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1. Insurance-Based Disparities in Stroke Center Access in California: A Network Science Approach.

Author

Zachrison, Kori, Hsia, Renee, Schwamm, Lee, Yan, Zhiyu, Samuels-Kalow, Margaret, Reeves, Mathew, Camargo, Carlos, and Onnela, Jukka-Pekka

Subjects
United States, hospitals, ischemic stroke, medically uninsured, patients, Humans, Female, Aged, United States, Male, Insurance, Health, Medicare, Retrospective Studies, Patient Transfer, Insurance Coverage, Medicaid, Medically Uninsured, Stroke, California, Ischemic Stroke
Abstract

BACKGROUND: Our objectives were to determine whether there is an association between ischemic stroke patient insurance and likelihood of transfer overall and to a stroke center and whether hospital cluster modified the association between insurance and likelihood of stroke center transfer. METHODS: This retrospective network analysis of California data included every nonfederal hospital ischemic stroke admission from 2010 to 2017. Transfers from an emergency department to another hospital were categorized based on whether the patient was discharged from a stroke center (primary or comprehensive). We used logistic regression models to examine the relationship between insurance (private, Medicare, Medicaid, uninsured) and odds of (1) any transfer among patients initially presenting to nonstroke center hospital emergency departments and (2) transfer to a stroke center among transferred patients. We used a network clustering method to identify clusters of hospitals closely connected through transfers. Within each cluster, we quantified the difference between insurance groups with the highest and lowest proportion of transfers discharged from a stroke center. RESULTS: Of 332 995 total ischemic stroke encounters, 51% were female, 70% were ≥65 years, and 3.5% were transferred from the initial emergency department. Of 52 316 presenting to a nonstroke center, 3466 (7.1%) were transferred. Relative to privately insured patients, there were lower odds of transfer and of transfer to a stroke center among all groups (Medicare odds ratio, 0.24 [95% CI, 0.22-0.26] and 0.59 [95% CI, 0.50-0.71], Medicaid odds ratio, 0.26 [95% CI, 0.23-0.29] and odds ratio, 0.49 [95% CI, 0.38-0.62], uninsured odds ratio, 0.75 [95% CI, 0.63-0.89], and 0.72 [95% CI, 0.6-0.8], respectively). Among the 14 identified hospital clusters, insurance-based disparities in transfer varied and the lowest performing cluster (also the largest; n=2364 transfers) fully explained the insurance-based disparity in odds of stroke center transfer. CONCLUSIONS: Uninsured patients had less stroke center access through transfer than patients with insurance. This difference was largely explained by patterns in 1 particular hospital cluster.

Published
2023

2. Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium.

Author

Soucy, Jonathan, Aguzzi, Erika, Cho, Julie, Gilhooley, Michael, Keuthan, Casey, Luo, Ziming, Monavarfeshani, Aboozar, Saleem, Meher, Wang, Xue-Wei, Wohlschlegel, Juilette, Baranov, Petr, Di Polo, Adriana, Fortune, Brad, Gokoffski, Kimberly, Goldberg, Jeffrey, Guido, William, Kolodkin, Alex, Mason, Carol, Ou, Yvonne, Reh, Thomas, Ross, Ahmara, Samuels, Brian, Welsbie, Derek, Zack, Donald, and Johnson, Thomas

Subjects
Glaucoma, Neuroprotection, Ophthalmology, Optic neuropathy, Organoids, Regenerative medicine, Retinal ganglion cells, Stem cells, Transplantation, Animals, Humans, Retinal Ganglion Cells, Optic Nerve Diseases, Retina, Brain, Cell Differentiation, Mammals
Abstract

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous systems limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortiums efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.

Published
2023

3. Behavioral Health Decision Support Systems and User Interface Design in the Emergency Department.

Author

Jones, Nicholas, Song, Sophia, Thomasian, Nicole, Samuels, Elizabeth, and Ranney, Megan

Subjects
Adult, Humans, Decision Support Systems, Clinical, Emergency Service, Hospital, Hospitals, University, Physicians, Qualitative Research
Abstract

OBJECTIVE: The objective of this qualitative study is to gauge physician sentiment about an emergency department (ED) clinical decision support (CDS) system implemented in multiple adult EDs within a university hospital system. This CDS system focuses on predicting patients likelihood of ED recidivism and/or adverse opioid-related events. METHODS: The study was conducted among adult emergency physicians working in three EDs of a single academic health system in Rhode Island. Qualitative, semistructured interviews were conducted with ED physicians. Interviews assessed physicians prior experience with predictive analytics, thoughts on the alerts placement, design, and content, the alerts overall impact, and potential areas for improvement. Responses were aggregated and common themes identified. RESULTS: Twenty-three interviews were conducted (11 preimplementation and 12 postimplementation). Themes were identified regarding each physician familiarity with predictive analytics, alert rollout, alert appearance and content, and on alert sentiments. Most physicians viewed these alerts as a neutral or positive EHR addition, with responses ranging from neutral to positive. The alert placement was noted to be largely intuitive and nonintrusive. The design of the alert was generally viewed positively. The alerts content was believed to be accurate, although the decision to respond to the alerts call-to-action was physician dependent. Those who tended to ignore the alert did so for a few reasons, including already knowing the information the alert contains, the alert offering information that is not relevant to this particular patient, and the alert not containing enough information to be useful. CONCLUSION: Ultimately, this alert appears to have a marginally positive effect on ED physician workflow. At its most beneficial, the alert reminded physicians to deeply consider the care provided to high-risk populations and to potentially adjust their care and referrals. At its least beneficial, the alert did not affect physician decision-making but was not intrusive to the point of negatively impacting workflow.

Published
2023

4. Outcome class imbalance and rare events: An underappreciated complication for overdose risk prediction modeling.

Author

Cerdá, Magdalena, Marshall, Brandon, Cartus, Abigail, and Samuels, Elizabeth

Subjects
Class imbalance, machine learning, overdose, rare events, risk prediction, substance use, Humans, Drug Overdose, Computer Simulation, Risk Factors, Analgesics, Opioid
Abstract

BACKGROUND AND AIMS: Low outcome prevalence, often observed with opioid-related outcomes, poses an underappreciated challenge to accurate predictive modeling. Outcome class imbalance, where non-events (i.e. negative class observations) outnumber events (i.e. positive class observations) by a moderate to extreme degree, can distort measures of predictive accuracy in misleading ways, and make the overall predictive accuracy and the discriminatory ability of a predictive model appear spuriously high. We conducted a simulation study to measure the impact of outcome class imbalance on predictive performance of a simple SuperLearner ensemble model and suggest strategies for reducing that impact. DESIGN, SETTING, PARTICIPANTS: Using a Monte Carlo design with 250 repetitions, we trained and evaluated these models on four simulated data sets with 100 000 observations each: one with perfect balance between events and non-events, and three where non-events outnumbered events by an approximate factor of 10:1, 100:1, and 1000:1, respectively. MEASUREMENTS: We evaluated the performance of these models using a comprehensive suite of measures, including measures that are more appropriate for imbalanced data. FINDINGS: Increasing imbalance tended to spuriously improve overall accuracy (using a high threshold to classify events vs non-events, overall accuracy improved from 0.45 with perfect balance to 0.99 with the most severe outcome class imbalance), but diminished predictive performance was evident using other metrics (corresponding positive predictive value decreased from 0.99 to 0.14). CONCLUSION: Increasing reliance on algorithmic risk scores in consequential decision-making processes raises critical fairness and ethical concerns. This paper provides broad guidance for analytic strategies that clinical investigators can use to remedy the impacts of outcome class imbalance on risk prediction tools.

Published
2023

5. Prevalence and correlates of lifetime suicide attempt in obsessive-compulsive disorder with major depression.

Author

Samuels, Jack, Bienvenu, O, Krasnow, Janice, Grados, Marco, Cullen, Bernadette, Goes, Fernando, McLaughlin, Nicole, Rasmussen, Steven, Fyer, Abby, Knowles, James, McCracken, James, Geller, Dan, Riddle, Mark, Stewart, S, Greenberg, Benjamin, Nestadt, Gerald, Nestadt, Paul, and Piacentini, John

Subjects
Major depression, Obsessive-compulsive disorder, Suicide attempt, Violent images, Adult, Male, Humans, Child, Suicide, Attempted, Depression, Depressive Disorder, Major, Prevalence, Prospective Studies, Obsessive-Compulsive Disorder, Comorbidity
Abstract

BACKGROUND: Little is known about specific obsessive-compulsive clinical features associated with lifetime history of suicide attempt in individuals with obsessive-compulsive disorder (OCD) and major depression. METHODS: The study sample included 515 adults with OCD and a history of major depression. In exploratory analyses, we compared the distributions of demographic characteristics and clinical features in those with and without a history of attempted suicide and used logistic regression to evaluate the association between specific obsessive-compulsive clinical features and lifetime suicide attempt. RESULTS: Sixty-four (12%) of the participants reported a lifetime history of suicide attempt. Those who had attempted suicide were more likely to report having experienced violent or horrific images (52% vs. 30%; p

Published
2023

6. Identifying problematic opioid use in electronic health record data: Are we looking in the right place?

Author

Schirle, Lori, Kwun, Shinwho, Suh, Ashley, Sanchez-Roige, Sandra, Jeffery, Alvin D, and Samuels, David C

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Clinical Research, Patient Safety, Pain Research, Chronic Pain, Generic health relevance, Good Health and Well Being, Humans, Electronic Health Records, Analgesics, Opioid, Retrospective Studies, Opioid-Related Disorders, Clinical Sciences, Public Health and Health Services, Cognitive Sciences, Anesthesiology, Clinical sciences, Pharmacology and pharmaceutical sciences, Health services and systems
Abstract

ObjectiveTo examine the value of data obtained outside of regular healthcare visits (clinical communications) to detect problematic opioid use in electronic health records (EHRs).DesignA retrospective cohort study.ParticipantsChronic pain patient records in a large academic medical center.InterventionsWe compared evidence for problematic opioid use in (1) clinic notes, (2) clinical communications, and (3) full EHR data. We analyzed keyword counts and calculated concordance and Cohen's κ between data sources.Main outcome measureEvidence of problematic opioid use in EHR defined as none, some, or high.ResultsTwenty-six percent of records were discordant in determination of problematic opioid use between clinical communications and clinic notes. Of these, 54 percent detected more evidence in clinical communications, and 46 percent in clinic notes. Compared to full EHR review, clinic notes exhibited higher concordance (78 percent; κ = 0.619) than clinical communications (60 percent; κ = 0.290).ConclusionClinical communications are a valuable addition to opioid EHR research.

Published
2023

7. Topical therapy for regression and melanoma prevention of congenital giant nevi.

Author

Choi, Yeon Sook, Erlich, Tal H, von Franque, Max, Rachmin, Inbal, Flesher, Jessica L, Schiferle, Erik B, Zhang, Yi, Pereira da Silva, Marcello, Jiang, Alva, Dobry, Allison S, Su, Mack, Germana, Sharon, Lacher, Sebastian, Freund, Orly, Feder, Ezra, Cortez, Jose L, Ryu, Suyeon, Babila Propp, Tamar, Samuels, Yedidyah Leo, Zakka, Labib R, Azin, Marjan, Burd, Christin E, Sharpless, Norman E, Liu, X Shirley, Meyer, Clifford, Austen, William Gerald, Bojovic, Branko, Cetrulo, Curtis L, Mihm, Martin C, Hoon, Dave S, Demehri, Shadmehr, Hawryluk, Elena B, and Fisher, David E

Subjects
Animals, Humans, Mice, Melanoma, Nevus, Pigmented, Skin Neoplasms, Neoplasm Transplantation, Heterografts, Nras, congenital melanocytic nevus, hapten, melanoma, mole, prevention, topical, Pediatric, Biotechnology, Cancer, Clinical Research, Prevention, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate immunity that ablated detectable nevocytes, fully prevented melanoma, and regressed human giant nevus xenografts. These findings reveal nevus mechanistic vulnerabilities and suggest opportunities for topical interventions that may alter the therapeutic options for children with congenital giant nevi.

Published
2022

8. Use of U.S. Blood Donors for National Serosurveillance of SARS-CoV-2 Antibodies: Basis for an Expanded National Donor Serosurveillance Program

Author

Stone, Mars, Di Germanio, Clara, Wright, David J, Sulaeman, Hasan, Dave, Honey, Fink, Rebecca V, Notari, Edward P, Green, Valerie, Strauss, Donna, Kessler, Debbie, Destree, Mark, Saa, Paula, Williamson, Phillip C, Simmons, Graham, Stramer, Susan L, Opsomer, Jean, Jones, Jefferson M, Kleinman, Steven, Busch, Michael P, Cassetti, C, Gerber, S, Patton, M, Havers, F, Basavaraju, S, Williams, AE, Anderson, S, Haynes, J, McCain, L, Hui, A, Samuels, C, Tanner, H, Kaidarova, Z, B, MP, Norris, PJ, S, M, Mathew, SM, Stramer, S, Kessler, D, Konkle, BA, Custer, B, Ness, PM, Kleinman, SH, Josephson, CD, Glynn, SA, and Malkin, K

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Lung, Prevention, Pneumonia, Pneumonia & Influenza, Biodefense, Cancer, Vaccine Related, Infectious Diseases, Emerging Infectious Diseases, Good Health and Well Being, Antibodies, Viral, Blood Donors, COVID-19, Child, Cross-Sectional Studies, Humans, SARS-CoV-2, Seroepidemiologic Studies, COVID-19 srological testing, seroprevalence, NHLBI Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric, Biological Sciences, Medical and Health Sciences, Microbiology, Clinical sciences
Abstract

BackgroundThe Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P) Epidemiology, Surveillance and Preparedness of the Novel SARS-CoV-2 Epidemic (RESPONSE) seroprevalence study conducted monthly cross-sectional testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in blood donors in 6 US metropolitan regions to estimate the extent of SARS-CoV-2 infections over time.MethodsDuring March-August 2020, approximately ≥1000 serum specimens were collected monthly from each region and tested for SARS-CoV-2 antibodies using a well-validated algorithm. Regional seroprevalence estimates were weighted based on demographic differences compared with the general population. Seroprevalence was compared with reported coronavirus disease 2019 (COVID-19) case rates over time.ResultsFor all regions, seroprevalence was

Published
2022

9. Association of Rurality With Annual Repeat Lung Cancer Screening in the Veterans Health Administration.

Author

Spalluto, Lucy, Lewis, Jennifer, Samuels, Lauren, Callaway-Lane, Carol, Matheny, Michael, Denton, Jason, Robles, Jennifer, Dittus, Robert, Yankelevitz, David, Henschke, Claudia, Massion, Pierre, Moghanaki, Drew, and Roumie, Christianne

Subjects
Lung cancer screening, Veterans, Veterans Health Administration, lung cancer, rural, Early Detection of Cancer, Humans, Lung Neoplasms, Retrospective Studies, Rural Population, United States, Veterans, Veterans Health
Abstract

PURPOSE: Lung cancer causes the largest number of cancer-related deaths in the United States. Lung cancer incidence rates, mortality rates, and rates of advanced stage disease are higher among those who live in rural areas. Known disparities in lung cancer outcomes between rural and nonrural populations may be in part because of barriers faced by rural populations. The authors tested the hypothesis that among Veterans who receive initial lung cancer screening, rural Veterans would be less likely to complete annual repeat screening than nonrural Veterans. METHODS: A retrospective cohort study was conducted of 10 Veterans Affairs medical centers from 2015 to 2019. Rural and nonrural Veterans undergoing lung cancer screening were identified. Rural status was defined using the rural-urban commuting area codes. The primary outcome was annual repeat lung cancer screening in the 9- to 15-month window (primary analysis) and 31-day to 18-month window (sensitivity analysis) after the first documented lung cancer screening. To examine rurality as a predictor of annual repeat lung cancer screening, multivariable logistic regression models were used. RESULTS: In the final analytic sample of 11,402 Veterans, annual repeat lung cancer screening occurred in 27.7% of rural Veterans (641 of 2,316) and 31.8% of nonrural Veterans (2,891 of 9,086) (adjusted odds ratio: 0.86; 95% confidence interval: 0.73-1.03). Similar results were seen in the sensitivity analysis, with 41.6% of rural Veterans (963 of 2,316) versus 45.2% of nonrural Veterans (4,110 of 9,086) (adjusted odds ratio: 0.88; 95% confidence interval: 0.73-1.04) having annual repeat screening in the expanded 31-day to 18-month window. CONCLUSIONS: Among a national cohort of Veterans, rural residence was associated with numerically lower odds of annual repeat lung cancer screening than nonrural residence. Continued, intentional outreach efforts to increase annual repeat lung cancer screening among rural Veterans may offer an opportunity to decrease deaths from lung cancer.

Published
2022

10. Discordances between pediatric and adult thresholds in the diagnosis of hypertension in adolescents with CKD

Author

Black, Elizabeth, Lee, Jason, Flynn, Joseph T, McCulloch, Charles E, Samuels, Joshua A, Seth, Divya, Warady, Bradley, Furth, Susan, Mitsnefes, Mark, and Ku, Elaine

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Pediatric, Cardiovascular, Kidney Disease, Prevention, Clinical Research, Hypertension, Renal and urogenital, Adolescent, Adult, Humans, Reference Values, Renal Insufficiency, Chronic, Retrospective Studies, Adolescents, Blood pressure, Chronic kidney disease, Paediatrics and Reproductive Medicine, Urology & Nephrology, Clinical sciences, Paediatrics
Abstract

BackgroundAdolescents with chronic kidney disease (CKD) are a unique population with a high prevalence of hypertension. Management of hypertension during the transition from adolescence to adulthood can be challenging given differences in normative blood pressure values in adolescents compared with adults.MethodsIn this retrospective analysis of the Chronic Kidney Disease in Children Cohort Study, we compared pediatric versus adult definitions of ambulatory- and clinic-diagnosed hypertension in their ability to discriminate risk for left ventricular hypertrophy (LVH) and kidney failure using logistic and Cox models, respectively.ResultsOverall, among 363 adolescents included for study, the prevalence of systolic hypertension was 27%, 44%, 12%, and 9% based on pediatric ambulatory, adult ambulatory, pediatric clinic, and adult clinic definitions, respectively. All definitions of hypertension were statistically significantly associated with LVH except for the adult ambulatory definition. Presence of ambulatory hypertension was associated with 2.6 times higher odds of LVH using pediatric definitions (95% CI 1.4-5.1) compared to 1.4 times higher odds using adult definitions (95% CI 0.8-3.0). The c-statistics for discrimination of LVH was statistically significantly higher for the pediatric definition of ambulatory hypertension (c=0.61) compared to the adult ambulatory definition (c=0.54), and the Akaike Information Criterion was lower for the pediatric definition. All definitions were associated with progression to kidney failure.ConclusionOverall, there was not a substantial difference in pediatric versus adult definitions of hypertension in predicting kidney outcomes, but there was slightly better risk discrimination of the risk of LVH with the pediatric definition of ambulatory hypertension.

Published
2022

11. Two data-driven approaches to identifying the spectrum of problematic opioid use: A pilot study within a chronic pain cohort

Author

Schirle, Lori, Jeffery, Alvin, Yaqoob, Ali, Sanchez-Roige, Sandra, and Samuels, David C

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Patient Safety, Clinical Research, Analgesics, Opioid, Chronic Pain, Humans, Natural Language Processing, Opioid-Related Disorders, Pilot Projects, Opioid use disorder, Electronic health records, Chronic pain, Natural language processing, Phenome-wide association study, Information and Computing Sciences, Engineering, Medical and Health Sciences, Medical Informatics, Biomedical and clinical sciences, Health sciences, Information and computing sciences
Abstract

BackgroundAlthough electronic health records (EHR) have significant potential for the study of opioid use disorders (OUD), detecting OUD in clinical data is challenging. Models using EHR data to predict OUD often rely on case/control classifications focused on extreme opioid use. There is a need to expand this work to characterize the spectrum of problematic opioid use.MethodsUsing a large academic medical center database, we developed 2 data-driven methods of OUD detection: (1) a Comorbidity Score developed from a Phenome-Wide Association Study of phenotypes associated with OUD and (2) a Text-based Score using natural language processing to identify OUD-related concepts in clinical notes. We evaluated the performance of both scores against a manual review with correlation coefficients, Wilcoxon rank sum tests, and area-under the receiver operating characteristic curves. Records with the highest Comorbidity and Text-based scores were re-evaluated by manual review to explore discrepancies.ResultsBoth the Comorbidity and Text-based OUD risk scores were significantly elevated in the patients judged as High Evidence for OUD in the manual review compared to those with No Evidence (p = 1.3E-5 and 1.3E-6, respectively). The risk scores were positively correlated with each other (rho = 0.52, p

Published
2021

12. Interim Analysis of Attrition Rates in Palliative Care Study on Dignity Therapy

Author

Samuels, Virginia, Schoppee, Tasha M, Greenlee, Amelia, Gordon, Destiny, Jean, Stacey, Smith, Valandrea, Reed, Tyra, Kittelson, Sheri, Quest, Tammie, O’Mahony, Sean, Hauser, Josh, Guay, Marvin O Delgado, Rabow, Michael W, Emanuel, Linda, Fitchett, George, Handzo, George, Chochinov, Harvey Max, Yao, Yingwei, and Wilkie, Diana J

Subjects
Health Services and Systems, Health Sciences, Clinical Research, Behavioral and Social Science, Cancer, Good Health and Well Being, Aged, COVID-19, Female, Humans, Male, Middle Aged, Neoplasms, Palliative Care, Pandemics, Respect, SARS-CoV-2, attrition, spirituality, cancer, palliative care, dignity therapy, Nursing, Gerontology, Health services and systems
Abstract

A routine threat to palliative care research is participants not completing studies. The purpose of this analysis was to quantify attrition rates mid-way through a palliative care study on Dignity Therapy and describe the reasons cited for attrition. Enrolled in the study were a total of 365 outpatients with cancer who were receiving outpatient specialty palliative care (mean age 66.7 ± 7.3 years, 56% female, 72% White, 22% Black, 6% other race/ethnicity). These participants completed an initial screening for cognitive status, performance status, physical distress, and spiritual distress. There were 76 eligible participants who did not complete the study (58% female, mean age 67.9 ± 7.3 years, 76% White, 17% Black, and 7% other race). Of those not completing the study, the average scores were 74.5 ± 11.7 on the Palliative Performance Scale and 28.3 ± 1.5 on the Mini-Mental Status Examination, whereas 22% had high spiritual distress scores and 45% had high physical distress scores. The most common reason for attrition was death/decline of health (47%), followed by patient withdrawal from the study (21%), and patient lost to follow-up (21%). The overall attrition rate was 24% and within the a priori projected attrition rate of 20%-30%. Considering the current historical context, this interim analysis is important because it will serve as baseline data on attrition prior to the outbreak of the COVID-19 pandemic. Future research will compare these results with attrition throughout the rest of the study, allowing analysis of the effect of the COVID-19 pandemic on the study attrition.

Published
2021

13. Higher CSF Ferritin Heavy-Chain (Fth1) and Transferrin Predict Better Neurocognitive Performance in People with HIV

Author

Kaur, Harpreet, Bush, William S, Letendre, Scott L, Ellis, Ronald J, Heaton, Robert K, Patton, Stephanie M, Connor, James R, Samuels, David C, Franklin, Donald R, Hulgan, Todd, and Kallianpur, Asha R

Subjects
Biomedical and Clinical Sciences, Immunology, Neurosciences, Brain Disorders, Clinical Research, Mental Health, Neurodegenerative, Acquired Cognitive Impairment, AIDS Dementia Complex, Adult, Biomarkers, Female, Ferritins, HIV Infections, Humans, Longitudinal Studies, Male, Mental Status and Dementia Tests, Middle Aged, Oxidoreductases, Predictive Value of Tests, Prospective Studies, Transferrin, HIV, Prospective study, Neurocognitive performance, CSF, Myelination, Iron metabolism, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biochemistry and cell biology
Abstract

HIV-associated neurocognitive disorder (HAND) remains prevalent despite antiretroviral therapy and involves white matter damage in the brain. Although iron is essential for myelination and myelin maintenance/repair, its role in HAND is largely unexplored. We tested the hypotheses that cerebrospinal fluid (CSF) heavy-chain ferritin (Fth1) and transferrin, proteins integral to iron delivery and myelination, are associated with neurocognitive performance in people with HIV (PWH). Fth1, transferrin, and the pro-inflammatory cytokines TNF-α and IL-6 were quantified in CSF at baseline (entry) in 403 PWH from a prospective observational study who underwent serial, comprehensive neurocognitive assessments. Associations of Fth1 and transferrin with Global Deficit Score (GDS)-defined neurocognitive performance at baseline and 30-42 months of follow-up were evaluated by multivariable regression. While not associated with neurocognitive performance at baseline, higher baseline CSF Fth1 predicted significantly better neurocognitive performance over 30 months in all PWH (p < 0.05), in PWH aged < 50 at 30, 36, and 42 months (all p < 0.05), and in virally suppressed PWH at all three visit time-points (all p < 0.01). Higher CSF transferrin was associated with superior neurocognitive performance at all visits, primarily in viremic individuals (all p < 0.05). All associations persisted after adjustment for neuro-inflammation. In summary, higher CSF Fth1 is neuroprotective over prolonged follow-up in all and virally suppressed PWH, while higher CSF transferrin may be most neuroprotective during viremia. We speculate that higher CSF levels of these critical iron-delivery proteins support improved myelination and consequently, neurocognitive performance in PWH, providing a rationale for investigating their role in interventions to prevent and/or treat HAND.

Published
2021

14. Mitochondrial DNA haplogroups and domain-specific neurocognitive performance in adults with HIV

Author

Volpe, Karen, Samuels, David, Kallianpur, Asha, Ellis, Ronald, Franklin, Donald, Letendre, Scott, Heaton, Robert K, and Hulgan, Todd

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Mental Health, HIV/AIDS, Infectious Diseases, Clinical Research, Genetics, AIDS Dementia Complex, Adult, Cross-Sectional Studies, DNA, Mitochondrial, Female, HIV Infections, Haplotypes, Humans, Male, Middle Aged, HIV, Neurocognitive disorders, DNA, Mitochondrial, Hispanic Americans, African Americans, Virology, Clinical sciences, Medical microbiology
Abstract

Neurocognitive (NC) impairment (NCI) is an important cause of morbidity in persons with HIV (PWH). In the high-energy environment of the central nervous system, mitochondria contribute to neuroinflammation and aging, which may ultimately drive the pathogenesis of neurodegenerative diseases. Mitochondrial DNA (mtDNA) haplogroups are associated with health outcomes in PWH. For example, we previously observed less global NCI in Hispanic ancestry PWH having mtDNA haplogroup B. Another study reported increased NCI among PWH having African subhaplogroup L2a. We therefore analyzed NC domains in relation to these haplogroups in CNS HIV Antiretroviral Therapy Effects Research (CHARTER), a multi-site observational neuro-HIV study. Haplogroups were assigned using mtDNA sequence in 1016 PWH. Outcomes were NCI, defined by domain deficit score and mean T-scores (TS) for seven NC domains. Ancestry-stratified analyses of NC performance included Wilcoxon rank sum, χ2, and Fisher's exact tests. Multivariable regression adjusted for NC comorbidity, antiretroviral therapy use, and nadir CD4+ T cells. Among 98 Hispanic ancestry PWH, executive function, learning, and recall performance were better with haplogroup B (N = 17) than other haplogroups. With adjustment for covariates, haplogroup B remained associated with better executive function (p = 0.04) and recall TS (p = 0.03). PWH with haplogroup B had fewer impaired domains than other haplogroups (p

Published
2021

15. Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

Author

Claudio‐Campos, Karla, Stevens, Daniel, Koo, Sang‐Wahn, Valko, Alexa, Bienvenu, Oscar Joseph, Budman, Cathy B, Cath, Danielle C, Darrow, Sabrina, Geller, Daniel, Goes, Fernando S, Grados, Marco A, Greenberg, Benjamin D, Greenberg, Erica, Hirschtritt, Matthew E, Illmann, Cornelia, Ivankovic, Franjo, King, Robert A, Knowles, James A, Krasnow, Janice, Lee, Paul C, Lyon, Gholson J, McCracken, James T, Robertson, Mary M, Osiecki, Lisa, Riddle, Mark A, Rouleau, Guy, Sandor, Paul, Nestadt, Gerald, Samuels, Jack, Scharf, Jeremiah M, Mathews, Carol A, and Study, for the Tourette Association of America International Consortium for Genetics and the OCD Collaborative Genetics Association

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Behavioral and Social Science, Anxiety Disorders, Tourette Syndrome, Neurodegenerative, Serious Mental Illness, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Mental health, Attention Deficit Disorder with Hyperactivity, Comorbidity, Humans, Obsessive-Compulsive Disorder, Tic Disorders, Tics, chronic tics, meta&#8208, analysis, severity, Tourette, Tourette Association of America International Consortium for Genetics (TAAICG) and the OCD Collaborative Genetics Association Study, meta-analysis, Human Movement and Sports Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundPersistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation.ObjectiveThe goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT.MethodsWe analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature.ResultsRates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates.ConclusionsOur findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2021

16. Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4.

Author

Toupin, Nicholas, Steinke, Sean, Nadella, Sandeep, Li, Ao, Rohrabaugh, Thomas, Samuels, Eric, Turro, Claudia, Sevrioukova, Irina, and Kodanko, Jeremy

Subjects
Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cell Survival, Coordination Complexes, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Drug Screening Assays, Antitumor, Humans, Models, Molecular, Molecular Structure, Photosensitizing Agents, Ruthenium
Abstract

We report the synthesis and photochemical and biological characterization of the first selective and potent metal-based inhibitors of cytochrome P450 3A4 (CYP3A4), the major human drug metabolizing enzyme. Five Ru(II)-based derivatives were prepared from two analogs of the CYP3A4 inhibitor ritonavir, 4 and 6: [Ru(tpy)(L)(6)]Cl2 (tpy = 2,2:6,2″-terpyridine) with L = 6,6-dimethyl-2,2-bipyridine (Me2bpy; 8), dimethylbenzo[i]dipyrido[3,2-a:2,3-c]phenazine (Me2dppn; 10) and 3,6-dimethyl-10,15-diphenylbenzo[i]dipyrido[3,2-a:2,3-c]phenazine (Me2Ph2dppn; 11), [Ru(tpy)(Me2bpy)(4)]Cl2 (7) and [Ru(tpy)(Me2dppn)(4)]Cl2 (9). Photochemical release of 4 or 6 from 7-11 was demonstrated, and the spectrophotometric evaluation of 7 showed that it behaves similarly to free 4 (type II heme ligation) after irradiation with visible light but not in the dark. Unexpectedly, the intact Ru(II) complexes 7 and 8 were found to inhibit CYP3A4 potently and specifically through direct binding to the active site without heme ligation. Caged inhibitors 9-11 showed dual action properties by combining photoactivated dissociation of 4 or 6 with efficient 1O2 production. In prostate adenocarcinoma DU-145 cells, compound 9 had the best synergistic effect with vinblastine, the anticancer drug primarily metabolized by CYP3A4 in vivo. Thus, our study establishes a new paradigm in CYP inhibition using metalated complexes and suggests possible utilization of photoactive CYP3A4 inhibitory compounds in clinical applications, such as enhancement of therapeutic efficacy of anticancer drugs.

Published
2021

17. Melanoma models for the next generation of therapies

Author

Patton, E Elizabeth, Mueller, Kristen L, Adams, David J, Anandasabapathy, Niroshana, Aplin, Andrew E, Bertolotto, Corine, Bosenberg, Marcus, Ceol, Craig J, Burd, Christin E, Chi, Ping, Herlyn, Meenhard, Holmen, Sheri L, Karreth, Florian A, Kaufman, Charles K, Khan, Shaheen, Kobold, Sebastian, Leucci, Eleonora, Levy, Carmit, Lombard, David B, Lund, Amanda W, Marie, Kerrie L, Marine, Jean-Christophe, Marais, Richard, McMahon, Martin, Robles-Espinoza, Carla Daniela, Ronai, Ze'ev A, Samuels, Yardena, Soengas, Maria S, Villanueva, Jessie, Weeraratna, Ashani T, White, Richard M, Yeh, Iwei, Zhu, Jiyue, Zon, Leonard I, Hurlbert, Marc S, and Merlino, Glenn

Subjects
Clinical Research, Cancer, Climate-Related Exposures and Conditions, 5.1 Pharmaceuticals, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Animals, Disease Models, Animal, Humans, Immunity, Immunotherapy, Melanoma, Skin Neoplasms, Tumor Microenvironment, animal models, drug discovery, immunotherapy, melanoma, targeted therapy, therapeutics, tumor microenvironment, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies.

Published
2021

18. Assessment of Racial Differences in Pharmacotherapy Efficacy for Smoking Cessation

Author

Nollen, Nicole L, Ahluwalia, Jasjit S, Cox, Lisa Sanderson, Okuyemi, Kolawole, Lawrence, David, Samuels, Larry, and Benowitz, Neal L

Subjects
Tobacco Smoke and Health, Neurosciences, Prevention, Substance Misuse, Clinical Trials and Supportive Activities, Clinical Research, Cancer, Tobacco, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Respiratory, Good Health and Well Being, Black People, Bupropion, Double-Blind Method, Female, Humans, Male, Middle Aged, Nicotinic Agonists, Race Factors, Smoking Cessation, Smoking Cessation Agents, Tobacco Use Cessation Devices, Varenicline, White People
Abstract

ImportanceUnderstanding Black vs White differences in pharmacotherapy efficacy and the underlying reasons is critically important to reducing tobacco-related health disparities.ObjectiveTo compare pharmacotherapy efficacy and examine variables to explain Black vs White differences in smoking abstinence.Design, setting, and participantsThis study is a secondary analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) double-blind, placebo-controlled, randomized clinical trial, which took place at clinical trial centers, academic centers, and outpatient clinics in 29 states in the US. US Black and White smokers who smoked 10 or more cigarettes per day with and without psychiatric comorbidity were enrolled between November 2011 and January 2015. Data analysis was performed from July 2019 to January 2020.InterventionsParticipants were randomized (1:1:1:1) in a double-blind, triple-dummy, placebo- and active-controlled (nicotine patch) trial of varenicline and bupropion for 12 weeks with follow-up through week 24.Main outcomes and measuresBiochemically verified continuous cigarette abstinence rate (CAR) from weeks 9 to 24. Baseline, postbaseline treatment, and safety characteristics were examined as variables to explain race differences in abstinence.ResultsOf the 1065 Black smokers enrolled, 255 were randomized to receive varenicline, 259 received bupropion, 286 received nicotine replacement therapy (NRT [ie, nicotine patch]), and 265 received placebo. Among the 3044 White smokers enrolled, 778 were randomized to receive varenicline, 769 received bupropion, 738 received NRT, and 759 received placebo. Participants were predominantly female (614 Black [57.7%] and 1786 White [58.7%] women) and heavy smokers (mean [SD] cigarettes per day, 18.2 [7.9] for Black and 20.0 [7.5] for White smokers), with a mean (SD) age of 47.2 (11.2) years for Black and 46.5 (12.7) years for White participants. Treatment and race were associated with CAR for weeks 9 to 24. The CAR was 4.9% lower for Black vs White participants (odds ratio [OR], 0.53; 95% CI, 0.41-0.69; P

Published
2021

19. Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength

Author

Samuels, Eric R and Sevrioukova, Irina F

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Binding Sites, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Drug Design, Humans, Molecular Docking Simulation, Protein Binding, Quantitative Structure-Activity Relationship, Ritonavir, ligand binding, inhibitor design, crystal structure, structure&#8211, activity relations, surface mutation, CYP3A4, structure–activity relations, Other Chemical Sciences, Genetics, Other Biological Sciences, Chemical Physics, Biochemistry and cell biology, Microbiology, Medicinal and biomolecular chemistry
Abstract

Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug-drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition of CYP3A4 remain to be established. We utilized a rational inhibitor design to investigate the structure-activity relationships in the analogues of ritonavir, the most potent CYP3A4 inhibitor in clinical use. This study elucidated the optimal length of the head-group spacer using eleven (series V) analogues with the R1/R2 side-groups as phenyls or R1-phenyl/R2-indole/naphthalene in various stereo configurations. Spectral, functional and structural characterization of the inhibitory complexes showed that a one-atom head-group linker elongation, from pyridyl-ethyl to pyridyl-propyl, was beneficial and markedly improved Ks, IC50 and thermostability of CYP3A4. In contrast, a two-atom linker extension led to a multi-fold decrease in the binding and inhibitory strength, possibly due to spatial and/or conformational constraints. The lead compound, 3h, was among the best inhibitors designed so far and overall, the strongest binder (Ks and IC50 of 0.007 and 0.090 µM, respectively). 3h was the fourth structurally simpler inhibitor superior to ritonavir, which further demonstrates the power of our approach.

Published
2021

20. Where will it end? Pathways to care and catastrophic costs following negative TB evaluation in Uganda

Author

Samuels, Thomas HA, Shete, Priya B, Ojok, Chris, Nalugwa, Talemwa, Farr, Katherine, Turyahabwe, Stavia, Katamba, Achilles, Cattamanchi, Adithya, and Moore, David AJ

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Rare Diseases, Clinical Research, Behavioral and Social Science, Health Services, Tuberculosis, Infection, Good Health and Well Being, Adult, Cost of Illness, Female, Health Equity, Humans, Male, Middle Aged, Office Visits, Uganda, General Science & Technology
Abstract

IntroductionCatastrophic costs incurred by tuberculosis (TB) patients have received considerable attention, however little is known about costs and pathways to care after a negative TB evaluation.Materials and methodsWe conducted a cross-sectional study of 70 patients with a negative TB evaluation at four community health centres in rural and peri-urban Uganda. Patients were traced 9 months post-evaluation using contact information from TB registers. We collected information on healthcare visits and implemented locally-validated costing questionnaires to assess the financial impact of their symptoms post-evaluation.ResultsOf 70 participants, 57 (81%) were traced and 53 completed the survey. 31/53 (58%) surveyed participants returned to healthcare facilities post-evaluation, making a median of 2 visits each (interquartile range [IQR] 1-3). 11.3% (95%CI 4.3-23.0%) of surveyed patients and 16.1% (95%CI 5.5-33.7%) of those returning to healthcare facilities incurred catastrophic costs (i.e., spent >20% annual household income). Indirect costs related to lost work represented 80% (IQR 32-100%) of total participant costs.ConclusionsPatients with TB symptoms who experience financial catastrophe after negative TB evaluation may represent a larger absolute number of patients than those suffering from costs due to TB. They may not be captured by existing definitions of non-TB catastrophic health expenditure.

Published
2021

21. Nucleic acid oxidation is associated with biomarkers of neurodegeneration in CSF in people with HIV

Author

Ellis, Ronald J, Moore, David J, Sundermann, Erin E, Heaton, Robert K, Mehta, Sanjay, Hulgan, Todd, Samuels, David, Fields, Jerel A, and Letendre, Scott L

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Infectious Diseases, Acquired Cognitive Impairment, Neurosciences, HIV/AIDS, Neurodegenerative, Brain Disorders, Infection, Adult, Aged, Amyloid beta-Peptides, Biomarkers, Cross-Sectional Studies, DNA Damage, Female, Guanine, HIV Infections, Humans, Male, Middle Aged, Nerve Degeneration, Neurofilament Proteins, Nucleic Acids, Oxidative Stress, Peptide Fragments, tau Proteins
Abstract

ObjectiveTo determine whether oxidative stress in virologically suppressed people with HIV (PWH) may contribute to or result from neurodegeneration, we measured 7,8-dihydro-8-oxoguanine (8-oxo-dG), a marker of DNA damage due to oxidative stress, and markers of age-related neurodegeneration, specifically, reduced levels of CSF Aβ-42, and elevated CSF total tau and neurofilament light (NFL).MethodsThis cross-sectional study prospectively enrolled participants at 6 US centers in the CNS HIV Antiretroviral Effects Research study. Inclusion criteria included HIV+ with a plasma level of HIV RNA ≤50 copies/mL. Exclusions included significant CNS confounding conditions. Measurements of total tau and Aβ-42 were performed by bead suspension array. NFL and 8-oxo-dG were measured using ELISA.ResultsParticipants were 53 PWH, mean age 55 (±9.3) years, 19% women, and 48% non-Hispanic White. Higher 8-oxo-dG correlated with markers of AD-related neurodegeneration including lower CSF Aβ-42 (r = -0.34; p = 0.012) and higher CSF NFL (r = 0.39; p = 0.0091) and total tau (r = 0.6696; p < 0.0001). Relationships remained after adjusting for demographic variables. Levels of protein carbonyls, a marker of protein oxidation, were not related to neurodegeneration markers.ConclusionsAmong virologically suppressed PWH, nucleic acid oxidation was associated with standard CSF biomarkers of neurodegeneration. Potential sources of oxidative stress in PWH include low-level HIV replication, inflammation, mitochondrial dysfunction, and specific antiretroviral drugs. Results suggest that the higher levels of oxidative stress among PWH may play a role in neurodegeneration.Classification of evidenceThis study provides Class II evidence that among virologically suppressed PWH, nucleic acid oxidation is associated with standard CSF biomarkers of neurodegeneration.

Published
2020

22. FaceBase 3: analytical tools and FAIR resources for craniofacial and dental research.

Author

Samuels, Bridget D, Aho, Robert, Brinkley, James F, Bugacov, Alejandro, Feingold, Eleanor, Fisher, Shannon, Gonzalez-Reiche, Ana S, Hacia, Joseph G, Hallgrimsson, Benedikt, Hansen, Karissa, Harris, Matthew P, Ho, Thach-Vu, Holmes, Greg, Hooper, Joan E, Jabs, Ethylin Wang, Jones, Kenneth L, Kesselman, Carl, Klein, Ophir D, Leslie, Elizabeth J, Li, Hong, Liao, Eric C, Long, Hannah, Lu, Na, Maas, Richard L, Marazita, Mary L, Mohammed, Jaaved, Prescott, Sara, Schuler, Robert, Selleri, Licia, Spritz, Richard A, Swigut, Tomek, van Bakel, Harm, Visel, Axel, Welsh, Ian, Williams, Cristina, Williams, Trevor J, Wysocka, Joanna, Yuan, Yuan, and Chai, Yang

Subjects
Skull, Facial Bones, Animals, Humans, Reproducibility of Results, Dental Research, Databases, Factual, Research Personnel, Craniofacial development, Data resource, FaceBase Consortium, Human, Mouse, Zebrafish, Databases, Factual, Biological Sciences, Medical and Health Sciences
Abstract

The FaceBase Consortium was established by the National Institute of Dental and Craniofacial Research in 2009 as a 'big data' resource for the craniofacial research community. Over the past decade, researchers have deposited hundreds of annotated and curated datasets on both normal and disordered craniofacial development in FaceBase, all freely available to the research community on the FaceBase Hub website. The Hub has developed numerous visualization and analysis tools designed to promote integration of multidisciplinary data while remaining dedicated to the FAIR principles of data management (findability, accessibility, interoperability and reusability) and providing a faceted search infrastructure for locating desired data efficiently. Summaries of the datasets generated by the FaceBase projects from 2014 to 2019 are provided here. FaceBase 3 now welcomes contributions of data on craniofacial and dental development in humans, model organisms and cell lines. Collectively, the FaceBase Consortium, along with other NIH-supported data resources, provide a continuously growing, dynamic and current resource for the scientific community while improving data reproducibility and fulfilling data sharing requirements.

Published
2020

23. MutEx: a multifaceted gateway for exploring integrative pan-cancer genomic data.

Author

Ping, Jie, Oyebamiji, Olufunmilola, Yu, Hui, Ness, Scott, Chien, Jeremy, Ye, Fei, Kang, Huining, Samuels, David, Ivanov, Sergey, Chen, Danqian, Zhao, Ying-yong, and Guo, Yan

Subjects
Genetics, Breast Cancer, Human Genome, Cancer, Genetic Testing, Computational Biology, Databases, Genetic, Genomics, High-Throughput Nucleotide Sequencing, Humans, Mutation, Neoplasms, Programming Languages, Survival Analysis, somatic mutation, gene expression, survival, Biochemistry and Cell Biology, Computation Theory and Mathematics, Other Information and Computing Sciences, Bioinformatics
Abstract

Somatic mutation and gene expression dysregulation are considered two major tumorigenesis factors. While independent investigations of either factor pervade, studies of associations between somatic mutations and gene expression changes have been sporadic and nonsystematic. Utilizing genomic data collected from 11 315 subjects of 33 distinct cancer types, we constructed MutEx, a pan-cancer integrative genomic database. This database records the relationships among gene expression, somatic mutation and survival data for cancer patients. MutEx can be used to swiftly explore the relationship between these genomic/clinic features within and across cancer types and, more importantly, search for corroborating evidence for hypothesis inception. Our database also incorporated Gene Ontology and several pathway databases to enhance functional annotation, and elastic net and a gene expression composite score to aid in survival analysis. To demonstrate the usability of MutEx, we provide several application examples, including top somatic mutations associated with the most extensive expression dysregulation in breast cancer, differential mutational burden downstream of DNA mismatch repair gene mutations and composite gene expression score-based survival difference in breast cancer. MutEx can be accessed at http://www.innovebioinfo.com/Databases/Mutationdb_About.php.

Published
2020

24. General personality dimensions, impairment and treatment response in obsessive–compulsive disorder

Author

Samuels, Jack, Bienvenu, O Joseph, Krasnow, Janice, Wang, Ying, Grados, Marco A, Cullen, Bernadette, Goes, Fernando S, Maher, Brion, Greenberg, Benjamin D, Mclaughlin, Nicole C, Rasmussen, Steven A, Fyer, Abby J, Knowles, James A, Mccracken, James T, Piacentini, John, Geller, Dan, Stewart, S Evelyn, Murphy, Dennis L, Shugart, Yin‐Yao, Riddle, Mark A, and Nestadt, Gerald

Subjects
Biological Psychology, Social and Personality Psychology, Psychology, Applied and Developmental Psychology, Behavioral and Social Science, Brain Disorders, Depression, Serious Mental Illness, Mental Health, Clinical Research, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Mental health, Adolescent, Adult, Aged, Cognitive Behavioral Therapy, Extraversion, Psychological, Female, Humans, Male, Middle Aged, Neuroticism, Obsessive-Compulsive Disorder, Serotonin Agents, Severity of Illness Index, Treatment Outcome, Young Adult, Clinical Sciences, Public Health and Health Services, Clinical sciences, Clinical and health psychology, Social and personality psychology
Abstract

General personality dimensions are associated with clinical severity and treatment response in individuals with depression and many anxiety disorders, but little is known about these relationships in individuals with obsessive-compulsive disorder (OCD). Individuals in the current study included 705 adults with OCD who had participated in family and genetic studies of the disorder. Participants self-completed the Neuroticism, Extraversion, Openness Personality Inventory or Neuroticism, Extraversion, Openness Five-Factor Inventory-3. Relationships between personality scores, and subjective impairment and OCD treatment response, were evaluated. The odds of subjective impairment increased with (unit increase in) the neuroticism score (odds ratio, OR = 1.03; 95% CI = 1.01-1.04; p < 0.01) and decreased with extraversion scores (OR = 0.98; 95% CI = 0.96-0.99; p < 0.01). The odds of reporting a good response to serotonin/selective serotonin reuptake inhibitors (OR = 1.02; 95% CI = 1.01-1.04; p < 0.01) or cognitive behavioural therapy (OR = 1.03; 95% CI = 1.01-1.05; p < 0.01) increased with the extraversion score. The magnitude of these relationships did not change appreciably after adjusting for other clinical features related to one or more of the personality dimensions. The findings suggest that neuroticism and extraversion are associated with subjective impairment, and that extraversion is associated with self-reported treatment response, in individuals with OCD. © 2019 John Wiley & Sons, Ltd.

Published
2020

25. An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4

Author

Samuels, Eric R and Sevrioukova, Irina F

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Dose-Response Relationship, Drug, Humans, Hydrophobic and Hydrophilic Interactions, Molecular Structure, Ritonavir, Structure-Activity Relationship, CYP3A4, Ligand binding, Inhibitor design, Crystal structure, Structure-activity relations, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, Biochemistry and cell biology, Medicinal and biomolecular chemistry, Organic chemistry
Abstract

Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R1 side-group as phenyl or naphthalene and R2 as indole or naphthalene in different stereo configuration showed that (i) analogues with the R2-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R2-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055-0.085 μM vs. 0.130 μM, respectively).

Published
2020

26. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee

Author

Kolasinski, Sharon L, Neogi, Tuhina, Hochberg, Marc C, Oatis, Carol, Guyatt, Gordon, Block, Joel, Callahan, Leigh, Copenhaver, Cindy, Dodge, Carole, Felson, David, Gellar, Kathleen, Harvey, William F, Hawker, Gillian, Herzig, Edward, Kwoh, C Kent, Nelson, Amanda E, Samuels, Jonathan, Scanzello, Carla, White, Daniel, Wise, Barton, Altman, Roy D, DiRenzo, Dana, Fontanarosa, Joann, Giradi, Gina, Ishimori, Mariko, Misra, Devyani, Shah, Amit Aakash, Shmagel, Anna K, Thoma, Louise M, Turgunbaev, Marat, Turner, Amy S, and Reston, James

Subjects
Clinical Research, Behavioral and Social Science, Chronic Pain, Complementary and Integrative Health, Osteoarthritis, Arthritis, Pain Research, Mind and Body, Rehabilitation, Prevention, Aging, Musculoskeletal, Hand Joints, Humans, Osteoarthritis, Hip, Osteoarthritis, Knee, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology
Abstract

ObjectiveTo develop an evidence-based guideline for the comprehensive management of osteoarthritis (OA) as a collaboration between the American College of Rheumatology (ACR) and the Arthritis Foundation, updating the 2012 ACR recommendations for the management of hand, hip, and knee OA.MethodsWe identified clinically relevant population, intervention, comparator, outcomes questions and critical outcomes in OA. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available educational, behavioral, psychosocial, physical, mind-body, and pharmacologic therapies for OA. Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. A Voting Panel, including rheumatologists, an internist, physical and occupational therapists, and patients, achieved consensus on the recommendations.ResultsBased on the available evidence, either strong or conditional recommendations were made for or against the approaches evaluated. Strong recommendations were made for exercise, weight loss in patients with knee and/or hip OA who are overweight or obese, self-efficacy and self-management programs, tai chi, cane use, hand orthoses for first carpometacarpal (CMC) joint OA, tibiofemoral bracing for tibiofemoral knee OA, topical nonsteroidal antiinflammatory drugs (NSAIDs) for knee OA, oral NSAIDs, and intraarticular glucocorticoid injections for knee OA. Conditional recommendations were made for balance exercises, yoga, cognitive behavioral therapy, kinesiotaping for first CMC OA, orthoses for hand joints other than the first CMC joint, patellofemoral bracing for patellofemoral knee OA, acupuncture, thermal modalities, radiofrequency ablation for knee OA, topical NSAIDs, intraarticular steroid injections and chondroitin sulfate for hand OA, topical capsaicin for knee OA, acetaminophen, duloxetine, and tramadol.ConclusionThis guideline provides direction for clinicians and patients making treatment decisions for the management of OA. Clinicians and patients should engage in shared decision-making that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

Published
2020

27. Trichotillomania comorbidity in a sample enriched for familial obsessive-compulsive disorder

Author

Gerstenblith, Ted Avi, Jaramillo-Huff, Ashley, Ruutiainen, Tuua, Nestadt, Paul S, Samuels, Jack F, Grados, Marco A, Cullen, Bernadette A, Riddle, Mark A, Liang, Kung-Yee, Greenberg, Benjamin D, Rasmussen, Steven A, Rauch, Scott L, McCracken, James T, Piacentini, John, Knowles, James A, Nestadt, Gerald, and Bienvenu, O Joseph

Subjects
Clinical and Health Psychology, Psychology, Brain Disorders, Mental Health, Clinical Research, Pediatric, Anxiety Disorders, Serious Mental Illness, Mental health, Good Health and Well Being, Adult, Comorbidity, Diagnostic and Statistical Manual of Mental Disorders, Disruptive, Impulse Control, and Conduct Disorders, Female, Genetic Linkage, Humans, Male, Middle Aged, Obsessive-Compulsive Disorder, Trichotillomania, Young Adult, classification, Impulse-control disorder, Obsessive-compulsive disorder, Clinical Sciences, Psychiatry, Clinical sciences, Clinical and health psychology
Abstract

BackgroundThis study addresses the strength of associations between trichotillomania (TTM) and other DSM-IV Axis I conditions in a large sample (n = 2606) enriched for familial obsessive-compulsive disorder (OCD), to inform TTM classification.MethodsWe identified participants with TTM in the Johns Hopkins OCD Family Study (153 families) and the OCD Collaborative Genetics Study, a six-site genetic linkage study of OCD (487 families). We used logistic regression (with generalized estimating equations) to assess the strength of associations between TTM and other DSM-IV disorders.ResultsTTM had excess comorbidity with a number of conditions from different DSM-IV chapters, including tic disorders, alcohol dependence, mood disorders, anxiety disorders, impulse-control disorders, and bulimia nervosa. However, association strengths (odds ratios) were highest for kleptomania (6.6), pyromania (5.8), OCD (5.6), skin picking disorder (4.4), bulimia nervosa (3.5), and pathological nail biting (3.4).ConclusionsTTM is comorbid with a number of psychiatric conditions besides OCD, and it is strongly associated with other conditions involving impaired impulse control. Though DSM-5 includes TTM as an OCD-related disorder, its comorbidity pattern also emphasizes the impulsive, appetitive aspects of this condition that may be relevant to classification.

Published
2019

28. Immune-Related Comorbidities in Childhood-Onset Obsessive Compulsive Disorder: Lifetime Prevalence in the Obsessive Compulsive Disorder Collaborative Genetics Association Study

Author

Westwell-Roper, Clara, Williams, Kyle A, Samuels, Jack, Bienvenu, O Joseph, Cullen, Bernadette, Goes, Fernando S, Grados, Marco A, Geller, Daniel, Greenberg, Benjamin D, Knowles, James A, Krasnow, Janice, McLaughlin, Nicole C, Nestadt, Paul, Shugart, Yin-Yao, Nestadt, Gerald, and Stewart, S Evelyn

Subjects
Biomedical and Clinical Sciences, Immunology, Arthritis, Infectious Diseases, Brain Disorders, Pediatric, Clinical Research, Autoimmune Disease, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Adult, Autoimmune Diseases, Child, Comorbidity, Female, Humans, Male, Obsessive-Compulsive Disorder, Prevalence, Prospective Studies, Psychiatric Status Rating Scales, Surveys and Questionnaires, autoimmune diseases, childhood-onset, communicable diseases, comorbidity, immune system diseases, inflammation, obsessive compulsive disorder, Pharmacology and Pharmaceutical Sciences, Developmental & Child Psychology, Pharmacology and pharmaceutical sciences
Abstract

Objective: To evaluate the lifetime prevalence of infectious, inflammatory, and autoimmune disorders in a multisite study of probands with childhood-onset obsessive compulsive disorder (OCD) and their first-degree relatives. Methods: Medical questionnaires were completed by 1401 probands and 1045 first-degree relatives in the OCD Collaborative Genetics Association Study. Lifetime prevalence of immune-related diseases was compared with the highest available population estimate and reported as a point estimate with 95% adjusted Wald interval. Worst-episode OCD severity and symptom dimensions were assessed with the Yale-Brown Obsessive Compulsive Scale (YBOCS) and Symptom Checklist (YBOCS-CL). Results: Probands reported higher-than-expected prevalence of scarlet fever (4.0 [3.1-5.2]% vs. 1.0%-2.0%, z = 1.491, p

Published
2019

29. Nuclear-Mitochondrial interactions influence susceptibility to HIV-associated neurocognitive impairment.

Author

Smieszek, S, Jia, P, Samuels, DC, Zhao, Z, Barnholtz-Sloan, J, Kaur, H, Letendre, S, Ellis, R, Franklin, DR, Hulgan, T, Kallianpur, A, Bush, WS, and CHARTER Study Group

Subjects
CHARTER Study Group, Cell Nucleus, Mitochondria, Humans, HIV Infections, AIDS Dementia Complex, Mitochondrial Proteins, Nuclear Proteins, Prospective Studies, Haplotypes, Polymorphism, Single Nucleotide, Genetic Association Studies, Racial Groups, Genomics, HIV, Haplogroups, Neurocognitive impairment, Nuclear mitochondrial interactions, Single nucleotide polymorphism, Acquired Cognitive Impairment, Brain Disorders, Mental Health, Genetics, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Biochemistry & Molecular Biology
Abstract

HIV-associated neurocognitive impairment (NCI) is a term established to capture a wide spectrum of HIV related neurocognitive deficits ranging in severity from asymptomatic to dementia. The genetic underpinnings of this complex phenotype are incompletely understood. Mitochondrial function has long been thought to play a role in neurodegeneration, along with iron metabolism and transport. In this work, we aimed to characterize the interplay of mitochondrial DNA (mtDNA) haplogroup and nuclear genetic associations to NCI phenotypes in the CHARTER cohort, encompassing 1025 individuals of European-descent, African-descent, or admixed Hispanic. We first employed a polygenic modeling approach to investigate the global effect of previous marginally associated nuclear SNPs, and to examine how the polygenic effect of these SNPs is influenced by mtDNA haplogroups. We see evidence of a significant interaction between nuclear SNPs en masse and mtDNA haplogroups within European-descent and African-descent individuals. Subsequently, we performed an analysis of each SNP by mtDNA haplogroup, and detected significant interactions between two nuclear SNPs (rs17160128 and rs12460243) and European haplogroups. These findings, which require validation in larger cohorts, indicate a potential new role for nuclear-mitochondrial DNA interactions in susceptibility to NCI and shed light onto the pathophysiology of this neurocognitive phenotype.

Published
2019

30. Cerebrospinal Fluid Ceruloplasmin, Haptoglobin, and Vascular Endothelial Growth Factor Are Associated with Neurocognitive Impairment in Adults with HIV Infection

Author

Kallianpur, AR, Gittleman, H, Letendre, S, Ellis, R, Barnholtz-Sloan, JS, Bush, WS, Heaton, R, Samuels, DC, Franklin, DR, Rosario-Cookson, D, Clifford, DB, Collier, AC, Gelman, B, Marra, CM, McArthur, JC, McCutchan, JA, Morgello, S, Grant, I, Simpson, D, Connor, JR, Hulgan, T, and the CHARTER Study Group

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Sexually Transmitted Infections, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Mental Health, Infectious Diseases, Neurosciences, HIV/AIDS, 2.1 Biological and endogenous factors, Adult, Antiretroviral Therapy, Highly Active, Biomarkers, Ceruloplasmin, Comorbidity, Female, HIV Infections, Haptoglobins, Humans, Inflammation, Iron, Male, Multivariate Analysis, Neurocognitive Disorders, Regression Analysis, Vascular Endothelial Growth Factor A, Haptoglobin, Vascular endothelial growth factor, Biomarker, HIV-associated neurocognitive disorder, Cerebrospinal fluid, CHARTER Study Group, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biochemistry and cell biology
Abstract

Dysregulated iron transport and a compromised blood-brain barrier are implicated in HIV-associated neurocognitive disorders (HAND). We quantified the levels of proteins involved in iron transport and/or angiogenesis-ceruloplasmin, haptoglobin, and vascular endothelial growth factor (VEGF)-as well as biomarkers of neuroinflammation, in cerebrospinal fluid (CSF) from 405 individuals with HIV infection and comprehensive neuropsychiatric assessments. Associations with HAND [defined by a Global Deficit Score (GDS) ≥ 0.5, GDS as a continuous measure (cGDS), or by Frascati criteria] were evaluated for the highest versus lowest tertile of each biomarker, adjusting for potential confounders. Higher CSF VEGF was associated with GDS-defined impairment [odds ratio (OR) 2.17, p = 0.006] and cGDS in unadjusted analyses and remained associated with GDS impairment after adjustment (p = 0.018). GDS impairment was also associated with higher CSF ceruloplasmin (p = 0.047) and with higher ceruloplasmin and haptoglobin in persons with minimal comorbidities (ORs 2.37 and 2.13, respectively; both p = 0.043). In persons with minimal comorbidities, higher ceruloplasmin and haptoglobin were associated with HAND by Frascati criteria (both p

Published
2019

31. Structure-Activity Relationships of Rationally Designed Ritonavir Analogues: Impact of Side-Group Stereochemistry, Headgroup Spacing, and Backbone Composition on the Interaction with CYP3A4.

Author

Samuels, Eric and Sevrioukova, Irina

Subjects
Binding, Competitive, Biocatalysis, Crystallography, X-Ray, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Drug Design, Humans, Ligands, Models, Molecular, Molecular Structure, Protein Binding, Protein Domains, Ritonavir, Spectrophotometry, Stereoisomerism, Structure-Activity Relationship
Abstract

In a continuing effort to identify structural attributes required for strong binding and potent inhibition of human drug-metabolizing CYP3A4, we designed ten ritonavir-like analogues differing in the side-group stereochemistry, backbone atomic composition, and headgroup spacing. All analogues had pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating head and tail groups, respectively, phenyl side groups, and either a methyl- or ethyl-pyridyl linker. Each linker subseries had S/ R, R/ S, R/ R, and S/S side-group conformers (4a-d and 4e-h, respectively), and one S/S stereoisomer with the backbone S-to-N-heteroatom substitution (6a and 6b). To elucidate structure-activity relationships, ligand-dependent changes in optical spectra, dissociation constant ( Ks), inhibitory potency (IC50), thermostability, and heme ligation and reduction kinetics were analyzed. Comparison of the subseries and individual compounds showed that CYP3A4 only weakly discriminates between side-group configurations, associates more tightly with the pyridyl-ethyl-linker analogues, and strongly disfavors the N-containing backbone. Ks and IC50 for the pyridyl-ethyl R/ R conformer, 4g, were the lowest and close to those for ritonavir: 0.04 and 0.31 μM versus 0.02 and 0.13 μM, respectively. Determination of the X-ray structures of the inhibitory complexes was critical for experimental data interpretation, especially for the uniquely oriented 4a and 4e. Based on structural analysis, we conclude that, for this series of analogues, the ligand-mediated interactions near the heme are dominant and define the binding mode and that fine-tuning of these interactions as well as the backbone spacing could further improve the affinity and inhibitory strength.

Published
2019

32. Peripheral Blood Mitochondrial DNA Copy Number Obtained From Genome-Wide Genotype Data Is Associated With Neurocognitive Impairment in Persons With Chronic HIV Infection

Author

Hulgan, Todd, Kallianpur, Asha R, Guo, Yan, Barnholtz-Sloan, Jill S, Gittleman, Haley, Brown, Todd T, Ellis, Ronald, Letendre, Scott, Heaton, Robert K, and Samuels, David C

Subjects
Brain Disorders, Infectious Diseases, Neurosciences, Genetics, Human Genome, HIV/AIDS, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, AIDS Dementia Complex, Adult, Anti-Retroviral Agents, DNA Copy Number Variations, DNA, Mitochondrial, Female, Genome-Wide Association Study, Genotype, HIV Infections, Humans, Male, Middle Aged, Mitochondria, Neurocognitive Disorders, Neuropsychological Tests, DNA, mitochondrial, HIV, neurocognitive disorders, CHARTER Study, Clinical Sciences, Public Health and Health Services, Virology
Abstract

BackgroundMitochondrial DNA (mtDNA) copy number varies by cell type and energy demands. Blood mtDNA copy number has been associated with neurocognitive function in persons without HIV. Low mtDNA copy number may indicate disordered mtDNA replication; high copy number may reflect a response to mitochondrial dysfunction. We hypothesized that blood mtDNA copy number estimated from genome-wide genotyping data is related to neurocognitive impairment (NCI) in persons with HIV.MethodsIn the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, peripheral blood mtDNA copy number was obtained from genome-wide genotyping data as a ratio of mtDNA single-nucleotide polymorphism probe intensities relative to nuclear DNA single-nucleotide polymorphisms. In a multivariable regression model, associations between mtDNA copy number and demographics, blood cell counts, and HIV disease and treatment characteristics were tested. Associations of mtDNA copy number with the global deficit score (GDS), GDS-defined NCI (GDS ≥ 0.5), and HIV-associated neurocognitive disorder (HAND) diagnosis were tested by logistic regression, adjusting for potential confounders.ResultsAmong 1010 CHARTER participants, lower mtDNA copy number was associated with longer antiretroviral therapy duration (P < 0.001), but not with d-drug exposure (P = 0.85). mtDNA copy number was also associated with GDS (P = 0.007), GDS-defined NCI (P < 0.001), and HAND (P = 0.002). In all analyses, higher mtDNA copy number was associated with poorer cognitive performance.ConclusionsHigher mtDNA copy number estimated from peripheral blood genotyping was associated with worse neurocognitive performance in adults with HIV. These results suggest a connection between peripheral blood mtDNA and NCI, and may represent increased mtDNA replication in response to mitochondrial dysfunction.

Published
2019

33. Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan.

Author

Chen, Dan-Qian, Cao, Gang, Chen, Hua, Argyopoulos, Christos P, Yu, Hui, Su, Wei, Chen, Lin, Samuels, David C, Zhuang, Shougang, Bayliss, George P, Zhao, Shilin, Yu, Xiao-Yong, Vaziri, Nosratola D, Wang, Ming, Liu, Dan, Mao, Jia-Rong, Ma, Shi-Xing, Zhao, Jin, Zhang, Yuan, Shang, You-Quan, Kang, Huining, Ye, Fei, Cheng, Xiao-Hong, Li, Xiang-Ri, Zhang, Li, Meng, Mei-Xia, Guo, Yan, and Zhao, Ying-Yong

Subjects
Kidney, Animals, Humans, Mice, Ureteral Obstruction, Disease Models, Animal, Disease Progression, Fibrosis, Inflammation, Taurine, Tryptophan Hydroxylase, Carnitine, Acetylcarnitine, Tryptophan, Canavanine, NF-kappa B, Severity of Illness Index, Case-Control Studies, Signal Transduction, I-kappa B Proteins, NF-E2-Related Factor 2, Renal Insufficiency, Chronic, Metabolomics, Gene Knockdown Techniques, Gene Knock-In Techniques, Kelch-Like ECH-Associated Protein 1, Kidney Disease, Prevention, Urologic Diseases, Renal and Urogenital, Disease Models, Animal, Renal Insufficiency, Chronic, MD Multidisciplinary
Abstract

Early detection and accurate monitoring of chronic kidney disease (CKD) could improve care and retard progression to end-stage renal disease. Here, using untargeted metabolomics in 2155 participants including patients with stage 1-5 CKD and healthy controls, we identify five metabolites, including 5-methoxytryptophan (5-MTP), whose levels strongly correlate with clinical markers of kidney disease. 5-MTP levels decrease with progression of CKD, and in mouse kidneys after unilateral ureteral obstruction (UUO). Treatment with 5-MTP ameliorates renal interstitial fibrosis, inhibits IκB/NF-κB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperfusion injury, as well as in cultured human kidney cells. Overexpression of tryptophan hydroxylase-1 (TPH-1), an enzyme involved in 5-MTP synthesis, reduces renal injury by attenuating renal inflammation and fibrosis, whereas TPH-1 deficiency exacerbates renal injury and fibrosis by activating NF-κB and inhibiting Nrf2 pathways. Together, our results suggest that TPH-1 may serve as a target in the treatment of CKD.

Published
2019

34. The African Descent and Glaucoma Evaluation Study (ADAGES) III Contribution of Genotype to Glaucoma Phenotype in African Americans: Study Design and Baseline Data

Author

Zangwill, Linda M, Ayyagari, Radha, Liebmann, Jeffrey M, Girkin, Christopher A, Feldman, Robert, Dubiner, Harvey, Dirkes, Keri A, Holmann, Matthew, Williams-Steppe, Eunice, Hammel, Naama, Saunders, Luke J, Vega, Suzanne, Sandow, Kevin, Roll, Kathryn, Slight, Rigby, Auerbach, Daniel, Samuels, Brian C, Panarelli, Joseph F, Mitchell, John P, Al-Aswad, A, Park, Sung Chul, Tello, Celso, Cotliar, Jeremy, Bansal, Rajendra, Sidoti, Paul A, Cioffi, George A, Blumberg, Dana, Ritch, Robert, Bell, Nicholas P, Blieden, Lauren S, Davis, Garvin, Medeiros, Felipe A, Ng, Maggie CY, Das, Swapan K, Palmer, Nicholette D, Divers, Jasmin, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Christopher, Mark A, Chen, Yii-der I, Guo, Xiuqing, Taylor, Kent D, Rotter, Jerome I, Weinreb, Robert N, and Group, African Descent and Glaucoma Evaluation Study III Genomics Study

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Neurosciences, Aging, Neurodegenerative, Clinical Research, Eye Disease and Disorders of Vision, Eye, Black or African American, Aged, Body Constitution, Case-Control Studies, Cross-Sectional Studies, Female, Gene-Environment Interaction, Genome-Wide Association Study, Genotype, Glaucoma, Open-Angle, Humans, Intraocular Pressure, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Research Design, Visual Acuity, Visual Fields, White People, African Descent and Glaucoma Evaluation Study III Genomics Study Group, Clinical Sciences, Opthalmology and Optometry, Public Health and Health Services, Ophthalmology & Optometry, Ophthalmology and optometry
Abstract

PurposeTo describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III.DesignCross-sectional, case-control study.ParticipantsThree thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States.MethodsIndividuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review.Main outcome measuresParticipant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded.ResultsThe 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients.ConclusionsWith its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.

Published
2019

35. Genetic Architecture of Primary Open-Angle Glaucoma in Individuals of African Descent The African Descent and Glaucoma Evaluation Study III

Author

Taylor, Kent D, Guo, Xiuqing, Zangwill, Linda M, Liebmann, Jeffrey M, Girkin, Christopher A, Feldman, Robert M, Dubiner, Harvey, Hai, Yang, Samuels, Brian C, Panarelli, Joseph F, Mitchell, John P, Al-Aswad, A, Park, Sung Chul, Tello, Celso, Cotliar, Jeremy, Bansal, Rajendra, Sidoti, Paul A, Cioffi, George A, Blumberg, Dana, Ritch, Robert, Bell, Nicholas P, Blieden, Lauren S, Davis, Garvin, Medeiros, Felipe A, Das, Swapan K, Divers, Jasmin, Langefeld, Carl D, Palmer, Nicholette D, Freedman, Barry I, Bowden, Donald W, Ng, Maggie CY, Chen, Yii-Der Ida, Ayyagari, Radha, Rotter, Jerome I, Weinreb, Robert N, and Group, African Descent and Glaucoma Evaluation Study III Genomics Study

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Neurosciences, Eye Disease and Disorders of Vision, Prevention, Genetics, Aging, Neurodegenerative, Human Genome, Black or African American, Aged, Case-Control Studies, Cross-Sectional Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glaucoma, Open-Angle, Humans, Intraocular Pressure, Male, Middle Aged, Phosphopyruvate Hydratase, Polymorphism, Single Nucleotide, ROC Curve, African Descent and Glaucoma Evaluation Study III Genomics Study Group, Clinical Sciences, Opthalmology and Optometry, Public Health and Health Services, Ophthalmology & Optometry, Ophthalmology and optometry
Abstract

PurposeTo find genetic contributions to glaucoma in African Americans.DesignCross-sectional, case-control study.ParticipantsOne thousand eight hundred seventy-five primary open-angle glaucoma (POAG) patients and 1709 controls, self-identified as being of African descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGES) III and Wake Forest School of Medicine.MethodsMegaChip genotypes were imputed to Thousand Genomes data. Association of single nucleotide polymorphisms (SNPs) with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by receiver operator characteristic curves (ROC-AUCs).Main outcome measuresPrimary open-angle glaucoma defined by visual field loss without other nonocular conditions (n = 1875). Advanced POAG was defined by age-based mean deviation of visual field (n = 946).ResultsEighteen million two hundred eighty-one thousand nine hundred twenty SNPs met imputation quality of r2 > 0.7 and minor allele frequency > 0.005. Association of a novel locus, EN04, was observed for advanced POAG (rs185815146 β, 0.36; standard error, 0.065; P < 3×10-8). For POAG, an AD signal was observed at the 9p21 European descent (ED) POAG signal (rs79721419; P < 6.5×10-5) independent of the previously observed 9p21 ED signal (rs2383204; P < 2.3×10-5) by conditional analyses. An association with POAG in FNDC3B (rs111698934; P < 3.9×10-5) was observed, not in linkage disequilibrium (LD) with the previously reported ED SNP. Additional previously identified loci associated with POAG in persons of AD were: 8q22, AFAP1, and TMC01. An AUC of 0.62 was observed with an unweighted genetic risk score comprising 11 SNPs in candidate genes. Two additional risk scores were studied by using a penalized matrix decomposition with cross-validation; risk scores of 50 and 400 SNPs were identified with ROC of AUC = 0.74 and AUC = 0.94, respectively.ConclusionsA novel association with advanced POAG in the EN04 locus was identified putatively in persons of AD. In addition to this finding, this genome-wide association study in POAG patients of AD contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine mapping of regions because of shorter average LD (FNDC3B). Although not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.

Published
2019

36. A cross-species approach to disorders affecting brain and behaviour

Author

Devinsky, Orrin, Boesch, Jordyn M, Cerda-Gonzalez, Sofia, Coffey, Barbara, Davis, Kathryn, Friedman, Daniel, Hainline, Brian, Houpt, Katherine, Lieberman, Daniel, Perry, Pamela, Prüss, Harald, Samuels, Martin A, Small, Gary W, Volk, Holger, Summerfield, Artur, Vite, Charles, Wisniewski, Thomas, and Natterson-Horowitz, Barbara

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Epilepsy, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Mental health, Good Health and Well Being, Animals, Anxiety Disorders, Cognitive Dysfunction, Disease Models, Animal, Encephalitis, Humans, Movement Disorders, Pain, Translational Research, Biomedical, Clinical sciences
Abstract

Structural and functional elements of biological systems are highly conserved across vertebrates. Many neurological and psychiatric conditions affect both humans and animals. A cross-species approach to the study of brain and behaviour can advance our understanding of human disorders via the identification of unrecognized natural models of spontaneous disorders, thus revealing novel factors that increase vulnerability or resilience, and via the assessment of potential therapies. Moreover, diagnostic and therapeutic advances in human neurology and psychiatry can often be adapted for veterinary patients. However, clinical and research collaborations between physicians and veterinarians remain limited, leaving this wealth of comparative information largely untapped. Here, we review pain, cognitive decline syndromes, epilepsy, anxiety and compulsions, autoimmune and infectious encephalitides and mismatch disorders across a range of animal species, looking for novel insights with translational potential. This comparative perspective can help generate novel hypotheses, expand and improve clinical trials and identify natural animal models of disease resistance and vulnerability.

Published
2018

37. Assembly and activation of the Hippo signalome by FAT1 tumor suppressor.

Author

Martin, Daniel, Degese, Maria S, Vitale-Cross, Lynn, Iglesias-Bartolome, Ramiro, Valera, Juan Luis Callejas, Wang, Zhiyong, Feng, Xiaodong, Yeerna, Huwate, Vadmal, Vachan, Moroishi, Toshiro, Thorne, Rick F, Zaida, Moraima, Siegele, Bradford, Cheong, Sok C, Molinolo, Alfredo A, Samuels, Yardena, Tamayo, Pablo, Guan, Kun Liang, Lippman, Scott M, Lyons, J Guy, and Gutkind, J Silvio

Subjects
Humans, Head and Neck Neoplasms, Protein-Serine-Threonine Kinases, Hepatocyte Growth Factor, Adaptor Proteins, Signal Transducing, Cadherins, Proto-Oncogene Proteins, Phosphoproteins, Transcription Factors, Signal Transduction, Gene Knockdown Techniques, HEK293 Cells, Squamous Cell Carcinoma of Head and Neck, Cancer, Genetics, Biotechnology, Dental/Oral and Craniofacial Disease, Rare Diseases, 2.1 Biological and endogenous factors
Abstract

Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.

Published
2018

38. Neurocognitive Function in Children with Primary Hypertension after Initiation of Antihypertensive Therapy

Author

Lande, Marc B, Batisky, Donald L, Kupferman, Juan C, Samuels, Joshua, Hooper, Stephen R, Falkner, Bonita, Waldstein, Shari R, Szilagyi, Peter G, Wang, Hongyue, Staskiewicz, Jennifer, and Adams, Heather R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Hypertension, Behavioral and Social Science, Basic Behavioral and Social Science, Cardiovascular, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adolescent, Antihypertensive Agents, Blood Pressure, Case-Control Studies, Child, Executive Function, Female, Humans, Male, Neuropsychological Tests, Prospective Studies, blood pressure, neuropsychological testing, obesity, treatment, Human Movement and Sports Sciences, Paediatrics and Reproductive Medicine, Pediatrics, Paediatrics
Abstract

OBJECTIVE:To determine the change in neurocognitive test performance in children with primary hypertension after initiation of antihypertensive therapy. STUDY DESIGN:Subjects with hypertension and normotensive control subjects had neurocognitive testing at baseline and again after 1 year, during which time the subjects with hypertension received antihypertensive therapy. Subjects completed tests of general intelligence, attention, memory, executive function, and processing speed, and parents completed rating scales of executive function. RESULTS:Fifty-five subjects with hypertension and 66 normotensive control subjects underwent both baseline and 1-year assessments. Overall, the blood pressure (BP) of subjects with hypertension improved (24-hour systolic BP load: mean baseline vs 1 year, 58% vs 38%, P

Published
2018

39. Inhibition of Human CYP3A4 by Rationally Designed Ritonavir-Like Compounds: Impact and Interplay of the Side Group Functionalities.

Author

Samuels, Eric and Sevrioukova, Irina

Subjects
CYP3A4, crystal structure, inhibitor design, ligand binding, structure−function relationships, Cytochrome P-450 CYP3A, Humans, Kinetics, Protein Binding, Ritonavir
Abstract

Structure-function relationships of nine rationally designed ritonavir-like compounds were investigated to better understand the ligand binding and inhibitory mechanism in human drug-metabolizing cytochrome P450 3A4 (CYP3A4). The analogs had a similar backbone and pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating and terminal groups, respectively. N-Isopropyl, N-cyclopentyl, or N-phenyl were the R1-side group substituents alone (compounds 5a-c) or in combination with phenyl or indole at the R2 position (8a-c and 8d-f subseries, respectively). Our experimental and structural data indicate that (i) for all analogs, a decrease in the dissociation constant (Ks) coincides with a decrease in IC50, but no relation with other derived parameters is observed; (ii) an increase in the R1 volume, hydrophobicity, and aromaticity markedly lowers Ks and IC50, whereas the addition of aromatic R2 has a more pronounced positive effect on the inhibitory potency than the binding strength; (iii) the ligands association mode is strongly influenced by the mutually dependent R1-R2 interplay, but the R1-mediated interactions are dominant and define the overall conformation in the active site; (iv) formation of a strong H-bond with Ser119 is a prerequisite for potent CYP3A4 inhibition; and (v) the strongest inhibitor in the series, the R1-phenyl/R2-indole containing 8f (Ks and IC50 of 0.08 and 0.43 μM, respectively), is still less potent than ritonavir, even under conditions that prevent the mechanism based inactivation of CYP3A4. Crystallographic data were essential for better understanding and interpretation of the experimental results, and suggested how the inhibitor design could be further optimized.

Published
2018

40. Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

Author

Patton, Stephanie M, Wang, Quan, Hulgan, Todd, Connor, James R, Jia, Peilin, Zhao, Zhongming, Letendre, Scott L, Ellis, Ronald J, Bush, William S, Samuels, David C, Franklin, Donald R, Kaur, Harpreet, Iudicello, Jennifer, Grant, Igor, and Kallianpur, Asha R

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Clinical Research, Mental Health, Pediatric AIDS, Acquired Cognitive Impairment, HIV/AIDS, Pediatric, Infectious Diseases, Brain Disorders, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Adult, Anti-Retroviral Agents, Apoferritins, Blood-Brain Barrier, Cohort Studies, Demography, Female, HIV Infections, Humans, Iron, Male, Middle Aged, Transferrin, Viral Load, Iron transport, Cerebrospinal fluid, HIV, H-ferritin, HIV-associated neurocognitive disorders, Biological Sciences, Medical and Health Sciences, Neurosciences
Abstract

BackgroundHIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). HIV dysregulates iron metabolism, but cerebrospinal fluid (CSF) levels of iron and iron-transport proteins in HIV-infected (HIV+) persons are largely unknown. The objectives of this study were to characterize CSF iron-related biomarkers in HIV+ adults and explore their relationships to known predictors of HAND.MethodsWe quantified total iron, transferrin and heavy-chain (H)-ferritin by immunoassay in CSF sampled by lumbar puncture in 403 HIV+ participants in a multi-center, observational study and evaluated biomarker associations with demographic and HIV-related correlates of HAND [e.g., age, sex, self-reported race/ethnicity, ART, and detectable plasma virus and CSF viral load (VL)] by multivariable regression. In a subset (N = 110) with existing CSF: serum albumin (QAlb) measurements, QAlb and comorbidity severity were also included as covariates to account for variability in the blood-CSF-barrier.ResultsAmong 403 individuals (median age 43 years, 19% women, 56% non-Whites, median nadir CD4+ T cell count 180 cells/µL, 46% with undetectable plasma virus), men had 25% higher CSF transferrin (median 18.1 vs. 14.5 µg/mL), and 71% higher H-ferritin (median 2.9 vs. 1.7 ng/mL) than women (both p-values ≤0.01). CSF iron was 41% higher in self-reported Hispanics and 27% higher in (non-Hispanic) Whites than in (non-Hispanic) Blacks (median 5.2 and 4.7 µg/dL in Hispanics and Whites, respectively, vs. 3.7 µg/dL in Blacks, both p ≤ 0.01); these findings persisted after adjustment for age, sex, and HIV-specific factors. Median H-ferritin was 25% higher (p  50 years) than in younger persons (age ≤ 35 years; both p

Published
2017

41. Feasibility of Lenalidomide Therapy for Persistent Chronic Lymphocytic Leukemia after Allogeneic Transplantation.

Author

Khouri, Maria, Jabbour, Elias, Gulbis, Alison, Turturro, Francesco, Ledesma, Celina, Korbling, Martin, Samuels, Barry, Ahmed, Sairah, Alousi, Amin, Ciurea, Stefan, Marin, David, Patel, Krina, Popat, Uday, Bueso-Ramos, Carlos, Bassett, Roland, and Khouri, Issa

Subjects
Allogeneic, Chronic lymphocytic leukemia, Lenalidomide, Nonmyeloablative, Transplantation, Acute Disease, Aged, Allografts, Disease-Free Survival, Female, Follow-Up Studies, Graft vs Host Disease, Humans, Lenalidomide, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocyte Transfusion, Male, Middle Aged, Stem Cell Transplantation, Survival Rate, Thalidomide
Abstract

In patients with chronic lymphocytic leukemia (CLL), persistence of disease after allogeneic stem cell transplantation (alloSCT) can result in poor outcomes. In an effort to improve these outcomes, patients with persistent CLL who were 90 to 100 days beyond alloSCT with no evidence of graft-versus-host-disease (GVHD) were randomized to receive lenalidomide or standard care (withdrawal of immunosuppression followed by donor lymphocyte infusion). Lenalidomide was initiated at 5 mg every other day and increased to 10 mg daily, if tolerated, in each patient. Of 38 patients enrolled, 17 (45%) met the eligibility criteria for randomization. Of these 17 patients, 8 were randomized to undergo lenalidomide therapy. Five (62%) patients had to stop taking the drug because of toxicity. The main reason for drug discontinuation was acute GVHD in 43% of patients. This incidence was 11% in the patients who were randomized to not receive lenalidomide. With a median follow-up of 2.6 years, the median survival was 3.4 years for those receiving lenalidomide. This was not reached in patients randomized to not receive lenalidomide and in patients in complete remission who were not randomized. These results suggested that treatments other than lenalidomide are needed for persistent CLL after alloSCT.

Published
2017

42. Genome‐wide association study of HIV‐associated neurocognitive disorder (HAND): A CHARTER group study

Author

Jia, Peilin, Zhao, Zhongming, Hulgan, Todd, Bush, William S, Samuels, David C, Bloss, Cinnamon S, Heaton, Robert K, Ellis, Ronald J, Schork, Nicholas, Marra, Christina M, Collier, Ann C, Clifford, David B, Gelman, Benjamin B, Sacktor, Ned, Morgello, Susan, Simpson, David M, McCutchan, J Allen, Barnholtz‐Sloan, Jill S, Franklin, Donald R, Rosario, Debralee, Letendre, Scott L, Grant, Igor, Kallianpur, Asha R, and Group, for the CHARTER Study

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Mental Health, HIV/AIDS, Human Genome, Infectious Diseases, Neurosciences, Prevention, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, AIDS Dementia Complex, Adult, Biomarkers, Female, Follow-Up Studies, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Neurocognitive Disorders, Neuropsychological Tests, Polymorphism, Single Nucleotide, Prognosis, Prospective Studies, HIV-associated neurocognitive disorder, neuro-cognitive impairment, GWAS, genotype, CHARTER study, global deficit score, CHARTER Study Group, neurocognitive impairment, Clinical Sciences, Clinical sciences
Abstract

HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive, and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded. Neurocognitive outcomes included GDS-defined neurocognitive impairment (NCI; binary GDS, 366 cases with GDS ≥ 0.5 and 684 controls with GDS

Published
2017

43. An investigation of doubt in obsessive–compulsive disorder

Author

Samuels, Jack, Bienvenu, O Joseph, Krasnow, Janice, Wang, Ying, Grados, Marco A, Cullen, Bernadette, Goes, Fernando S, Maher, Brion, Greenberg, Benjamin D, McLaughlin, Nicole C, Rasmussen, Steven A, Fyer, Abby J, Knowles, James A, Nestadt, Paul, McCracken, James T, Piacentini, John, Geller, Dan, Pauls, David L, Stewart, S Evelyn, Murphy, Dennis L, Shugart, Yin-Yao, Kamath, Vidya, Bakker, Arnold, Riddle, Mark A, and Nestadt, Gerald

Subjects
Biomedical and Clinical Sciences, Applied and Developmental Psychology, Clinical and Health Psychology, Social and Personality Psychology, Clinical Sciences, Psychology, Behavioral and Social Science, Brain Disorders, Anxiety Disorders, Serious Mental Illness, Mental Health, Mental health, Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Cognitive Behavioral Therapy, Compulsive Personality Disorder, Depressive Disorder, Major, Emotions, Female, Humans, Male, Middle Aged, Neuroticism, Obsessive-Compulsive Disorder, Personality Disorders, Young Adult, Psychiatry, Clinical sciences, Clinical and health psychology
Abstract

BackgroundClinicians have long considered doubt to be a fundamental characteristic of obsessive-compulsive disorder (OCD). However, the clinical relevance of doubt in OCD has not been addressed.MethodsParticipants included 1182 adults with OCD who had participated in family and genetic studies of OCD. We used a clinical measure of the severity of doubt, categorized as none, mild, moderate, severe, or extreme. We evaluated the relationship between doubt and OCD clinical features, Axis I disorders, personality and personality disorder dimensions, impairment, and treatment response.ResultsThe severity of doubt was inversely related to the age at onset of OCD symptoms. Doubt was strongly related to the number of checking symptoms and, to a lesser extent, to the numbers of contamination/cleaning and hoarding symptoms. Doubt also was related to the lifetime prevalence of recurrent major depression and generalized anxiety disorder; to the numbers of avoidant, dependent, and obsessive-compulsive personality disorder traits; and to neuroticism and introversion. Moreover, doubt was strongly associated with global impairment and poor response to cognitive behavioral treatment (CBT), even adjusting for OCD severity and other correlates of doubt.ConclusionsDoubt is associated with important clinical features of OCD, including impairment and cognitive-behavioral treatment response.

Published
2017

44. Parental bonding and hoarding in obsessive–compulsive disorder

Author

Chen, David, Bienvenu, O Joseph, Krasnow, Janice, Wang, Ying, Grados, Marco A, Cullen, Bernadette, Goes, Fernando S, Maher, Brion, Greenberg, Benjamin D, McLaughlin, Nicole C, Rasmussen, Steven A, Fyer, Abby J, Knowles, James A, McCracken, James T, Piacentini, John, Geller, Dan, Pauls, David L, Stewart, S Evelyn, Murphy, Dennis L, Shugart, Yin-Yao, Riddle, Mark A, Nestadt, Gerald, and Samuels, Jack

Subjects
Social and Personality Psychology, Psychology, Mental Health, Behavioral and Social Science, Clinical Research, Serious Mental Illness, Reproductive health and childbirth, Good Health and Well Being, Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Diagnostic and Statistical Manual of Mental Disorders, Female, Hoarding, Humans, Male, Middle Aged, Object Attachment, Obsessive-Compulsive Disorder, Parenting, Sex Characteristics, Young Adult, Clinical Sciences, Psychiatry, Clinical sciences, Clinical and health psychology
Abstract

BackgroundHoarding behavior may indicate a clinically and possibly etiologically distinct subtype of obsessive-compulsive disorder (OCD). Empirical evidence supports a relationship between hoarding and emotional over-attachment to objects. However, little is known about the relationship between hoarding and parental attachment in OCD.MethodThe study sample included 894 adults diagnosed with DSM-IV OCD who had participated in family and genetic studies of OCD. Participants were assessed for Axis I disorders, personality disorders, and general personality dimensions. The Parental Bonding Instrument (PBI) was used to assess dimensions of perceived parental rearing (care, overprotection, and control). We compared parental PBI scores in the 334 hoarding and 560 non-hoarding participants, separately in men and women. We used logistic regression to evaluate the relationship between parenting scores and hoarding in women, adjusting for other clinical features associated with hoarding.ResultsIn men, there were no significant differences between hoarding and non-hoarding groups in maternal or paternal parenting scores. In women, the hoarding group had a lower mean score on maternal care (23.4 vs. 25.7, p

Published
2017

45. Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL.

Author

Khouri, I, Sui, D, Jabbour, E, Samuels, B, Turturro, F, Alatrash, G, Anderlini, P, Ahmed, S, Oran, B, Ciurea, S, Marin, D, Olson, A, Patel, K, Popat, U, Ledesma, C, Kadia, T, Ferrajoli, A, Burger, J, Jorgensen, J, Medeiros, L, Bassett, R, and Gulbis, A

Subjects
Adult, Aged, Bendamustine Hydrochloride, Cyclophosphamide, Disease-Free Survival, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Rituximab, Survival Rate, Transplantation Conditioning, Vidarabine
Abstract

Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received bendamustine, fludarabine and rituximab (BFR) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR-treated patients vs only two (3%) FCR-treated patients did not experience severe neutropenia (P=

Published
2017

46. Neurocognitive Function in Children with Primary Hypertension

Author

Lande, Marc B, Batisky, Donald L, Kupferman, Juan C, Samuels, Joshua, Hooper, Stephen R, Falkner, Bonita, Waldstein, Shari R, Szilagyi, Peter G, Wang, Hongyue, Staskiewicz, Jennifer, and Adams, Heather R

Subjects
Paediatrics, Biomedical and Clinical Sciences, Neurosciences, Mental Health, Clinical Research, Basic Behavioral and Social Science, Cardiovascular, Behavioral and Social Science, Pediatric, Mental health, Adolescent, Child, Cognition, Cross-Sectional Studies, Executive Function, Female, Humans, Hypertension, Male, Neuropsychological Tests, Prospective Studies, adolescence, blood pressure, neuropsychological testing, obesity, pediatric, Human Movement and Sports Sciences, Paediatrics and Reproductive Medicine, Pediatrics
Abstract

ObjectiveTo compare neurocognitive test performance of children with primary hypertension with that of normotensive controls.Study designSeventy-five children (10-18 years of age) with newly diagnosed, untreated hypertension and 75 frequency-matched normotensive controls had baseline neurocognitive testing as part of a prospective multicenter study of cognition in primary hypertension. Subjects completed tests of general intelligence, attention, memory, executive function, and processing speed. Parents completed rating scales of executive function and the Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire (PSQ-SRBD).ResultsHypertension and control groups did not differ significantly in age, sex, maternal education, income, race, ethnicity, obesity, anxiety, depression, cholesterol, glucose, insulin, and C-reactive protein. Subjects with hypertension had greater PSQ-SRBD scores (P = .04) and triglycerides (P = .037). Multivariate analyses showed that hypertension was independently associated with worse performance on the Rey Auditory Verbal Learning Test (List A Trial 1, P = .034; List A Total, P = .009; Short delay recall, P = .013), CogState Groton Maze Learning Test delayed recall (P = .002), Grooved Pegboard dominant hand (P = .045), and Wechsler Abbreviated Scales of Intelligence Vocabulary (P = .016). Results indicated a significant interaction between disordered sleep (PSQ-SRBD score) and hypertension on ratings of executive function (P = .04), such that hypertension heightened the association between increased disordered sleep and worse executive function.ConclusionsYouth with primary hypertension demonstrated significantly lower performance on neurocognitive testing compared with normotensive controls, in particular, on measures of memory, attention, and executive functions.

Published
2017

47. Thyroid Function Variations Within the Reference Range Do Not Affect Quality of Life, Mood, or Cognitive Function in Community-Dwelling Older Men.

Author

Samuels, Mary H, Kaimal, Rajani, Waring, Avantika, Fink, Howard A, Yaffe, Kristine, Hoffman, Andrew R, Orwoll, Eric, and Bauer, Douglas

Subjects
Thyroid Gland, Humans, Thyrotropin, Thyroxine, Prospective Studies, Affect, Cognition, Reference Values, Quality of Life, Aged, Aged, 80 and over, Male, Aging, Clinical Research, Behavioral and Social Science, Clinical Sciences, Endocrinology & Metabolism
Abstract

BackgroundVariations in thyroid function within the laboratory reference range have been associated with a number of clinical outcomes. However, quality of life, mood, and cognitive function have not been extensively studied, and it is not clear whether mild variations in thyroid function have major effects on these neurocognitive outcomes.MethodsData were analyzed from the Osteoporotic Fractures in Men (MrOS) Study, a cohort of community-dwelling men aged 65 years and older in the United States. A total of 539 participants who were not taking thyroid medications and had age-adjusted TSH levels within the reference range underwent detailed testing of quality of life, mood, and cognitive function at baseline. The same quality of life, mood, and cognitive outcomes were measured again in 193 of the men after a mean follow-up of 6 years. Outcomes were analyzed using thyrotropin (TSH) and free thyroxine (FT4) levels as continuous independent variables, adjusting for relevant covariates.ResultsAt baseline, there were no associations between TSH or FT4 levels and measures of quality of life, mood, or cognition in the 539 euthyroid men. Baseline thyroid function did not predict changes in these outcomes over a mean of 6 years in the 193 men in the longitudinal analysis.ConclusionsVariations in thyroid function within the age-adjusted laboratory reference range are not associated with variations in quality of life, mood, or cognitive function in community-dwelling older men.

Published
2016

48. Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.

Author

Abdel-Mohsen, Mohamed, Chavez, Leonard, Tandon, Ravi, Chew, Glen M, Deng, Xutao, Danesh, Ali, Keating, Sheila, Lanteri, Marion, Samuels, Michael L, Hoh, Rebecca, Sacha, Jonah B, Norris, Philip J, Niki, Toshiro, Shikuma, Cecilia M, Hirashima, Mitsuomi, Deeks, Steven G, Ndhlovu, Lishomwa C, and Pillai, Satish K

Subjects
CD4-Positive T-Lymphocytes, Humans, HIV-1, HIV Infections, Galectins, Anti-HIV Agents, Blotting, Western, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Expression Profiling, Polymerase Chain Reaction, Virus Latency, Virus Activation, Transcription, Genetic, Transcriptome, Blotting, Western, Transcription, Genetic, Virology, Microbiology, Immunology, Medical Microbiology
Abstract

Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p

Published
2016

49. Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Author

Qin, H, Samuels, JF, Wang, Y, Zhu, Y, Grados, MA, Riddle, MA, Greenberg, BD, Knowles, JA, Fyer, AJ, McCracken, JT, Murphy, DL, Rasmussen, SA, Cullen, BA, Piacentini, J, Geller, D, Stewart, SE, Pauls, D, Bienvenu, OJ, Goes, FS, Maher, B, Pulver, AE, Valle, D, Lange, C, Mattheisen, M, McLaughlin, NC, Liang, K-Y, Nurmi, EL, Askland, KD, Nestadt, G, and Shugart, YY

Subjects
Humans, Genetic Predisposition to Disease, Membrane Proteins, Serotonin Uptake Inhibitors, Treatment Outcome, Obsessive-Compulsive Disorder, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Adolescent, Adult, Aged, Middle Aged, Child, Female, Male, Genetic Variation, Genome-Wide Association Study, Self Report, Polymorphism, Single Nucleotide, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P

Published
2016

50. 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, 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Tak-Yan Ellis, Yvette Ellis, Alison C Ellwood, Rahma Elmahdi, Einas Elmahi, Hannah-May Elmasry, Mohammed El-Naggar, Najla Elndari, Omer Elneima, Mohamed Elokl, Ahmed Elradi, Mohamed Elsaadany, Mohammed A S A Elsayed, Sally El-Sayeh, Hana El-Sbahi, Mohammad Elsebaei, Tarek Elsefi, Karim El-Shakankery, Alguili Elsheikh, Hosni El-Taweel, Sarah Elyoussfi, Jonathan Emberey, Jonathan R Emberson, John Emberton, Anna Emery, Julian Emmanuel, Ingrid Emmerson, Michael Emms, Florence Emond, Marieke Emonts, Nicu Enachi, Dickson Enenche, Angila Engden, Katy English, Emma Entwistle, Hene Enyi, Marios Erotocritou, Peter Eskander, Hanif Esmail, Fatheha Essa, Brynach Evans, Chris Evans, Debra Evans, E Evans, Emrys Evans, Gail Evans, Gareth Evans, Isabel Evans, Jack Evans, Jacqueline Evans, Jennifer Evans, John Evans, Jolanta Evans, Lisa Evans, Lynn Evans, Mim Evans, Morgan Evans, Ranoromanana Evans, Sharon Evans, Sian Evans, Teriann Evans, Tomos Evans, Caroline Everden, Serenydd Everden, Lynette Every, Hayley Evison, Lynsey Evison, Chiamaka Ezenduka, Jacqueline Faccenda, Leila Fahel, Youstina Fahmay, Ian Fairbairn, Sara Fairbairn, Terry Fairbairn, Andy Fairclough, Louise Fairlie, Mark Fairweather, Anne Fajardo, Naomi Falcone, Euan Falconer, John Fallon, Andrea Fallow, David Faluyi, Victoria Fancois, Ayaan Farah, Muna Farah, Qayyum Farah, Nowin Z Fard, Leila Fares, Amr Farg, Adam Farmer, Katie Farmer, Toni Farmery, Samantha Farnworth, Faiyaz Farook, Hadia Farooq, Sidrah Farooq, Fiona Farquhar, Holly Farr, Aaron Farrell, Barbara Farrell, Fayed Farrukh, James Farthing, Syeda Farzana, Rahmatu Fasina, Azam Fatemi, Mina Fatemi, Suman Fathima, Nibah Fatimah, Maria Faulkner, Saul N Faust, Clair Favager, Joe Fawke, Sinmidele Fawohunre, Abul Fazal, Aisthath Fazleen, Simon Fearby, Connie Fearnley, Alex Feben, Federico Fedel, Daria Fedorova, Christopher Fegan, Mae Felongo, Lynsey Felton, Tim Felton, Kate Fenlon, Andrea Fenn, Ruth Fennelly, Isabelle Fenner, Ciara Fenton, Melisa Fenton, Gloria Ferenando, Cameron Ferguson, Jenny Ferguson, Kathryn Ferguson, Katie Ferguson, Susan Ferguson, Susie Ferguson, Victoria Ferguson, Denzil Fernandes, Candida Fernandez, Eduardo Fernandez, Maria Fernandez, Sonia Fernandez Lopez, Jaime Fernandez Roman, Callum J Fernando, Jessica Fernando, Ahmed Feroz, Pietro Ferranti, Thais Ferrari, Eleanor Ferrelly, Alexandra Ferrera, Emma Ferriman, Sheldon Ferron, Nicholas Fethers, Ben Field, Janet Field, Rebecca Field, Karen Fielder, Lindsey Fieldhouse, Andra Fielding, Julie Fielding, Sarah Fielding, Asma Fikree, Santos Filipa, Sarah A Filson, Shona Finan, Sarah Finbow, Deborah J Finch, Joanne Finch, Laurie Finch, Simon Finch, Spencer Finch, Natalie Fineman, Jim Finlayson, Lauren Finlayson, Adam Finn, Joanne Finn, Dylan Finnerty, Clare Finney, Deborah Finucane, Sofia Fiouni, Jo Fiquet, Promise Firi, James Fisher, Neil Fisher, Daniel Fishman, Krystofer Fishwick, Carolyn Fitton, Felicity Fitzgerald, Fiona Fitzgerald, Karen Fitzjohn, Jan Flaherty, Michael 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, Jonathan Fox, Laura Fox, Lauren Fox, Natalie Fox, Olivia Fox, Simon Fox, Sarah-Jane Foxton, Eva Fraile, Rebecca Frake, Alex Francioni, Olesya Francis, Rebecca Francis, Sarah Francis, Theodora Francis-Bacon, Helen Frankland, Jessica Franklin, Siobhan Franklin, Catherine Fraser, Andi Fratila, Sharon Frayling, Martyn Fredlund, Anna Freeman, Carol Freeman, Elaine Freeman, Hannah Freeman, Nicola Freeman, Clare Freer, Eleanor French, Thomas French, Karen Freshwater, Matthew Frise, Renate Fromson, Adam Frosh, John Frost, Victoria Frost, Oliver Froud, Rachel Frowd, Arun Fryatt, Andrzej Frygier, Bridget Fuller, Liz Fuller, Lucy Fuller, Tracy Fuller, Duncan Fullerton, Carrie Fung, Gayle Fung, Sarah Funnell, John Furness, Andrew Fyfe, Nytianandan G, Elizabeth Gabbitas, Claire Gabriel, Zoë Gabriel, Hadiza Gachi, Sophie Gaffarena, Sarah Gage, Joshua Gahir, Sarveen Gajebasia, Katarzyna Gajewska-Knapik, Babita Gajmer, Zacharoula Galani, Christopher Gale, Hugo Gale, Linda Gale, Rebecca Gale, Swetha Gali, Bernadette Gallagher, Jude Gallagher, Rosie Gallagher, William Gallagher, Feroze Gallam, Joanne Galliford, Catherine Galloway, Chris Galloway, Emma Galloway, Jacqui Galloway, James Galloway, Anna Galvin, Victoria Galvis, Gareth Gamble, Laura Gamble, Liz Gamble, Brian Gammon, Chien N Gan, Muhammad B Ganaie, Jaikumar Ganapathi, Ramesh Ganapathy, Kaminiben Gandhi, Sarah Gandhi, Usha Ganesh, Thenugan Ganeshanathan, Saibal Ganguly, Abrar Gani, Pauline Ganley, Ukraina Garcia, Emma-James Garden, Antoni D Gardener, Emma Gardiner, Michael Gardiner, Phil Gardiner, Siobhan Gardiner, Caroline Gardiner-Hill, Jonathan Gardner, Louis Gardner, Mark Garfield, Atul Garg, Isha Garg, Nathan Garlick, Daniel Garner, Justin Garner, Lucie Garner, Zoe Garner, Rosaline Garr, Kathryn A Garrero, Manisha Gartaula, Florence Garty, Rachel Gascoyne, Hyeriju Gashau, Aoife Gatenby, Erin Gaughan, Alok Gaurav, Mariana Gavrila, Jane Gaylard, Sophie Gayle, Catherine Geddie, Ian Gedge, Sarah Gee, Fartuun Geele, Kalaichelvi Geerthan, Minnie Gellamucho, Karzan Gelly, Leila Gelmon, Sandra Gelves-Zapata, Gemma Genato, Neal Gent, Susan Gent, Natalie Geoghegan, Aparna George, Bini George, Sam George, Susan George, Tina George, Valerie P George, Simon Georges, Domonique Georgiou, Peter Gerard, Leigh Gerdes, Louise Germain, Helen Gerrish, Abel Getachew, Louise Gethin, Siobhan Gettings, Hisham Ghanayem, Bijan Ghavami Kia, Shaista Ghazal, Anca Gherman, Alison Ghosh, Dipansu Ghosh, Justin Ghosh, Subhamay Ghosh, Sarra Giannopoulou, Malick Gibani, Chris Gibb, Ben Gibbison, Kerry Gibbons, Alex Gibson, Bethan Gibson, Jamie Gibson, Kimberley Gibson, Kirsty Gibson, Sian Gibson, Mary Gigi, Cat Gilbert, Jeanette Gilbert, Kayleigh Gilbert, Benjamin Giles, James Gilham, Mandy Gill, Lynne Gill, Paul Gillen, Annelies Gillesen, Katherine Gillespie, Elizabeth Gillham, Andrew Gillian, Deborah Gilliland, Robert Gillott, Danielle Gilmour, Kate Gilmour, Lesley Gilmour, Louis Ginn, Franciscus Ginting, Theodora 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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Christopher A Green, David Green, Frederick Green, Joel Green, Marie Green, Nicola Green, Stacey Green, Diarra Greene, Philippa Greenfield, Alan Greenhalgh, Daniel Greenwood, Sandra Greer, James Gregory, Jane Gregory, Katie Gregory, Tamsin Gregory, Jill Greig, Julia Greig, Rebecca Grenfell, Teena Grenier, Jack Grenville, Jo Gresty, Susan Grevatt, Glaxy Grey, Samuel Gribben, Andrew Gribbin, Amy Gribble, Natasha Grieg, Douglas Grieve, Ben Griffin, Denise Griffin, Mel Griffin, Sian Griffith, Andrew Griffiths, Daniel Griffiths, David Griffiths, Donna Griffiths, Isabel Griffiths, Mark Griffiths, Nicola Griffiths, Oliver Griffiths, Sandra Griffiths, Sarah Griffiths, Scott Griffiths, Yvonne Griffiths, Sofia Grigoriadou, Steph Grigsby, Paul Grist, Evelina Grobovaite, Dorothy Grogono, Clarissa Grondin, Rachel Groome, Pauline Grose, Liliana Grosu, Jenny Grounds, Margaret Grout, Helen Grover, Jayne Groves, Neil Grubb, Julie Grundy, Francesca Guarino, Sharada Gudur, Jacinta Guerin, Sharazeq 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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 Hannington, Merhej Hannun, Aidan Hanrath, Helena Hanratty, Daniel Hansen, Anita Hanson, Ashley Hanson, Helen Hanson, Jane Hanson, Kathryn Hanson, Steve Hanson, Ala Haqiqi, Monjurul Haque, Henry Harcourt, Lesley Harden, Zoe Harding, Simon Hardman, Marc Hardwick, Gareth Hardy, Joanna Hardy, Yasmine Hardy, Kumar Haresh, Rachel Harford, Beverley Hargadon, James Hargraves, Carolyn Hargreaves, Alice Harin, Mohammed Haris, Edward Harlock, Paula Harman, Tracy Harman, Mark Harmer, Muhammad A Haroon, Charlie Harper, Heather Harper, James Harper, Peter Harper, Rosemary Harper, Sarah Harrhy, Kate Harrington, Sian Harrington, Yasmin Harrington-Davies, Jade Harris, Jess Harris, John Harris, Laura Harris, Marie-Clare Harris, Nichola Harris, Sophie Harris, David Harrison, Laura Harrison, Melanie Harrison, Olakunbi A Harrison, Rachael Harrison, Rowan Harrison, Susie Harrison, Thomas Harrison, Wendy Harrison, Elizabeth Harrod, Ciaran Hart, Dominic Hart, Jessica Hartley, Lisa Hartley, Rosemary Hartley, 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, Mike Hodson, Alison Hogan, Matthew Hogben, Lucy Hogg, Lee Hoggett, Abigail Holborow, Catherine Holbrook, Rebecca Holbrook, Catherine Holden, Jill Holden, Melinda Holden, Sophie Holden, Thomas Holder, Niels Holdhof, Hannah Holdsworth, Lisa Holland, Maureen Holland, Nicky Holland, Poppy Holland, Susan Holland, Marie L Hollands, Elizabeth Holliday, Kyra Holliday, Mark Holliday, Nina Holling, Laszlo Hollos, Nora Hollos, Leah Holloway, Simon Holloway, Max Hollowday, Marcus Hollyer, Amy Holman, Ann Holmes, Megan Holmes, Raphael Holmes, Rebecca Holmes, Kelly Holroyd, Beth Holroyd-Hind, Lyndsey Holt, Siobhan Holt, Susie Holt, Alexandra Holyome, Marie Home, Renate Homewood, Kate Hong, Louise Hoole, Clare Hooper, Samantha Hope, Susan Hope, Bridget Hopkins, Peter W Horby, Stephanie Horler, Anil Hormis, Daniel Hornan, Nicola Hornby, Thomas Horne, Zoey Horne, Rebecca Horner, Caroline Horrobin, Latoya Horsford, Megan Horsford, Mark Horsford, Valana Horsham, Alexander Horsley, Ashley Horsley, 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 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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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Nicholas A Scriven, Angela Scullion, Therese Scullion, Emily Seager, Cathy Seagrave, Rebecca Seaman, Eleanor Sear, Isabella Seaton, Annette Seatter, Anna Seckington, Joanna Sedano, Gabrielle Seddon, Gemma Sedgwick, Yee Yong See, Muhammad A Seelarbokus, Christopher Sefton, Matias Segovia, Fatima Seidu, Gillian Sekadde, Faye Selby, Georgina Selby, Claire Sellar, Rachael Sellars, Katharine Sellers, Joseph Selley, Victoria Sellick, Gobika Selvadurai, Brintha Selvarajah, Haresh Selvaskandan, Subothini S Selvendran, Jeyakumar Selwyn, Alison Semmens, Gary Semple, Michael Sen, Nandini Sen, Seema Sen, Aditya Sengupta, Niladri Sengupta, Susana Senra, HoJan Senya, Teona Serafimova, Elisa Sernicola, Dheeraj Sethi, Shivam Sethi, Niranjan Setty, Abigail Seward, Teswaree Sewdin, Terri-Ann Sewell, Jack Seymour, Katherine Seymour, Hussam Shabbir, Fiona Shackley, Tariq Shafi, Faiza Shafique, Aashni Shah, Ahmar Shah, Anand Shah, Bhavni Shah, Hussun-Ara Shah, Momin Shah, Neil Shah, Pallav Shah, Priyank Shah, Qasim Shah, Rupal Shah, Sarfaraz H Shah, Snehal Shah, Suraj Shah, Syed Shah, Wajid Shah, Saarma Shahad, Sousan Shahi, Sipan Shahnazari, Najam Shahzad, Muhammad Shahzeb, Aisha Shaibu, Zara Shaida, Amina Y Shaikh, Maliha Shaikh, Rajit Shail, Mariya Shaji, Muhammad Shakeel, Roshni Shakya, Korah Shalan, Nadia Shamim, Ummulbaneen Shamji, Anindya Shams, Kazi Shams, Rasha Shamsah, Thomas Shanahan, Hamed Sharaf, Asir Sharif, Ajay Sharma, Ash Sharma, Bhawna Sharma, Mona Sharma, Ojasvi Sharma, Poonam Sharma, Rajeev Sharma, Sagar Sharma, Sanjeev Sharma, Sarkhara Sharma, Seema D Sharma, Shriv Sharma, Sonal Sharma, Alexander Sharp, Charles Sharp, Gemma Sharp, Kerry Sharp, Louise M Sharp, Paula Sharratt, Phoebe Sharratt, Katherine Sharrocks, Serene Shashaa, Alexandra Shaw, Christopher Shaw, Daisy Shaw, David Shaw, Deborah Shaw, Joanne Shaw, Jonathon Shaw, Lisa Shaw, Michele Shaw, Tomos G Shaw, Anna Shawcross, James Shawcross, Jill Shawe, Lou Shayler, Sophy Shedwell, Jonathan Sheffield, Zak Shehata, Arshiya Sheik, Asif Sheikh, Noorann Sheikh, Benjamin Shelley, Sarah Shelton, Anil Shenoy, Julie Shenton, Sarah Shephardson, Amy Shepherd, Kate Shepherd, Lorna Shepherd, Scott Shepherd, Gareth Sheppard, Rhian Sheppeard, Helen Sheridan, Ray Sheridan, Samuel Sherridan, Leanne Sherris, Susanna Sherwin, Shaad Shibly, Fathimath F Shiham, Cassandra Shilladay, Ben Shillitoe, Delane Shingadia, Chiaki Shioi, Anand Shirgaonkar, Kim Shirley, Helen Shirt, Adebusola Shonubi, Jane Shoote, Ruth Shorrocks, Rob Shortman, Rohan Shotton, Sarah Shotton, Charmaine Shovelton, Ervin Shpuza, Anil Shrestha, Apurba Shrestha, Nora Shrestha, Reema Shrestha, Suchita Shrestha, Karen Shuker, Jonathan Shurlock, Jack Shurmer, Erfanur R Shuvo, Gilbert Siame, Loria Siamia, Moses Siaw-Frimpong, Seshnag Siddavaram, Nasir Siddique, Shahla Siddique, Sohail Siddique, Elaine Siddle, Emma Sidebotham, Jo Sidebottom, Roy Sievers, Katie Siggens, Nyma Sikondari, Ilman Silanas, Sofia V Silva, Claudia Silva Moniz, Malcolm Sim, Theresa Simangan, Vimbai Simbi, Robert Sime, George Simmons, Oliver Simmons, Richard Simms, Laura Simon, Merritt Simon, Natalie Simon, Samantha Simpkins, Angela Simpson, Anna Simpson, Danny Simpson, Georgina Simpson, Joanne Simpson, Kerry Simpson, Maria Simpson, Phillip Simpson, Thomas Simpson, Kathryn Simpson, Simon Sinclair, Cindy Sing, Ankita Singh, Claire Singh, Davinder Singh, Jayaprakash Singh, Jyoti Singh, Lokeshwar Singh, Manjeet Singh, Nadira Singh, Pankaj Singh, Prabhsimran Singh, Salil Singh, Saurabh Singh, Shivani Singh, Sumi Singh, Parag Singhal, Bryan Singizi, Vicky Singler, Manas Sinha, Punam Sinha, Sharad Sinha, Utkarsh Sinha, Guy Sisson, Sarah Sithiravel, Karthikadevi Sivakumar, Shanmugasundaram Sivakumar, Darsh Sivakumran, Sivanthi Sivanadarajah, Pasupathy-Rajah Sivasothy, Asok Skaria, Nicole Skehan, Robert Skelly, Orlagh Skelton, Imogen Skene, Denise Skinner, Tabitha Skinner, Victoria Skinner, Agnieszka Skorko, Iwona Skorupinska, Mariola Skorupinska, Amy Slack, Katie Slack, Heather Slade, Mark Slade, Lynda Slater, Nicola Slawson, Rachel Slingsby, Andrew Sloan, Brendan Sloan, Derek Sloan, Geraldine Sloane, Malgorzata Slowinska, Benjamin Small, Ellen Small, Samuel Small, Adam Smallridge, Dawn Smalls, Karen Denise Smallshaw, Andy Smallwood, Brittany Smart, Lynne Smart, Justyna Smeaton, Carien Smit, Aileen Smith, Alex Smith, Amanda Smith, Amy Smith, Andrew Smith, Catherine Smith, Chris Smith, Christopher Smith, Coral Smith, Debra Smith, Dominic Smith, Eleanor Smith, Harriet Smith, Hazel Smith, Helen Smith, Jacky Smith, Jessica Smith, Kate Smith, Kerry Smith, Lara Smith, Linda Smith, Lisa Smith, Loren Smith, Maria Smith, Mark Smith, Martha A Smith, Mel Smith, Nicholas Smith, Oliver Smith, Philippa Smith, Rachel Smith, Rebecca Smith, Rheanna Smith, Richard Smith, Sally Smith, Samantha Smith, Stacey Smith, Stephanie Smith, Susan Smith, Tracy Smith, Victoria Smith, Imogen Smith, John Smith, Sue Smolen, Sara Smuts, Naoise Smyth, Annette Snell, David Snell, Luke Snell, Alfred So, Beng So, Michelle Soan, Toluleyi Sobande, Sonia Sobowiec Kouman, Alberto Sobrino Diaz, Basit Sohail, Bina Sohail, Herminder Sohal, Roy Soiza, Olajumoke Solademi, Babak Soleimani, Amanda Solesbury, Mohamed Soliman, Bernadette Solis, Reanne Solly, Louise Solomon, Subash Somalanka, Chandrashekaraiah Somashekar, Sven Sommerfield, Govind Soni, Raj Sonia, Temi Sonoiki, Shiu-Ching Soo, Pavandeep Soor, Germander Soothill, Jennifer Soren, Apina Sothinathan, Pragalathan Sothirajah, Jessica Sousa, Najwa Soussi, Donna Southam, David Southern, Iain Southern, Louise Southern, Sara M Southin, Jessica Southwell, Thomas Southworth, Sandra Sowden, Jason Sowter, Claudia Spalding, Enti Spata, Catherine Speare, Katie Spears, Mark Spears, Lynne Speirs, Susan Speirs, Michelle Spence, Niamh Spence, Branwell Spencer, Gisele Spencer, Rebecca Spencer, Sue Spencer, Tom Spencer, Helen Spickett, Jennifer Spillane, William Spiller, Kerry Spinks, Michelle Spinks, Nick Spittle, Sarah Spray, Janet Spriggs, Oliver Spring, Gemma Squires, Jack Squires, Rebecca Squires, Ram Sreenivasan, Shiva Sreenivasan, K Sri Paranthamen, Rajesh Srikantaiah, Koottalai Srinivasan, Ramesh Srinivasan, Asha Srirajamadhuveeti, Vino Srirathan, Rhodri Stacey, Sybil Stacpoole, Louise Stadon, William J Stagg, Jocasta Staines, Nikki Staines, Katie Stammers, Roxana Stanciu, Grazyna Stanczuk, Thomas Standley, Brittany Staniforth, Andrew Stanton, Lisa Stanton, Robyn Staples, Simon Stapley, Natalie Staplin, Adam Stark, Elizabeth Starkey, David S Starnes, Michelle Starr, Rachel Stead, Clare Stebbing, Conor Steele, Henry Steer, John Steer, Vergnano Stefania, Paula Stefanowska, Femke Steffensen, Caroline Stemp, Emma Stenson, Alison Stephens, David Stephensen, Elaine Stephenson, Monique Sterrenburg, Jennifer Stevens, Melanie Stevens, Will Stevens, Amy Stevenson, Andrew Stevenson, Lesley Stevenson, Sarah Stevenson, Matthew Steward, Christopher Stewart, Claire Stewart, Colin Stewart, Dobree A Stewart, Katelyn Stewart, Keely Stewart, Kristina Stewart, McKenna Stewart, Melissa Stewart, Rachel Stewart, Richard Stewart, Jo Stickley, Gemma Stiller, Sarah Stirrup, Sarah Stock, Alexander Stockdale, Danielle Stocker, Lynne Stockham, Paul Stockton, Emma Stoddard, Kevin Stoffberg, Chelsea Stokes, Chris Stokes, Ben Stone, Roisin Stone, Sarah Stone, Emma-Jane Stoner, Imogen Storey, Kim Storton, Frederick Stourton, Angela Strachan, Catherine Strait, Emma Stratton, Jane Stratton, Sam Straw, Dieter Streit, Emma Stride, Sally Stringer, Sophia Strong-Sheldrake, Siske Struik, Carmel Stuart, Anna Stubbs, Harrison Stubbs, Ann Sturdy, Sharon Sturney, Matt Stuttard, Cristina Suarez, Karuna Subba, Christian P Subbe, Keerth Subramaniam, Manjula Subramanian, Vaidyanathan Subramanian, Venkatram Subramanian, Chinari Subudhi, Rebecca Suckling, Srivatsan Sudershan, Peter Sugden, Putri A Suherman, Rudresh Sukla, Anila Sukumaran, Ezoubi Suleiman, Ali Suliman, Fatimah Suliman, Sugrah Sultan, Uun Sumardi, Samyukta Sundar, Radha Sundaram, Reka Sundhar, Edmond Sung, Nadia Sunni, Jay Suntharalingam, Amitava Sur, Dharmic Suresh, Nayanika Suresh, Shilpa Suresh, Michael Surtees, C Susan, Danielle Suter, Rohan Suthar, Helen Sutherland, Rachel Sutherland, Rebecca Sutherland, Sara-Beth Sutherland, Dovile Sutinyte, Deborah Sutton, Sam Sutton, Siobhan Sutton, Mihaela Sutu, Marie-Louise Svensson, Sima Svirpliene, Andrew Swain, Rose Swain, Thomas Swaine, Christopher Swales, Carla Swanson-Low, Tirion Swart, Stephen Sweetman, Ealish Swift, Paul Swift, Pauline Swift, Rachael Swift, Rachel Swingler, Sophie Swinhoe, Katarzyna Swist-Szulik, Luke Swithenbank, Omair Syed, Catriona Sykes, Daisy Sykes, Eliot Sykes, Luke Sylvester, Declan Symington, Dominic Symon, Andrew Syndercombe, Zoe Syrimi, Jen Syson, Gemma Szabo, Denise Szabó, Tamas Szakmany, Nina Szarazova, Megan Szekely, Adele Szekeres, Matthew Szeto, Kinga Szymiczek, Maria Tadros, Amr Tageldin, Lucy Tague, Hasan Tahir, Muhammad Tahir, Michael Tai, Jennifer Tait, Abigail Takyi, Peter Talbot, Alison Talbot -Smith, James Talbot-Ponsonby, Richard Tallent, Bradley Tallon, Adrian Tan, Bee Theng Tan, Hock Tan, Huey Tan, Jenny Tan, Jun Seng Tan, Keith Tan, WeiTeen Tan, Anand Tana, Alex Tanner, Christina Tanney, Tabitha Tanqueray, Emma Tanton, Anita Tantri, Tm Tanzil-Al-Imran, Hayley Tarft, Priyal Taribagil, Obaid Tarin, Syed Tariq, David Tarpey, Esther Tarr, Lisa Tarrant, Antonia Tasiou, Alex Tate, Margaret L Tate, Matthew Tate, Paul Tate, Kate Tatham, Silvia S Tavares, Vera Tavoukjian, Shao An Isaac Tay, Alexander Taylor, Beverley Taylor, Charlie Taylor, Charlotte A Taylor, David Taylor, Elisabeth Taylor, Holly Taylor, Janet Taylor, Jennifer Taylor, Joanne Taylor, Julie Taylor, Karen Taylor, Leanne Taylor, Margaret Taylor, Matthew Taylor, Melanie Taylor, Natalie Taylor, Rachael Taylor, Rachel Taylor, Samantha Taylor, Suzanne Taylor, Tracey Taylor, Vicky Taylor, Victoria Taylor, Michelle Taylor-Siddons, Thomas Taynton, Amelia Te, Francesca Teasdale, Jessica Teasdale, Katherine Teasdale, Julie Tebbutt, Caroline Tee, Izla Teeluck, Borja Tejero Moya, Rajni Tejwani, Adam Telfer, Vibha Teli, Jennifer Tempany, Julie Temple, Natalie Temple, Helen Tench, Yi He Teoh, Radoslaw Tereszkowski-Kaminski, Lynne Terrett, Louise Terry, Tesha Islami Monika Tesha, Dariusz Tetla, Shirish Tewari, Daniel Tewkesbury, Joana Texeira, ChiaLing Tey, Miriam Thake, Clare Thakker, Manish Thakker, Jayna Thakrar, Bishal Jung Thakuri, Bhavneet Thamu, Nguyen Thi Thao, Amita Thapa, Hilary Thatcher, Andrew Thayanandan, Krishna Thazhatheyil, Eaint Thein, Lambrini Theocharidou, Phyu Thet, Kapeendran Thevarajah, Mayooran Thevendra, Nang Thiri Phoo, Yvette Thirlwall, Muthu Thirumaran, Alice Thomas, Andrew Thomas, Caradog Thomas, Emma Thomas, Enson Thomas, Esther Thomas, Helen Thomas, James Thomas, Jordan L Thomas, Karen Thomas, Koshy Thomas, Lucy Thomas, Rachel Thomas, Rebecca Thomas, Rhys Thomas, Ruth Thomas, Sarah Thomas, Sherine Thomas, Tessy Thomas, Vicky Thomas, Kirsty Thomasson, Rhian Thomas-Turner, Catherine Thompson, Christopher Thompson, Clara Thompson, Emma Thompson, Fiona Thompson, Hilary Thompson, Jessica Thompson, Katharine Thompson, Laura Thompson, Liz Thompson, Luke Thompson, Michael Thompson, Orla Thompson, Rebecca Thompson, Roger Thompson, Yolanda Thompson, Nicola Thomson, Patrick Thorburn, Natasha Thorn, Charlotte Thorne, Nicola Thorne, Alice Thornton, Danielle Thornton, Jim Thornton, Richard Thornton, Sara Thornton, Susan Thornton, Thomas Thornton, Tracey Thornton, Christopher Thorpe, Nigel Thorpe, Sarah Thorpe, Paradeep Thozthumparambil, Laura Thrasyvoulou, Hannah Thraves, Genevieve Thueux, Pinky Thu-Ta, Vicky Thwaiotes, C Louise Thwaites, Guy Thwaites, Simon Tiberi, Serena Tieger, Carey Tierney, Caroline Tierney, Mark Tighe, Sorrell Tilbey, Christopher Till, Amanda Tiller, Heather Tiller, John Timerick, Elizabeth Timlick, Alan Timmins, Alison Timmis, Hayley Timms, Anne-Marie Timoroksa, Samakomva Tinashe, Stephanie Tingley, Nicola Tinker, Heather Tinkler, Marianne Tinkler, Jacqui Tipper, Ajay Tirumalai Adisesh, Helen Tivenan, Katarzyna Tluchowska, Helen T-Michael, Anne Todd, Jackie Todd, Shirley Todd, Stacy Todd, Olga Toffoletti, Mohamed Tohfa, Sue Tohill, Melanie Tolson, Ana L Tomas, Natalia Tomasova, Sharon Tomlin, Simon Tomlins, Jo Tomlinson, Kerry Tomlinson, James Tonkin, Ivan Tonna, Catherine Toohey, Kirsty Topham, Mathew Topping, Audrey Torokwa, Collette Torrance, Omar Touma, Laura Tous Sampol, Ruhaif Tousis, Melissa Tout, Peter Tovey, Gareth Towersey, Jill Townley, Richard Tozer, Dang Khoa Tran, Hien Tran, Huyen Bang Tran, Michelle Tran, Nguyen Bao Tran, Van Giang Tran, Van Kien Tran, Helen Tranter, Jenny Travers, Christopher Travill, Sarah Traynor, Leanne Trethowan, Estefania Treus Gude, Mary Trevelyan, Nicola A Trewick, Ascanio Tridente, Sanchia Triggs, Fiona Trim, Alex Trimmings, Tom Trinick, Kate Trivedi, Sven Troedson, Emily Tropman, Amy Trotter, Spyridon Trous, Helen Trower, Madeleine Trowsdale Stannard, Nigel Trudgill, Robert Truell, Nick Truman, Maria Truslove, Shaun Trussell, Tariq Trussell, Kyriaki Tsakiridou, Christine Tsang, Peter Tsang, Tan Tsawayo, Kyriaki K Tsilimpari, Georgios Tsinaslanidis, Merika Tsitsi, Simon Tso, Natasha Tucker, Sally Tucker, Stephanie Tucker, Daisy E Tudor, Aisha Tufail, Jess Tuff, Jemma Tuffney, Redmond Tully, Tulus Tulus Satriasih, Grace Tunesi, Killiam Turbitt, Rezon Turel, Tolga Turgut, Claudia Turley, Alison Turnbull, Aine Turner, Ash Turner, Charlotte Turner, Gail Turner, Georgina Turner, Kate Turner, Kelly Turner, Kim Turner, Lucy Turner, Lynne C Turner, Mark Turner, Patricia Turner, Sally Turner, Samantha Turner, Sarah Turner, Victoria Turner, Ian Turner-bone, Sharon Turney, Jon Turvey, Conor Tweed, David Tweed, Rebecca Twemlow, Emma Twohey, Bhavya Tyagi, Vedang Tyagi, Abigail Tyer, Amanda Tyler, Jayne Tyler, Jennifer Tyler, Alison Tyzack, Petros Tzavaras, Ioannis Tzinieris, A Wahid Uddin, Mohammad S Uddin, Ruhama Uddin, Ruzena Uddin, Jacinta Ugoji, Edith N Ukaegbu, Mazhar Ul Haq, Waqar Ul Hassan, Zia Ul-Haq, Salamat Ullah, Sana Ullah, Sanda Ullah, Ju Um, Athavan Umaipalan, Anil Umate, Judith Umeadi, Akudo Umeh, Wilfred Umeojiako, Ben Ummat, Emma Underhill, Charlotte Underwood, Jonathan Underwood, Adam Unsworth, Veerpal Uppal, Veerpal S Uppal, Gerry Upson, Masood Ur Rasool, Alison Uriel, Sebastian Urruela, Hiromi Uru, Jess Usher, Miranda Usher, Rebecca Usher, Alexandra Usher-Rea, Andrew Ustianowski, Effua Usuf, Febriansyah Nur Utomo, Hiromi Uzu, Linda C Vaccari, Uddhav Vaghela, Abhay Vaidya, Denny Vail, Bernardas Valecka, Jennifer Valentine, Balan Valeria, Pramodh Vallabhaneni, Nick Vallotton, Luke Vamplew, Ekaterini Vamvakiti, Joannis Vamvakopoulos, Sarah Van Blydenstein, Lucia van Bruggen, Maud van de Venne, Alex van der Meer, Nora van der Stelt, Lynne van Koutrik, Alexander Van Loggerenberg, Joseph Vance-Daniel, Rama Vancheeswaran, Samuel I Vandeyoon, Padma Vankayalapati, Piyush Vanmali, Chloe Vansomeren, William Van't Hoff, Sejal Vara, Stehen J Vardy, Anu Varghese, Maria Varghese, William Varney, Giulia Varnier, Anna-Nektaria Varouxaki, Resti Varquez, Valeria Vasadi, Olivia Vass, Katherine Vassell, Vimal Vasu, Vasanthi Vasudevan, Manu Vatish, Sue Vaughan, Heloyes Vayalaman, Darini Vayapooree, Christopher Vaz, Niki Veale, Sachuda Veerasamy, Swati Velankar, Luxmi Velauthar, Neyme Veli, Nicola Vella, Aravind Velugupati, Anitha Velusamy, Ian Venables, Mavi Venditti, Ramya Venkataramakrishnan, Richard Venn, Robert Venn, Michelle Venter, Lyn Ventilacion, Joanne Vere, Mark Veres, Stefania Vergnano, Will Verling, Amit Verma, Rachel Vernall, Britney Vernon, Mark Vertue, Liberty Verueco, Jerik Verula, Anna Veterini, Natalie Vethanayagam, Shambavi Vettikumaran, Lucy Veys, Carinna Vickers, Saji Victor, SImpson Victoria, Celine P Vidaillac, Jennifer Vidler, Bavithra Vijayakumar, Vinod W Vijayaraghavan Nalini, Brigita Vilcinskaite, Alicija Vileito, Neringa Vilimiene, Lynn Vinall, Sylvia Vinay, Latha Vinayakarao, Olivia Vincent, Rachel Vincent, Rosie Vincent, Pritpal Virdee, Emma Virgilio, Abdullah M Virk, Elisa Visentin, Martina Vitaglione, Karunakaran Vithian, Sorice Vittoria, Sankkita Vivekananthan, Elena Vlad, Ben Vlies, Linda von Oven, Claire Vooght, Kim Thi Vu Thai, Kritchai Vutipongsatorn, Alain Vuylsteke, Eleftheria Vyras, Richard Wach, Beverley Wadams, Susan Wadd, Natalia Waddington, Phillip Wade, Jonathan Wadsley, Kirsten Wadsworth, Syed E I Wafa, Daniel Wagstaff, Lynda Wagstaff, Dalia Wahab, Zaroug Wahbi, Abiodun Waheed Adigun, Sawan Waidyanatha, Alicia Waite, Rachel Wake, Alice Wakefield, William Wakeford, Fiona Wakinshaw, Emma Waldeck, Andrew Walden, Lorna Walding, Alexandria Waldron, Joanne Waldron, Emma Wales, Batool Wali, Danielle Walker, Gemma Walker, Harriet Walker, Ian Walker, Kevin Walker, Kim Walker, Lauren Walker, Linda Walker, Lynne Walker, Olivia Walker, Rachel Walker, Rebecca Walker, Sara Walker, Susan Walker, Gillian Wallace, Rebecca Wallbutton, Jessica Wallen, Karl Wallendszus, Arabella Waller, Rosemary Waller, Gabiel Wallis, Gabriel Wallis, Louise Wallis, Matthew Wallis, Emma Walmsley, Donna Walsh, Elizabeth Walsh, Livia Walsh, Deborah Walstow, Daniel Walter, Alex Walters, Holt Walters, James Walters, Jocelyn Walters, Eileen Walton, Lucy Walton, Maisie Walton, Michael Walton, Olivia Walton, Sharon Walton, Susan Walton, Mandy Wan, Junita Wanda, Mary Wands, Rachel Wane, Frank Wang, Nick Wang, Ran Wang, Shentong Wang, Deborah Warbrick, Samantha Warburton, Christopher Ward, Deborah Ward, Emma Ward, Hannah Ward, Janice Ward, Joanna Ward, Luke Ward, Nicola Ward, Rachael Ward, Thomas Ward, Tom Ward, Scott A Warden, Gibril Wardere, Steve Wardle, Hassan Wardy, Gareth Waring, Scott Waring, Jenny Warmington, Ben Warner, Christian Warner, Lewis Warnock, Sarah Warran, Jade Warren, Lisa Warren, Rebecca Warren, Yolanda Warren, Davina Warrender, Hannah Warren-Miell, Adilia Warris, Gill Warwick, Helen Wassall, Sean Wasserman, Elizabeth Wasson, Hazel J Watchorn, Holly Waterfall, Abby Waters, Donald Waters, Mark Waterstone, Abigail Watkin, Catherine Watkins, Catrin Watkins, Eleanor Watkins, Karen Watkins, Lynn Watkins, Abigail Watson, Adam J R Watson, Ekaterina Watson, Eleanor Watson, Felicity Watson, J G R Watson, Louisa Watson, Paul Watson, Rebecca Watson, Robert Watson, Kathleen Watson, Malcolm Watters, Donna Watterson, Khairiah Wattimena, Daniel Watts, John Watts, Merlin Watts, Victoria Waugh, Emma Wayman, Matthew Wayman, Akhlaq Wazir, Mark Weatherhead, Nick Weatherly, Chloe Webb, Claire Webb, Hayley Webb, Kathryn Webb, Kylie Webb, Stephen Webb, Cheryl Websdale, Deborah Webster, Ian Webster, Jemma Webster, Tim Webster, Jordan Wedlin, Ling Wee, Rebecca Weerakoon, Thanuja Weerasinghe, Janaka Weeratunga, Maria Weetman, Shuying Wei, Immo Weichert, Emma Welch, Hugh Welch, James Welch, Leanne Welch, Steven Welch, Benjamin Welham, Samantha Weller, Lucy Wellings, Brian Wells, Susan Wellstead, Berni Welsh, Richard Welsh, Ingeborg Welters, Rachael Welton, Victoria Wenn, Lauren Wentworth, Joan Wesonga, Kate Wesseldine, Joe West, Magdelena West, Raha West, Ruth West, Sophie West, Luke Western, Ruth Westhead, Heather Weston, Alice Westwood, Kelly Westwood, Sharon Westwood, Bill Wetherill, Sharon Wheaver, Helen Wheeler, Ben Whelan, Matthew Whelband, Amanda Whileman, Alison Whitcher, Andrew White, Ayesha White, Benjamin White, Catherine White, Christopher White, Duncan White, James White, Jonathan White, Katie White, Marie White, Nick White, Nikki White, Sarah White, Sonia White, Tracey White, Catherine Whitehead, Kelly Whitehorn, Anne Whitehouse, Claire Whitehouse, Tony Whitehouse, Julia Whiteley, Louiza Whiteley, Sophie Whiteley, Rachael Whitham, Gabriel Whitlingum, David Whitmore, Elizabeth Whittaker, Lindsay Whittam, Ashley Whittington, Helen Whittle, Robert Whittle, Eunice Wiafe, Lou Wiblin, Olivia Wickens, John Widdrington, Jason Wieboldt, Hannah Wieringa, Cornelia Wiesender, Laura Wiffen, Andrew Wight, Ashleigh Wignall, Christopher Wignall, Annamaria Wilce, Danielle Wilcock, Emma Wilcock, Louise Wilcox, Ben Wild, Laura Wild, Stephen Wild, Michael Wilde, Laura Wilding, Peter Wilding, Tracey Wildsmith, Joe Wileman, Joy Wiles, Kate Wiles, Elva Wilhelmsen, Thomas Wiliams, Janet Wilkie, David Wilkin, Hannah Wilkins, Joy Wilkins, Suzanne Wilkins, Iain Wilkinson, Lesley Wilkinson, Nicola Wilkinson, Sophia Wilkinson, Susan Wilkinson, Tim Wilkinson, Sylvia Willetts, Aimee Williams, Alexandra Williams, Alison Williams, Angharad Williams, Anna Williams, Ava Williams, Carl Williams, Caroline V Williams, Claire Williams, Dewi Williams, Eleri Williams, Gail Williams, Gemma Williams, Gina Williams, Hannah Williams, Heledd Williams, James Williams, Jennie Williams, Jill Williams, John Williams, Joseph Williams, Karen Williams, Kathryn Williams, Mandy Williams, Marie Williams, Mark Williams, Matthew Williams, Patricia Williams, Penny Williams, Rachel Williams, Robin Williams, Rupert Williams, Samson Williams, Sarah Williams, Sophie Williams, Steffan Williams, Tamanna Williams, Tania Williams, Annie Williamson, Cath Williamson, Catherine Williamson, Dawn Williamson, James D Williamson, Jodie Williamson, Rachel Williamson, Helen Williamson, Elaine Willis, Elizabeth Willis, Emily Willis, Heather Willis, Herika Willis, Joanna Willis, Louise Wills, Lucy Willsher, Catherine Willshire, Francesca Willson, Jayne Willson, Alison Wilson, Andrea Wilson, Anna Wilson, Antoinette Wilson, Billy Wilson, David Wilson, Imogen Wilson, James Wilson, Karen Wilson, Kate Wilson, Kristy-Ann Wilson, Lucinda Wilson, Mark Wilson, Stephen Wilson, Toni Wilson, John Wilson, Khin Lei Yee Win, Marlar Win, Than Win, Tin Tin Win, Wut Yee Win Win, Lucinda Winckworth, Laura Winder, Piers Winder, Stuart Winearl, Helen Winmill, Simon Winn, Carmen Winpenny, Helen Winslow, Helen Winter, Jonathan Winter, Barbara Winter-Goodwin, Joseph Winterton, Hannah Winwood, Jack Wischhusen, Stephen Wisdom, Matthew Wise, Martin Wiselka, Rebecca Wiseman, Sophie Wiseman, Steven Wishart, Tabitha WIshlade, Eric Witele, Nicholas Withers, Janet Wittes, Donna Wixted, Therese Wodehouse, Will Wolf, Nicola Wolff, Kirsten Wolffsohn, Rebecca Wolf-Roberts, Elena Wolodimeroff, Adam Wolstencroft, Alan Wong, Charlotte Wong, Chi-Hung Wong, Chi-Man Wong, Edwin Wong, Jessica S Y Wong, Kit Y Wong, Mei Yin Wong, Nick Wong, Sam Wong, Ting Wong, Aaron B Wongkyezeng, Amanda Wood, Caroline Wood, Dianne Wood, Fiona Wood, Gordon Wood, Hannah Wood, Jennifer Wood, Joe Wood, Lisa Wood, Louise Wood, Madeleine Wood, Stephen Wood, Tracy Wood, Katharine Woodall, Rebecca Woodfield, Christopher Woodford, Elizabeth Woodford, Jill Woodford, Louise Woodhead, Timothy Woodhead, Philip Woodland, Marc Woodman, Myles Woodman, Stephen Woodmansey, Charlotte Woods, Jane Woods, Katherine Woods, Sarah Woods, Zoe Woodward, Megan Woolcock, Gemma Wooldridge, Rebecca Woolf, Chris Woollard, Christopher Woollard, Louisa Woollen, Emma Woolley, Jade Woolley, Daniel Woosey, Dan Wootton, Joanne Wootton, Daniel Worley, Stephy Worton, Jonathan Wraight, Maria Wray, Kim Wren, Lynn Wren, Caroline Wrey Brown, Catherine Wright, Demi Wright, Francesca Wright, Holly Wright, Imogen Wright, Lianne Wright, Rachel Wright, Sarah Wright, Stephanie Wright, Tim Wright, Caroline Wroe, Hannah Wroe, Henry Wu, Peishan Wu, Pensee Wu, Jonathan Wubetu, Fitria Wulandari, Retno Wulandari, Subie Wurie, Craig Wyatt, Frederick Wyn-Griffiths, Inez Wynter, Bindhu Xavier, Arnold Xhikola, Bingru E Xia, Zhongyang Xia, Effua Yacoba, Santosh Yadav, Masseh Yakubi, May Yan, Yuuki Yanagisawa, Freda Yang, Yingjia Yang, Michael Yanney, Woei Lin Yap, Nabil Yaqoob, Salima Yasmin, Bryan Yates, David Yates, Edward Yates, Helen Yates, Thomas Yates, Mark Yates, Jessica Ye, Charlotte Yearwood Martin, Khin Yein, Fiona Yelnoorkar, Lam Minh Yen, Alastair Yeoh, Chun Yu Yeung, Peter Yew, Durgesh Yewatkar, Laura Ylquimiche Melly, Inez Ynter, H Yong, Jemma Yorke, Jasmine Youens, Abdel Younes Ibrahim, Eoin Young, Gail Young, Louise Young, Asfand Yousafzar, Sajeda Youssouf, Ahmed Yousuf, Hartantri Yovita, Chrissie Yu, Jack S J Yuan, Nindya Yufaniaputri, Bernard Yung, Daniel Yusef, Said Yusef, Intekhab Yusuf, Anna-Sophia Zafar, Silvia Zagalo, Su Zaher, Aqsa Zahoor, Mahrukh Zainab, Thornton Zak, Kareem Zaki, Nabhan Zakir, Kasia Zalewska, Ane Zamalloa, Mohsin Zaman, Shakir Zaman, Julie Zamikula, Louise Zammit, Marie Zammit-Mangion, Marcelina Zawadzka, Mohammed Zayed, Esther Zebracki, Daniel Zehnder, Lisa Zeidan, Darius Zeinali, Jing Zhang, Xiaobei Zhao, Dongling Zheng, Doreen Zhu, Madiha Zia, Omar Zibdeh, Rabia Zill-E-Huma, Ei Thankt Zin, Eva Zincone, Garikai Zindoga, Eleanor Zinkin, Vivian Zinyemba, Christos Zipitis, Letizia Zitter, Arkadiusz Zmierczak, Garazi Zubikarai, Azam Zubir, Naz Zuhra, Rasha Zulaikha, Sabrina Zulfikar, Carol Zullo, Ana Zuriaga-Alvaro, University of St Andrews. 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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