, Chemical, arsenic, bronchitis, chronic obstructive pulmonary disease, lung cancer, lung diseases, pulmonary fibrosis, small-cell carcinoma, smoking, Environmental Sciences, Medical and Health Sciences, Toxicology, Biomedical and clinical sciences, Environmental sciences, Health sciences
Abstract

BackgroundLittle is known about the carcinogenic potential of arsenic in areas with low to moderate concentrations of arsenic (< 100 microg/L) in drinking water.ObjectivesWe examined associations between arsenic and lung cancer.MethodsA population-based case-control study of primary incident lung cancer was conducted in 10 counties in two U.S. states, New Hampshire and Vermont. The study included 223 lung cancer cases and 238 controls, each of whom provided toenail clippings for arsenic exposure measurement by inductively coupled-plasma mass spectrometry. We estimated odds ratios (ORs) of the association between arsenic exposure and lung cancer using unconditional logistic regression with adjustment for potential confounders (age, sex, race/ethnicity, smoking pack-years, education, body mass index, fish servings per week, and toenail selenium level).ResultsArsenic exposure was associated with small-cell and squamous-cell carcinoma of the lung [OR = 2.75; 95% confidence interval (CI), 1.00-7.57] for toenail arsenic concentration > or = 0.114 microg/g, versus < 0.05 microg/g. A history of lung disease (bronchitis, chronic obstructive pulmonary disease, or fibrosis) was positively associated with lung cancer (OR = 2.86; 95% CI, 1.39-5.91). We also observed an elevated risk of lung cancer among participants with a history of lung disease and toenail arsenic > or = 0.05 microg/g (OR = 4.78; 95% CI, 1.87-12.2) than among individuals with low toenail arsenic and no history of lung disease.ConclusionAlthough this study supports the possibility of an increased risk of specific lung cancer histologic types at lower levels of arsenic exposure, we recommend large-scale population-based studies.

Published
2009

50. Burnout prevalence and degree among undergraduate medical students in Indonesia during 1 month of the COVID-19 pandemic: A cross-sectional descriptive survey

Author

Darien Alfa Cipta, Felix Wijovi, Leslie Melisa, Rossalina Lili, Elizabeth Marcella, Angeline Tancherla, Febby Gunawan Siswanto, Dewa Ayu Kalista Liani Adiya, Sharon Chen, Gabriel Julio Caesar Ika Dermawan, Mellybeth Indriani Louis, Theresia Citraningtyas, and Andrew Molodynski

Subjects
Psychiatry and Mental health, Cross-Sectional Studies, Students, Medical, Indonesia, Surveys and Questionnaires, Prevalence, COVID-19, Humans, Burnout, Psychological, Burnout, Professional, Pandemics
Abstract

Background: Medical students are under high pressure to perform academically and also face the impact of the COVID-19 pandemic, putting them at risk of developing burnout. Aims: This study aims to evaluate the prevalence and degree of burnout among medical students in Indonesia during 1 month of the COVID-19 pandemic. Methods: From April to May 2021, we conducted an online survey of Indonesian medical students to assess burnout (using Maslach Burnout Inventory-Student Survey, MBI-SS). Results: A total of 1,947 students from 27 universities participated in the study. About 35.5% had burnout, 41.7% with a moderate to high level of emotional exhaustion, 45% had moderate to high level of depersonalization and 66.7% had a low level of personal accomplishment. Conclusion: A total of 35.5% of medical students in our sample experienced burnout. We suggest further research to explore and identify factors related to these findings and the need for potential interventions at global and national level to enhance the well-being of medical students.

Published
2022
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