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1. Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.

Author: Lemire, Gabrielle, Sanchis-Juan, Alba, Russell, Kathryn, Baxter, Samantha, Chao, Katherine, Singer-Berk, Moriel, Groopman, Emily, Wong, Isaac, England, Eleina, Goodrich, Julia, Pais, Lynn, Austin-Tse, Christina, DiTroia, Stephanie, OHeir, Emily, Ganesh, Vijay, Wojcik, Monica, Evangelista, Emily, Snow, Hana, Osei-Owusu, Ikeoluwa, Fu, Jack, Singh, Mugdha, Mostovoy, Yulia, Huang, Steve, Garimella, Kiran, Kirkham, Samantha, Neil, Jennifer, Shao, Diane, Walsh, Christopher, Argilli, Emanuela, Le, Carolyn, Sherr, Elliott, Gleeson, Joseph, Shril, Shirlee, Schneider, Ronen, Hildebrandt, Friedhelm, Sankaran, Vijay, Madden, Jill, Genetti, Casie, Beggs, Alan, Agrawal, Pankaj, Bujakowska, Kinga, Place, Emily, Pierce, Eric, Donkervoort, Sandra, Bönnemann, Carsten, Gallacher, Lyndon, Stark, Zornitza, Tan, Tiong, White, Susan, Töpf, Ana, Straub, Volker, Fleming, Mark, Pollak, Martin, Õunap, Katrin, Pajusalu, Sander, Donald, Kirsten, Bruwer, Zandre, Ravenscroft, Gianina, Laing, Nigel, MacArthur, Daniel, Rehm, Heidi, Talkowski, Michael, Brand, Harrison, and ODonnell-Luria, Anne
Subjects: CNV, GATK-gCNV, copy number variant, diagnostic yield, exome, variant classification, Humans, DNA Copy Number Variations, Rare Diseases, Exome, Male, Female, Exome Sequencing, Cohort Studies, Genetic Testing
Abstract: Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.
Published: 2024

2. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Author: Weng, Patricia, Majmundar, Amar, Khan, Kamal, Lim, Tze, Shril, Shirlee, Jin, Gina, Musgrove, John, Wang, Minxian, Ahram, Dina, Aggarwal, Vimla, Bier, Louise, Heinzen, Erin, Onuchic-Whitford, Ana, Mann, Nina, Buerger, Florian, Schneider, Ronen, Deutsch, Konstantin, Kitzler, Thomas, Klämbt, Verena, Kolb, Amy, Mao, Youying, Moufawad El Achkar, Christelle, Mitrotti, Adele, Martino, Jeremiah, Beck, Bodo, Altmüller, Janine, Benz, Marcus, Yano, Shoji, Mikati, Mohamad, Gunduz, Talha, Cope, Heidi, Shashi, Vandana, Trachtman, Howard, Bodria, Monica, Caridi, Gianluca, Pisani, Isabella, Fiaccadori, Enrico, AbuMaziad, Asmaa, Martinez-Agosto, Julian, Yadin, Ora, Zuckerman, Jonathan, Kim, Arang, John-Kroegel, Ulrike, Tyndall, Amanda, Parboosingh, Jillian, Innes, A, Bierzynska, Agnieszka, Koziell, Ania, Muorah, Mordi, Saleem, Moin, Hoefele, Julia, Riedhammer, Korbinian, Gharavi, Ali, Jobanputra, Vaidehi, Pierce-Hoffman, Emma, Seaby, Eleanor, ODonnell-Luria, Anne, Rehm, Heidi, Mane, Shrikant, DAgati, Vivette, Pollak, Martin, Ghiggeri, Gian, Lifton, Richard, Goldstein, David, Davis, Erica, Hildebrandt, Friedhelm, and Sanna-Cherchi, Simone
Subjects: FSGS, SRNS, TRIM8, epilepsy, genomics, monogenic, nuclear body, Adult, Animals, Carrier Proteins, Cell Line, Child, Child, Preschool, Codon, Nonsense, Developmental Disabilities, Epilepsy, Female, Glomerulosclerosis, Focal Segmental, Humans, Intranuclear Space, Kidney, Male, Mice, Mutation, Nephrotic Syndrome, Nerve Tissue Proteins, Phenotype, Podocytes, Exome Sequencing
Abstract: Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.
Published: 2021

3. Circulating testican-2 is a podocyte-derived marker of kidney health

Author: Ngo, Debby, Wen, Donghai, Gao, Yan, Keyes, Michelle J, Drury, Erika R, Katz, Dan H, Benson, Mark D, Sinha, Sumita, Shen, Dongxiao, Farrell, Laurie A, Peterson, Bennet D, Friedman, David J, Elmariah, Sammy, Young, Bessie A, Smith, J Gustav, Yang, Qiong, Vasan, Ramachandran S, Larson, Martin G, Correa, Adolfo, Humphreys, Benjamin D, Wang, Thomas J, Pollak, Martin R, Wilson, James G, Gerszten, Robert E, and Rhee, Eugene P
Subjects: Kidney Disease, Clinical Research, Underpinning research, 1.1 Normal biological development and functioning, Renal and urogenital, Cardiovascular, Black or African American, Aptamers, Peptide, Biomarkers, Female, Glomerular Filtration Rate, Humans, Hypertension, Kidney, Kidney Function Tests, Kidney Glomerulus, Male, Middle Aged, Podocytes, Proteoglycans, Proteomics, testican-2, proteomics, chronic kidney disease
Abstract: In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.
Published: 2020

4. “Cure” Versus “Clinical Remission”: The Impact of a Medication Description on the Willingness of People Living with HIV to Take a Medication

Author: Fridman, Ilona, Ubel, Peter A, Blumenthal-Barby, Jennifer, England, Cameron V, Currier, Judith S, Eyal, Nir, Freedberg, Kenneth A, Halpern, Scott D, Kelley, Colleen F, Kuritzkes, Daniel R, Le, Catherine N, Lennox, Jeffrey L, Pollak, Kathryn I, Zikmund-Fisher, Brian J, and Scherr, Karen A
Subjects: Public Health, Health Sciences, Clinical Research, Behavioral and Social Science, Clinical Trials and Supportive Activities, HIV/AIDS, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Decision Making, Drug Therapy, Female, HIV Infections, Humans, Intention, Male, Middle Aged, Patients, Research Personnel, Surveys and Questionnaires, Behavior, Cure, Decision-making, HIV, PLWHIV, Remission, Public Health and Health Services, Social Work, Public health
Abstract: Many people living with HIV (PLWHIV) state that they would be willing to take significant risks to be "cured" of the virus. However, how they interpret the word "cure" in this context is not clear. We used a randomized survey to examine whether PLWHIV had a different willingness to take a hypothetical HIV medication if it causes flu-like symptoms, but provides: (a) cure, (b) remission that was labeled "cure", or (c) remission. PLWHIV (n = 454) were more willing to take a medication that provided a "cure" versus a "remission" if the side effects lasted less than 1 year. PLWHIV were more willing to take a medication that provided a remission that was labeled "cure" versus a "remission" (p = 0.01) if the side effects lasted 2 weeks. Clinicians and researchers should be aware of the impact of the word "cure" and ensure that PLWHIV fully understand the possible outcomes of their treatment options.
Published: 2020

5. The Co-occurrence of Daily Smoking, Binge Drinking and IPV Among Latino Expectant Fathers

Author: Noonan, Devon, Lyna, Pauline, Simmons, Leigh Ann, Gordon, Kristina Coop, and Pollak, Kathryn I
Subjects: Health Services and Systems, Health Sciences, Human Society, Violence Against Women, Substance Misuse, Clinical Research, Prevention, Mental Health, Tobacco Smoke and Health, Tobacco, Behavioral and Social Science, Clinical Trials and Supportive Activities, Violence Research, Prevention of disease and conditions, and promotion of well-being, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, Good Health and Well Being, Adult, Binge Drinking, Fathers, Hispanic or Latino, Humans, Intimate Partner Violence, Male, North Carolina, Risk-Taking, Smoking, Surveys and Questionnaires, Young Adult, Alcohol, Latinos, Violence, Stress, Public Health and Health Services, Public Health, Epidemiology, Public health, Sociology
Abstract: Many Latino men have multiple risk factors that predispose them to chronic disease morbidity and mortality, yet few have examined patterns in this population. We describe the co-occurrence of daily smoking, binge drinking, and intimate partner violence (IPV) behaviors among Latino expectant fathers and examine factors associated with the co-occurrence of these behaviors. We conducted a secondary analysis of baseline data from the Parejas Trial, a randomized controlled trial testing a culturally tailored couples-based smoking cessation intervention. We used Kruskal-Wallis test statistics to explore the relationship of the co-occurring behavior and demographic and cultural factors. All participants smoked as was a requirement of being in the trial, but only 39% smoked daily. Forty three percent of the participants engaged in one behavior, 32% engaged in two behaviors, and 5% engaged in three behaviors, with binge drinking being the most common co-occurring behavior. In the bivariate analysis, higher stress (p = 0.01) and having more children (p = 0.003) were found to be positively significantly associated with the number of behaviors. Helping Latino expectant fathers manage with their stress may serve as tailoring points for future interventions to reduce risk behaviors.
Published: 2020

6. A Phase IIa Trial of Metformin for Colorectal Cancer Risk Reduction among Individuals with History of Colorectal Adenomas and Elevated Body Mass Index

Author: Zell, Jason A, McLaren, Christine E, Morgan, Timothy R, Lawson, Michael J, Rezk, Sherif, Albers, C Gregory, Chen, Wen-Pin, Carmichael, Joseph C, Chung, Jinah, Richmond, Ellen, Rodriguez, LM, Szabo, Eva, Ford, Leslie G, Pollak, Michael N, and Meyskens, Frank L
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Clinical Trials and Supportive Activities, Colo-Rectal Cancer, Prevention, Nutrition, Digestive Diseases, Adenoma, Administration, Oral, Aged, Biomarkers, Tumor, Biopsy, Body Mass Index, Colonic Polyps, Colonoscopy, Colorectal Neoplasms, Female, Humans, Intestinal Mucosa, Intestine, Large, Male, Metformin, Middle Aged, Obesity, Proctoscopy, Rectum, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract: Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6Ser235/S6Ser235 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6Ser235 among obese patients with recent history of CRA. A phase IIa clinical biomarker trial was conducted via the U.S. National Cancer Institute-Chemoprevention Consortium. Nondiabetic, obese subjects (BMI ≥30) ages 35 to 80 with recent history of CRA were included. Subjects received 12 weeks of oral metformin 1,000 mg twice every day. Rectal mucosa biopsies were obtained at baseline and end-of-treatment (EOT) endoscopy. Tissue S6Ser235 and Ki-67 immunostaining were analyzed in a blinded fashion using Histo score (Hscore) analysis. Among 32 eligible subjects, the mean baseline BMI was 34.9. Comparing EOT to baseline tissue S6Ser235 by IHC, no significant differences were observed. Mean (SD) Hscore at baseline was 1.1 (0.57) and 1.1 (0.51) at EOT; median Hscore change was 0.034 (P = 0.77). Similarly, Ki-67 levels were unaffected by the intervention. The adverse events were consistent with metformin's known side-effect profile. Among obese patients with CRA, 12 weeks of oral metformin does not reduce rectal mucosa pS6 or Ki-67 levels. Further research is needed to determine what effects metformin has on the target tissue of origin as metformin continues to be pursued as a colorectal cancer chemopreventive agent.
Published: 2020

7. The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 in a pooled analysis of 16,024 men from 22 studies

Author: Watts, Eleanor L, Perez‐Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Ardanaz, Eva, Black, Amanda, Bueno‐de‐Mesquita, H Bas, Chan, June M, Chen, Chu, Chubb, SA Paul, Cook, Michael B, Deschasaux, Mélanie, Donovan, Jenny L, English, Dallas R, Flicker, Leon, Freedman, Neal D, Galan, Pilar, Giles, Graham G, Giovannucci, Edward L, Gunter, Marc J, Habel, Laurel A, Häggström, Christel, Haiman, Christopher, Hamdy, Freddie C, Hercberg, Serge, Holly, Jeff M, Huang, Jiaqi, Huang, Wen‐Yi, Johansson, Mattias, Kaaks, Rudolf, Kubo, Tatsuhiko, Lane, J Athene, Layne, Tracy M, Le Marchand, Loic, Martin, Richard M, Metter, E Jeffrey, Mikami, Kazuya, Milne, Roger L, Morris, Howard A, Mucci, Lorelei A, Neal, David E, Neuhouser, Marian L, Oliver, Steven E, Overvad, Kim, Ozasa, Kotaro, Pala, Valeria, Pernar, Claire H, Pollak, Michael, Rowlands, Mari‐Anne, Schaefer, Catherine A, Schenk, Jeannette M, Stattin, Pär, Tamakoshi, Akiko, Thysell, Elin, Touvier, Mathilde, Trichopoulou, Antonia, Tsilidis, Konstantinos K, Van Den Eeden, Stephen K, Weinstein, Stephanie J, Wilkens, Lynne, Yeap, Bu B, Key, Timothy J, Allen, Naomi E, and Travis, Ruth C
Subjects: Cancer, Aging, Urologic Diseases, Adult, Aged, Aged, 80 and over, Anthropometry, Biomarkers, Tumor, Cross-Sectional Studies, Humans, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Male, Middle Aged, Neoplasms, Prospective Studies, Young Adult, IGFs, IGFBPs, pooled analysis, correlates, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.
Published: 2019

8. Improving Access to Integrative Oncology Through Group Medical Visits: A Pilot Implementation Project

Author: Thompson-Lastad, Ariana, Atreya, Chloe E, Chao, Maria T, Pollak, Christine, Dhruva, Anand, Santana, Trilce, and Abrams, Donald I
Subjects: Health Services and Systems, Nursing, Health Sciences, Cancer, Clinical Research, 7.1 Individual care needs, Management of diseases and conditions, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Female, Health Services Accessibility, Humans, Integrative Oncology, Male, Middle Aged, Pilot Projects, Quality Improvement, Shared Medical Appointments, access to care, group medical visits, integrative medicine, integrative oncology, quality improvement, Complementary and Alternative Medicine, Complementary & Alternative Medicine, Traditional, complementary and integrative medicine
Abstract: Objectives: This article describes the implementation of a group medical visit (GMV) model to increase access to integrative oncology (IO) care. The most challenging and critical time to access high-quality IO care is while patients are receiving conventional cancer therapy. Often demand for individual IO clinic consultations precludes this from occurring. A three-session GMV program was designed to alleviate barriers to receiving integrative care during active cancer treatment. Design: A consolidated framework was used for implementation research and focused ethnography methods to describe the IO GMV implementation process. Data sources included patient evaluations, participant observation, and brief provider and patient interviews. Setting: A pilot program was created to assess the feasibility and acceptability of implementing IO GMVs at a comprehensive cancer center. Intervention: Each three-session GMV consisted of a didactic session, followed by individual visits with the integrative oncologist. Results: The setting, intervention, and implementation process of the IO GMV program were described. Thirty-two patients participated in the first five cohorts of the program. Twenty-two were women; 24 were White. The median age of participants was 52. Patient evaluations demonstrate high levels of satisfaction with the program with all scored aspects rated >4.0 on a five-point Likert scale. For the medical center, group visits are a financially viable alternative to individual IO visits; revenue from group visits exceeded the revenue potential of 6 h of individual visits by an average of 38%. Conclusion: GMVs are a feasible and promising model for increasing access to IO. Patients in active cancer treatment were able to participate in the program. Future research and implementation efforts could examine health outcomes over time after participation in GMVs, as well as the feasibility of using this model with more diverse patient populations.
Published: 2019

9. A Neural Circuit Mechanism for Encoding Aversive Stimuli in the Mesolimbic Dopamine System

Author: de Jong, Johannes W, Afjei, Seyedeh Atiyeh, Dorocic, Iskra Pollak, Peck, James R, Liu, Christine, Kim, Christina K, Tian, Lin, Deisseroth, Karl, and Lammel, Stephan
Subjects: Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Neurosciences, Drug Abuse (NIDA only), Behavioral and Social Science, Basic Behavioral and Social Science, Substance Misuse, Neurological, Mental health, Good Health and Well Being, Animals, Avoidance Learning, Dopaminergic Neurons, Limbic System, Male, Mesencephalon, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Organ Culture Techniques, Photometry, Ventral Tegmental Area, Vesicular Glutamate Transport Protein 2, aversion, dopamine, dorsal raphe, lateral hypothalamus, nucleus accumbens, reward, ventral tegmental area, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract: Ventral tegmental area (VTA) dopamine (DA) neurons play a central role in mediating motivated behaviors, but the circuitry through which they signal positive and negative motivational stimuli is incompletely understood. Using in vivo fiber photometry, we simultaneously recorded activity in DA terminals in different nucleus accumbens (NAc) subnuclei during an aversive and reward conditioning task. We find that DA terminals in the ventral NAc medial shell (vNAcMed) are excited by unexpected aversive outcomes and to cues that predict them, whereas DA terminals in other NAc subregions are persistently depressed. Excitation to reward-predictive cues dominated in the NAc lateral shell and was largely absent in the vNAcMed. Moreover, we demonstrate that glutamatergic (VGLUT2-expressing) neurons in the lateral hypothalamus represent a key afferent input for providing information about aversive outcomes to vNAcMed-projecting DA neurons. Collectively, we reveal the distinct functional contributions of separate mesolimbic DA subsystems and their afferent pathways underlying motivated behaviors. VIDEO ABSTRACT.
Published: 2019

10. Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease

Author: Ahearn, Thomas U, Peisch, Sam, Pettersson, Andreas, Ebot, Ericka M, Zhou, Cindy Ke, Graff, Rebecca E, Sinnott, Jennifer A, Fazli, Ladan, Judson, Gregory L, Bismar, Tarek A, Rider, Jennifer R, Gerke, Travis, Chan, June M, Fiorentino, Michelangelo, Flavin, Richard, Sesso, Howard D, Finn, Stephen, Giovannucci, Edward L, Gleave, Martin, Loda, Massimo, Li, Zhe, Pollak, Michael, and Mucci, Lorelei A
Subjects: Clinical Research, Aging, Prostate Cancer, Diabetes, Urologic Diseases, Cancer, 2.1 Biological and endogenous factors, Aetiology, Aged, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Disease Progression, Gene Expression Regulation, Neoplastic, Humans, Insulin, Insulin-Like Growth Factor I, Male, Oncogene Proteins, Fusion, Prostatic Neoplasms, Receptor, IGF Type 1, Receptor, Insulin, Receptors, Somatomedin, Signal Transduction, Transcriptional Regulator ERG, Transdisciplinary Prostate Cancer Partnership, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.
Published: 2018

11. Feasibility of a text-based smoking cessation intervention in rural older adults.

Author: Noonan, D, Silva, S, Njuru, J, Bishop, T, Fish, LJ, Simmons, LA, Choi, SH, and Pollak, KI
Subjects: Health Services and Systems, Public Health, Health Sciences, Behavioral and Social Science, Rare Diseases, Clinical Trials and Supportive Activities, Prevention, Clinical Research, Tobacco, Tobacco Smoke and Health, Cancer, Rural Health, Prevention of disease and conditions, and promotion of well-being, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, Cardiovascular, Respiratory, Good Health and Well Being, Aged, Female, Humans, Male, Middle Aged, Rural Population, Smoking Cessation, Socioeconomic Factors, Text Messaging, Time Factors, Public Health and Health Services, Curriculum and Pedagogy, Curriculum and pedagogy, Public health
Abstract: Text-based interventions are effective for smoking cessation, but have not been tested in rural older adults. The purpose of this study was to compare the feasibility, acceptability and preliminary efficacy of a text-based Scheduled Gradual Reduction (SGR) program to a non-SGR text messaging support condition among rural older adults. Adults over 60 years were randomized to either: (i) the SGR program (n = 20), a text-based program to reduce smoking over 4-weeks plus text-based support messages; or (ii) control (n = 20), receipt of text-based support messages only. Participants completed surveys at baseline and end of program to assess feasibility and acceptability of the intervention, and biochemically validated 7-day point prevalence cessation was assessed at end of treatment. Most participants (81%) reported reading all the messages they received. Participants found both interventions useful in quitting smoking (SGR = 57%, Control = 63%) and would recommend it to a friend (SGR = 72%, Control = 79%). Although not statically significant, the SGR group had a higher rate of biochemically validated cessation (SGR = 15%, Control = 5%, Cohen d = 0.67). Among those still smoking, the median percent reduction in cigarettes was 33.3% for both groups. Text-based cessation interventions are feasible, acceptable and can be easily disseminated to rural older adult tobacco users.
Published: 2018

12. Genomewide meta‐analysis identifies loci associated with IGF‐I and IGFBP‐3 levels with impact on age‐related traits

Author: Teumer, Alexander, Qi, Qibin, Nethander, Maria, Aschard, Hugues, Bandinelli, Stefania, Beekman, Marian, Berndt, Sonja I, Bidlingmaier, Martin, Broer, Linda, Group, CHARGE Longevity Working, Cappola, Anne, Ceda, Gian Paolo, Chanock, Stephen, Chen, Ming‐Huei, Chen, Tai C, Chen, Yii‐Der Ida, Chung, Jonathan, Del Greco Miglianico, Fabiola, Eriksson, Joel, Ferrucci, Luigi, Friedrich, Nele, Gnewuch, Carsten, Goodarzi, Mark O, Grarup, Niels, Guo, Tingwei, Hammer, Elke, Hayes, Richard B, Hicks, Andrew A, Hofman, Albert, Houwing‐Duistermaat, Jeanine J, Hu, Frank, Hunter, David J, Husemoen, Lise L, Isaacs, Aaron, Jacobs, Kevin B, Janssen, Joop AMJL, Jansson, John‐Olov, Jehmlich, Nico, Johnson, Simon, Juul, Anders, Karlsson, Magnus, Kilpelainen, Tuomas O, Kovacs, Peter, Kraft, Peter, Li, Chao, Linneberg, Allan, Liu, Yongmei, Loos, Ruth JF, Consortium, Body Composition Genetics, Lorentzon, Mattias, Lu, Yingchang, Maggio, Marcello, Magi, Reedik, Meigs, James, Mellström, Dan, Nauck, Matthias, Newman, Anne B, Pollak, Michael N, Pramstaller, Peter P, Prokopenko, Inga, Psaty, Bruce M, Reincke, Martin, Rimm, Eric B, Rotter, Jerome I, Pierre, Aude Saint, Schurmann, Claudia, Seshadri, Sudha, Sjögren, Klara, Slagboom, P Eline, Strickler, Howard D, Stumvoll, Michael, Suh, Yousin, Sun, Qi, Zhang, Cuilin, Svensson, Johan, Tanaka, Toshiko, Tare, Archana, Tönjes, Anke, Uh, Hae‐Won, van Duijn, Cornelia M, van Heemst, Diana, Vandenput, Liesbeth, Vasan, Ramachandran S, Völker, Uwe, Willems, Sara M, Ohlsson, Claes, Wallaschofski, Henri, and Kaplan, Robert C
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Aging, Clinical Research, Human Genome, 2.1 Biological and endogenous factors, Cardiovascular, Adult, Female, Gene Expression Regulation, Genome-Wide Association Study, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Metabolome, Quantitative Trait Loci, Quantitative Trait, Heritable, Regulatory Sequences, Nucleic Acid, aging, genomewide association study, growth hormone axis, IGF-I, IGFBP-3, longevity, CHARGE Longevity Working Group, Body Composition Genetics Consortium, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract: The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.
Published: 2016

13. A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk

Author: Travis, Ruth C, Appleby, Paul N, Martin, Richard M, Holly, Jeff MP, Albanes, Demetrius, Black, Amanda, Bueno-de-Mesquita, HB As, Chan, June M, Chen, Chu, Chirlaque, Maria-Dolores, Cook, Michael B, Deschasaux, Mélanie, Donovan, Jenny L, Ferrucci, Luigi, Galan, Pilar, Giles, Graham G, Giovannucci, Edward L, Gunter, Marc J, Habel, Laurel A, Hamdy, Freddie C, Helzlsouer, Kathy J, Hercberg, Serge, Hoover, Robert N, Janssen, Joseph AMJL, Kaaks, Rudolf, Kubo, Tatsuhiko, Le Marchand, Loic, Metter, E Jeffrey, Mikami, Kazuya, Morris, Joan K, Neal, David E, Neuhouser, Marian L, Ozasa, Kotaro, Palli, Domenico, Platz, Elizabeth A, Pollak, Michael, Price, Alison J, Roobol, Monique J, Schaefer, Catherine, Schenk, Jeannette M, Severi, Gianluca, Stampfer, Meir J, Stattin, Pär, Tamakoshi, Akiko, Tangen, Catherine M, Touvier, Mathilde, Wald, Nicholas J, Weiss, Noel S, Ziegler, Regina G, Key, Timothy J, and Allen, Naomi E
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Aging, Prostate Cancer, Cancer, Urologic Diseases, Aged, Humans, Insulin-Like Growth Factor I, Male, Middle Aged, Prostatic Neoplasms, Risk Factors, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract: The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288-300. ©2016 AACR.
Published: 2016

14. Family Inequality: Diverging Patterns in Marriage, Cohabitation, and Childbearing.

Author: Lundberg, Shelly, Pollak, Robert A, and Stearns, Jenna
Subjects: Humans, Family, Family Characteristics, Divorce, Marriage, Single Parent, Spouses, Pregnancy, Socioeconomic Factors, History, 20th Century, History, 21st Century, Adult, Men, Women, Educational Status, United States, Female, Male, Pediatric, Behavioral and Social Science, Reduced Inequalities, D10, H31, I30, J10, N30, college premium, educational attainment, family inequality, household income inequality, Economics
Abstract: Popular discussions of changes in American families over the past 60 years have revolved around the “retreat from marriage.” Concern has focused on increasing levels of nonmarital childbearing, as well as falling marriage rates that stem from both increases in the age at first marriage and greater marital instability. Often lost in these discussions is the fact that the decline of marriage has coincided with a rise in cohabitation. Many “single” Americans now live with a domestic partner and a substantial fraction of “single” mothers are cohabiting, often with the child's father. The share of women who have ever cohabited has nearly doubled over the past 25 years, and the majority of nonmarital births now occur to cohabiting rather than to unpartnered mothers at all levels of education. The emergence of cohabitation as an alternative to marriage has been a key feature of the post–World War II transformation of the American family. These changes in the patterns and trajectories of family structure have a strong socioeconomic gradient. The important divide is between college graduates and others: individuals who have attended college but do not have a four-year degree have family patterns and trajectories that are very similar to those of high school graduates.
Published: 2016

15. Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

Author: Yu, Dongmei, Mathews, Carol A, Scharf, Jeremiah M, Neale, Benjamin M, Davis, Lea K, Gamazon, Eric R, Derks, Eske M, Evans, Patrick, Edlund, Christopher K, Crane, Jacquelyn, Fagerness, Jesen A, Osiecki, Lisa, Gallagher, Patience, Gerber, Gloria, Haddad, Stephen, Illmann, Cornelia, McGrath, Lauren M, Mayerfeld, Catherine, Arepalli, Sampath, Barlassina, Cristina, Barr, Cathy L, Bellodi, Laura, Benarroch, Fortu, Berrió, Gabriel Bedoya, Bienvenu, O Joseph, Black, Donald W, Bloch, Michael H, Brentani, Helena, Bruun, Ruth D, Budman, Cathy L, Camarena, Beatriz, Campbell, Desmond D, Cappi, Carolina, Silgado, Julio C Cardona, Cavallini, Maria C, Chavira, Denise A, Chouinard, Sylvain, Cook, Edwin H, Cookson, MR, Coric, Vladimir, Cullen, Bernadette, Cusi, Daniele, Delorme, Richard, Denys, Damiaan, Dion, Yves, Eapen, Valsama, Egberts, Karin, Falkai, Peter, Fernandez, Thomas, Fournier, Eduardo, Garrido, Helena, Geller, Daniel, Gilbert, Donald L, Girard, Simon L, Grabe, Hans J, Grados, Marco A, Greenberg, Benjamin D, Gross-Tsur, Varda, Grünblatt, Edna, Hardy, John, Heiman, Gary A, Hemmings, Sian MJ, Herrera, Luis D, Hezel, Dianne M, Hoekstra, Pieter J, Jankovic, Joseph, Kennedy, James L, King, Robert A, Konkashbaev, Anuar I, Kremeyer, Barbara, Kurlan, Roger, Lanzagorta, Nuria, Leboyer, Marion, Leckman, James F, Lennertz, Leonhard, Liu, Chunyu, Lochner, Christine, Lowe, Thomas L, Lupoli, Sara, Macciardi, Fabio, Maier, Wolfgang, Manunta, Paolo, Marconi, Maurizio, McCracken, James T, Mesa Restrepo, Sandra C, Moessner, Rainald, Moorjani, Priya, Morgan, Jubel, Muller, Heike, Murphy, Dennis L, Naarden, Allan L, Nurmi, Erika, Ochoa, William Cornejo, Ophoff, Roel A, Pakstis, Andrew J, Pato, Michele T, Pato, Carlos N, Piacentini, John, Pittenger, Christopher, and Pollak, Yehuda
Subjects: Humans, Tourette Syndrome, Severity of Illness Index, Obsessive-Compulsive Disorder, Psychiatric Status Rating Scales, Comorbidity, Polymorphism, Single Nucleotide, Adult, Female, Male, Genome-Wide Association Study, Human Genome, Genetics, Brain Disorders, Serious Mental Illness, Neurodegenerative, Prevention, Anxiety Disorders, Mental Health, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Mental health, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract: ObjectiveObsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.MethodThe authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.ResultsAlthough no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).ConclusionsPrevious work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.
Published: 2015

16. Copy Number Variation in Obsessive-Compulsive Disorder and Tourette Syndrome: A Cross-Disorder Study

Author: McGrath, Lauren M, Yu, Dongmei, Marshall, Christian, Davis, Lea K, Thiruvahindrapuram, Bhooma, Li, Bingbin, Cappi, Carolina, Gerber, Gloria, Wolf, Aaron, Schroeder, Frederick A, Osiecki, Lisa, O'Dushlaine, Colm, Kirby, Andrew, Illmann, Cornelia, Haddad, Stephen, Gallagher, Patience, Fagerness, Jesen A, Barr, Cathy L, Bellodi, Laura, Benarroch, Fortu, Bienvenu, O Joseph, Black, Donald W, Bloch, Michael H, Bruun, Ruth D, Budman, Cathy L, Camarena, Beatriz, Cath, Danielle C, Cavallini, Maria C, Chouinard, Sylvain, Coric, Vladimir, Cullen, Bernadette, Delorme, Richard, Denys, Damiaan, Derks, Eske M, Dion, Yves, Rosário, Maria C, Eapen, Valsama, Evans, Patrick, Falkai, Peter, Fernandez, Thomas V, Garrido, Helena, Geller, Daniel, Grabe, Hans J, Grados, Marco A, Greenberg, Benjamin D, Gross-Tsur, Varda, Grünblatt, Edna, Heiman, Gary A, Hemmings, Sian MJ, Herrera, Luis D, Hounie, Ana G, Jankovic, Joseph, Kennedy, James L, King, Robert A, Kurlan, Roger, Lanzagorta, Nuria, Leboyer, Marion, Leckman, James F, Lennertz, Leonhard, Lochner, Christine, Lowe, Thomas L, Lyon, Gholson J, Macciardi, Fabio, Maier, Wolfgang, McCracken, James T, McMahon, William, Murphy, Dennis L, Naarden, Allan L, Neale, Benjamin M, Nurmi, Erika, Pakstis, Andrew J, Pato, Michele T, Pato, Carlos N, Piacentini, John, Pittenger, Christopher, Pollak, Yehuda, Reus, Victor I, Richter, Margaret A, Riddle, Mark, Robertson, Mary M, Rosenberg, David, Rouleau, Guy A, Ruhrmann, Stephan, Sampaio, Aline S, Samuels, Jack, Sandor, Paul, Sheppard, Brooke, Singer, Harvey S, Smit, Jan H, Stein, Dan J, Tischfield, Jay A, Vallada, Homero, Veenstra-VanderWeele, Jeremy, Walitza, Susanne, Wang, Ying, Wendland, Jens R, Shugart, Yin Yao, Miguel, Euripedes C, Nicolini, Humberto, and Oostra, Ben A
Subjects: Human Genome, Genetics, Brain Disorders, Serious Mental Illness, Neurodegenerative, Mental Health, Tourette Syndrome, Neurosciences, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, DNA Copy Number Variations, Diagnostic and Statistical Manual of Mental Disorders, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Obsessive-Compulsive Disorder, Polymorphism, Single Nucleotide, Tourette syndrome, obsessive-compulsive disorder, copy number variation, genetics, 16p13.11, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental & Child Psychology
Abstract: ObjectiveObsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (
Published: 2014

17. Genome-wide association study of Tourettes syndrome.

Author: Neale, B, Stewart, S, Fagerness, J, Evans, P, Gamazon, E, Edlund, C, Service, S, Tikhomirov, A, Osiecki, L, Illmann, C, Pluzhnikov, A, Konkashbaev, A, Davis, L, Han, B, Crane, J, Scharf, J, Yu, D, Rangel-Lugo, M, Chouinard, S, Dion, Y, Girard, S, Cath, D, Smit, J, King, R, Fernandez, T, Leckman, J, Kidd, K, Kidd, J, Pakstis, A, Herrera, L, Romero, R, Fournier, E, Sandor, P, Barr, C, Phan, N, Gross-Tsur, V, Benarroch, F, Pollak, Y, Budman, C, Bruun, R, Erenberg, G, Naarden, A, Lee, P, Weiss, N, Kremeyer, B, Berrío, G, Campbell, D, Cardona Silgado, J, Ochoa, W, Mesa Restrepo, S, Muller, H, Valencia Duarte, A, Lyon, G, Leppert, M, Morgan, J, Weiss, R, Grados, M, Anderson, K, Davarya, S, Singer, H, Walkup, J, Jankovic, J, Tischfield, J, Heiman, G, Gilbert, D, Hoekstra, P, Robertson, M, Kurlan, R, Liu, C, Gibbs, J, Singleton, A, Hardy, J, Strengman, E, Crenshaw, A, Parkin, M, Wagner, M, Moessner, R, Mirel, D, Posthuma, D, Sabatti, C, Conti, D, Knowles, J, Ruiz-Linares, A, Rouleau, G, Purcell, S, Heutink, P, Oostra, B, McMahon, W, Cox, N, Pauls, D, Reus, Victor, State, Matthew, Eskin, Eleazar, Mathews, Carol, Lowe, Thomas, Freimer, Nelson, Ophoff, Roel, and Moorjani, Priya
Subjects: Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Chromosomes, Human, Pair 9, Female, Fibrillar Collagens, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, International Cooperation, Male, Meta-Analysis as Topic, Obsessive-Compulsive Disorder, Polymorphism, Single Nucleotide, Tourette Syndrome, White People, Young Adult
Abstract: Tourettes syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P
Published: 2013

18. Genome-wide association study of Tourette's syndrome.

Author: Scharf, JM, Yu, D, Mathews, CA, Neale, BM, Stewart, SE, Fagerness, JA, Evans, P, Gamazon, E, Edlund, CK, Service, SK, Tikhomirov, A, Osiecki, L, Illmann, C, Pluzhnikov, A, Konkashbaev, A, Davis, LK, Han, B, Crane, J, Moorjani, P, Crenshaw, AT, Parkin, MA, Reus, VI, Lowe, TL, Rangel-Lugo, M, Chouinard, S, Dion, Y, Girard, S, Cath, DC, Smit, JH, King, RA, Fernandez, TV, Leckman, JF, Kidd, KK, Kidd, JR, Pakstis, AJ, State, MW, Herrera, LD, Romero, R, Fournier, E, Sandor, P, Barr, CL, Phan, N, Gross-Tsur, V, Benarroch, F, Pollak, Y, Budman, CL, Bruun, RD, Erenberg, G, Naarden, AL, Lee, PC, Weiss, N, Kremeyer, B, Berrío, GB, Campbell, DD, Cardona Silgado, JC, Ochoa, WC, Mesa Restrepo, SC, Muller, H, Valencia Duarte, AV, Lyon, GJ, Leppert, M, Morgan, J, Weiss, R, Grados, MA, Anderson, K, Davarya, S, Singer, H, Walkup, J, Jankovic, J, Tischfield, JA, Heiman, GA, Gilbert, DL, Hoekstra, PJ, Robertson, MM, Kurlan, R, Liu, C, Gibbs, JR, Singleton, A, North American Brain Expression Consortium, Hardy, J, UK Human Brain Expression Database, Strengman, E, Ophoff, RA, Wagner, M, Moessner, R, Mirel, DB, Posthuma, D, Sabatti, C, Eskin, E, Conti, DV, Knowles, JA, Ruiz-Linares, A, Rouleau, GA, Purcell, S, Heutink, P, Oostra, BA, McMahon, WM, Freimer, NB, Cox, NJ, and Pauls, DL
Subjects: North American Brain Expression Consortium, UK Human Brain Expression Database, Chromosomes, Human, Pair 9, Humans, Tourette Syndrome, Genetic Predisposition to Disease, Fibrillar Collagens, Case-Control Studies, Obsessive-Compulsive Disorder, Attention Deficit Disorder with Hyperactivity, Genotype, Polymorphism, Single Nucleotide, International Cooperation, Adolescent, Adult, Female, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Young Adult, White People, Genetics, Human Genome, Mental Health, Brain Disorders, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, genetics, GWAS, neurodevelopmental disorder, tics, Tourette's syndrome, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract: Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P
Published: 2013

19. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing

Author: Kirby, Andrew, Gnirke, Andreas, Jaffe, David B, Barešová, Veronika, Pochet, Nathalie, Blumenstiel, Brendan, Ye, Chun, Aird, Daniel, Stevens, Christine, Robinson, James T, Cabili, Moran N, Gat-Viks, Irit, Kelliher, Edward, Daza, Riza, DeFelice, Matthew, Hůlková, Helena, Sovová, Jana, Vylet'al, Petr, Antignac, Corinne, Guttman, Mitchell, Handsaker, Robert E, Perrin, Danielle, Steelman, Scott, Sigurdsson, Snaevar, Scheinman, Steven J, Sougnez, Carrie, Cibulskis, Kristian, Parkin, Melissa, Green, Todd, Rossin, Elizabeth, Zody, Michael C, Xavier, Ramnik J, Pollak, Martin R, Alper, Seth L, Lindblad-Toh, Kerstin, Gabriel, Stacey, Hart, P Suzanne, Regev, Aviv, Nusbaum, Chad, Kmoch, Stanislav, Bleyer, Anthony J, Lander, Eric S, and Daly, Mark J
Subjects: Biotechnology, Kidney Disease, Genetics, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Cytosine, Female, Genetic Linkage, Haplotypes, High-Throughput Nucleotide Sequencing, Humans, Male, Minisatellite Repeats, Mucin-1, Mutation, Polycystic Kidney, Autosomal Dominant, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (∼1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.
Published: 2013

20. The efficacy of three different mask styles on a PAP titration night

Author: Ebben, Matthew R, Oyegbile, Temitayo, and Pollak, Charles P
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Sleep Research, Lung, Respiratory, Good Health and Well Being, Adult, Aged, Continuous Positive Airway Pressure, Equipment Design, Face, Female, Humans, Male, Masks, Middle Aged, Nose, Oxyhemoglobins, Polysomnography, Pressure, Severity of Illness Index, Sleep Apnea Syndromes, Treatment Outcome, Psychology, Neurology & Neurosurgery, Clinical sciences, Clinical and health psychology
Abstract: BACKGROUND: This study compared the efficacy of three different masks, nasal pillows, nasal masks and full face (oronasal) masks, during a single night of titration with continuous positive airway pressure (CPAP). METHODS: Fifty five subjects that included men (n=33) and women (n=22) were randomly assigned to one of three masks and underwent a routine titration with incremental CPAP applied through the different masks. RESULTS: CPAP applied through the nasal pillows and nasal mask was equally effective in treating mild, moderate, and severe sleep apnea. However, CPAP applied through the oronasal mask required a significantly higher pressure compared to nasal masks to treat moderately severe (2.8 cm of H(2)O ± 2.1 SD) and severe (6.0 cm of H(2)O ± 3.2 SD) obstructive sleep apnea. CONCLUSION: CPAP applied with either nasal mask was effective in treating mild, moderate, and severe sleep apnea. The oronasal mask required significantly higher pressures in subjects with moderate to severe disease. Therefore, when changing from a nasal to an oronasal mask, a repeat titration is required to ensure effective treatment of sleep apnea, especially in patients with moderate to severe disease.
Published: 2012

21. Peripheral Arterial Disease in Patients With Acute Coronary Syndrome: Results From a Large Real-World Registry

Author: Shlomi Matetzky, Sharon Shalom Natanzon, Nir Shlomo, Shaul Atar, Arthur Pollak, Chaim Yosefy, Doron Zahger, Paul Fefer, Zaza Iakobishvili, Israel Mazin, and Roy Beigel
Subjects: Male, Pulmonary and Respiratory Medicine, Peripheral Arterial Disease, Treatment Outcome, Risk Factors, Myocardial Infarction, Humans, Female, Registries, Acute Coronary Syndrome, Cardiology and Cardiovascular Medicine
Abstract: Limited data exist regarding the significance of peripheral arterial disease (PAD) in patients with acute coronary syndrome (ACS).We evaluated 16,922 consecutive ACS patients who were prospectively included in a national ACS registry. The co-primary endpoint included 30 days major adverse cardiovascular event (MACE) (re-infarction, stroke, and/or cardiovascular death) and 1-year mortality.PAD patients were older (70±11 vs 63±13; p0.01), male predominance (80% vs 77%; p=0.01), and more likely to sustain prior cardiovascular events. PAD patients were less likely to undergo coronary angiography (69% vs 83%; p0.001) and revascularisation (80% vs 86%; p0.001). Patients with PAD were more likely to sustain 30-day MACE (22% vs 14%; p0.001) and mortality (10% vs 4.4%; p0.001), as well as re-hospitalisation (23% vs 19%; p=0.001). After adjusting for potential confounders, PAD remained an independent predictor of 30-day MACE (odds ratio [OR], 1.6 [95% confidence interval (CI), 1.24-2.06]). Patients with compared to those without PAD had 2.5 times higher 1-year mortality rate (22% vs 9%; p0.001). Co-existence of PAD remained an independent predictor of 1-year mortality after adjustment for potential confounders by multivariable regression analysis (OR, 1.62; 95% CI, 1.4-1.9). PAD was associated with a significant higher 1-year mortality rate across numerous sub-groups of patients including type of myocardial infarction (ST-elevation myocardial infarction vs non-ST-elevation myocardial infarction), and whether the patient underwent revascularisation.Acute coronary syndrome with concomitant PAD represents a high-risk subgroup that warrants special attention and a more tailored approach.
Published: 2022
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22. Serum markers, obesity and prostate cancer risk: results from the prostate cancer prevention trial

Author: Cindy H Chau, Cathee Till, Douglas K Price, Phyllis J Goodman, Marian L Neuhouser, Michael N Pollak, Ian M Thompson, and William D Figg
Subjects: Male, Cancer Research, Endocrinology, Oncology, Risk Factors, Case-Control Studies, Endocrinology, Diabetes and Metabolism, Finasteride, Humans, Prostatic Neoplasms, Obesity, Biomarkers, Article
Abstract: Molecular mechanisms linking obesity to prostate cancer involve steroid hormone and insulin/insulin-like growth factor-1 (IGF-1) pathways. We investigated the association of circulating serum markers (e.g., androgens & IGFs/IGFBPs) with BMI and in modifying the association of obesity with prostate cancer risk. Data and specimens for this nested case-control study are from the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Serum samples were assayed for sex steroid hormone concentrations and IGF-1 axis analytes. Logistic regression estimated odds ratio and 95% confidence intervals (CIs) for risk of overall, low-grade (Gleason 2–6), and high-grade (Gleason 7–10) cancers. We found significant associations between BMI with serum steroids and IGFs/IGFBPs; the IGF-1 axis significantly associated with several serum steroids. Serum steroid levels did not affect the association of BMI with prostate cancer risk; however, IGFBP2 and IGFs modified the association of obesity with low- and high-grade disease. While serum steroids and IGFs/IGFBPs are associated with BMI, only the IGF-1 axis contributed to obesity-related prostate cancer risk. Understanding the biological mechanisms linking obesity to prostate cancer risk as it relates to circulating serum markers will aid in developing effective prostate cancer prevention strategies and treatments.
Published: 2022
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23. Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome

Author: Jain, Pritesh, Miller-Fleming, Tyne, Topaloudi, Apostolia, Yu, Dongmei, Drineas, Petros, Georgitsi, Marianthi, Yang, Zhiyu, Rizzo, Renata, Müller-Vahl, Kirsten R., Tumer, Zeynep, Mol Debes, Nanette, Hartmann, Andreas, Depienne, Christel, Worbe, Yulia, Mir, Pablo, Cath, Danielle C., Boomsma, Dorret I., Roessner, Veit, Wolanczyk, Tomasz, Janik, Piotr, Szejko, Natalia, Zekanowski, Cezary, Barta, Csaba, Nemoda, Zsofia, Tarnok, Zsanett, Buxbaum, Joseph D., Grice, Dorothy, Glennon, Jeffrey, Stefansson, Hreinn, Hengerer, Bastian, Benaroya-Milshtein, Noa, Cardona, Francesco, Hedderly, Tammy, Heyman, Isobel, Huyser, Chaim, Morer, Astrid, Mueller, Norbert, Munchau, Alexander, Plessen, Kerstin J., Porcelli, Cesare, Walitza, Susanne, Schrag, Anette, Martino, Davide, Dietrich, Andrea, Mathews, Carol A., Scharf, Jeremiah M., Hoekstra, Pieter J., Davis, Lea K., Paschou, Peristera, Als, Thomas D., Aschauer, Harald, Atzmon, Gil, Bækvad-Hansen, Matie, Barr, Cathy L., Barzilai, Nir, Batterson, James R., Batterson, Robert, Benarroch, Fortu, Berlin, Cheston, Boberg, Julia, Bodmer, Benjamin, Bohnenpoll, Julia, Børglum, Anders D., Brown, Lawrence W., Bruun, Ruth, Budman, Cathy L., Buckner, Randy L., Bybjerg-Grauholm, Jonas, Cheon, Keun-Ah, Chouinard, Sylvain, Coffey, Barbara J., Coppola, Giovanni, Crowley, James J., Dahl, Niklas, Darrow, Sabrina M., Daly, Mark J., De Rubeis, Silvia, Dion, Yves, Djurfeldt, Diana R., Domenech-Salgado, Laura, Eapen, Valsamma, Elzerman, Lonneke, Fernandez, Thomas V., Freimer Carolin Fremer, Nelson B., Garcia-Delgar, Blanca, Garrido, Marcos, Gilbert, Donald L., Giusti-Rodriguez, Paola, Grados, Marco, Greenberg, Erica, Grove, Jakob, Hagstrom, Julie, Halvorsen, Matt, Hansen, Bjarne, Haavik, Jan, Hebebrand, Johannes, Heiman, Gary A., Herrera, Luis, Hinney, Anke, Hirschtritt, Matthew E., Sul, Jae Hoon, Hong, Hyun Ju, Hougaard, David M., Huang, Alden Y., Ibanez-Gomez, Laura, Ivankovic, Franjo, Jankovic, Joseph, Karlsson, Elinor K., Kaprio, Jakko A., Kim, Young Key, Kim, Young-Shin, King, Robert A., Knowles, James A., Koh, Yun-Joo, Kook, Sodham, Khalifa, Najah, Konstantinidis, Anastasios, Kuperman, Samuel, Kurlan, Roger, Kvale, Gerd, Leckman, James, Lee, Paul C., Leventhal, Bennett, Lichtenstein, Paul, Lindbald-Toh, Kerstin, Lowe, Thomas, Ludolph, Andrea, da Silva, Claudia Luhrs, Luðvigsson, Pétur, Luykx, Jurjen, Lyon, Gholson J., Mahjani, Behrang, Maras, Athanasios, Mataix-Cols, David, Mattheisen, Manuel, Malaty, Irene A., McMahon, William M., McQuillin, Andrew, Meier, Sandra M., Moessner, Rainald, Mortensen, Preben B., Mors, Ole, Mudgal, Poorva, Nagy, Peter, Naarden, Allan, Neale, Benjamin M., Nawaz, Muhammad S., Nissen, Judith Becker, Nöthen Merete Nordentoft, Markus M., Nordsletten, Ashley E., Okun, Michael S., Ophoff, Roel, Osiecki, Lisa, Palotie, Aarno, Palviainen, Teemu P., Pato Michele T. Pato, Carlos N., Pittenger, Christopher, Pollak, Yehuda, Posthuma, Danielle, Ramos, Eliana, Reichert, Jennifer, Robertson, Mary M., Roffman, Joshua L., Rouleau, Guy, Rück, Christian, Sæmundsen, Evald, Samuels, Jack, Sandin, Sven, Sandor, Paul, Schlögelhofer, Monika, Shin, Eun-Young, Singer, Harvey S., Smit, Jan, Smoller, Jordan W., State, Matthew, Solem, Stian, Song, Dong-Ho, Song, Jungeun, Stamenkovic, Mara, Stefansson, Kári, Strom, Nora, Stuhrmann, Manfred, Szatkiewicz, Jin, Szymanska, Urszula, Tischfield, Jay A., Tsetsos, Fotis, Thorarensen, Ólafur, Tubing, Jennifer, Visscher, Frank, Wagner, Michael, Wanderer, Sina, Wang, Sheng, Werge, Thomas, Willsey, Jeremy A., Wolancyk, Tomasz, Woods, Douglas W., Woods, Martin, Zelaya, Ivette, Zinner, Samuel H., Apter, Alan, Ball, Juliane, Bognar, Emese, Buse, Judith, Vela, Marta Correa, Fremer, Carolin, Gulisano, Mariangela, Hagen, Annelieke, Hagstrøm, Julie, Madruga-Garrido, Marcos, Pellico, Alessandra, Ruhrman, Daphna, Schnell, Jaana, Silvestri, Paola Rosaria, Skov, Liselotte, Steinberg, Tamar, Gloor, Friederike Tagwerker, Turner, Victoria L., Weidinger, Elif, Alexander, John, Aranyi, Tamas, Buisman, Wim R., Buitelaar, Jan K., Driessen, Nicole, Fan, Siyan, Forde, Natalie J., Gerasch, Sarah, van den Heuvel, Odile A., Jespersgaard, Cathrine, Kanaan, Ahmad S., Möller, Harald E., Nespoli, Ester, Pagliaroli, Luca, Poelmans, Geert, Pouwels, Petra J. W., Rizzo, Francesca, Veltman, Dick J., van der Werf, Ysbrand D., Widomska, Joanna, Zilhäo, Nuno R., Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Dynamic Earth and Resources, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Medizin, Autism Spectrum Disorder/genetics, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Diabetes Mellitus, Type 2, Risk Factors, Diabetes Mellitus, Tourette Syndrome/genetics, Humans, Female, Attention Deficit Disorder with Hyperactivity/genetics, Type 2, Biological Psychiatry
Abstract: Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders. Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.
Published: 2023
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24. Initial Invasive or Conservative Strategy for Stable Coronary Disease

Author: Maron D. J., Hochman J. S., Reynolds H. R., Bangalore S., O'Brien S. M., Boden W. E., Chaitman B. R., Senior R., Lopez-Sendon J., Alexander K. P., Lopes R. D., Shaw L. J., Berger J. S., Newman J. D., Sidhu M. S., Goodman S. G., Ruzyllo W., Gosselin G., Maggioni A. P., White H. D., Bhargava B., Min J. K., John Mancini G. B., Berman D. S., Picard M. H., Kwong R. Y., Ali Z. A., Mark D. B., Spertus J. A., Krishnan M. N., Elghamaz A., Moorthy N., Hueb W. A., Demkow M., Mavromatis K., Bockeria O., Peteiro J., Miller T. D., Szwed H., Doerr R., Keltai M., Selvanayagam J. B., Gabriel Steg P., Held C., Kohsaka S., Mavromichalis S., Kirby R., Jeffries N. O., Harrell F. E., Rockhold F. W., Broderick S., Bruce Ferguson T., Williams D. O., Harrington R. A., Stone G. W., Rosenberg Y, ISCHEMIA Research Group: Joseph Ricci, A Tello Montoliu, A I Robero Aniorte, Abbey Mulder, Abhay A Laddu, Abhinav Goyal, Abhishek Dubey, Abhishek Goyal, Abigail Knighton, Abraham Oomman, Adam J Jaskowiak, Adam Kolodziej, Adam Witkowski, Adnan Hameed, Adriana Anesini, Afshan Hussain, Agne Juceviciene, Agne Urboniene, Agnes Jakal, Agnieszka Szramowska, Ahmad Khairuddin, Ahmed Abdel-Latif, Ahmed Adel, Ahmed Aljzeeri, Ahmed Kamal, Ahmed Talaat, Aimee Mann, Aira Contreras, Ajit Kumar, V K Kumar, Akemi Furukawa, Akshay Bagai, Akvile Smigelskaite, Alain Furber, Alain Rheault, Alaine Melanie Loehr, Alan Rosen, Albert Varga, Albertina Qelaj, Alberto Barioli, Aldo Russo, Alec Moorman, Alejandro Gisbert, Aleksandra Fratczak, Aleksandras Laucevicius, Alena Kuleshova, Alessandro Sionis, Alexander A Sirker, Alexander M Chernyavskiy, Alexandra Craft, Alexandra Vazquez, Alexandre Ciappina Hueb, Alexandre S Colafranseschi, Alexandre Schaan de Quadros, Alexandre Tognon, Ali Alghamdi, Alice Manica Muller, Aline Nogueira Rabaça, Aline Peixoto Deiro, Alison Hallam, Allegra Stone, Allison Schley, Almudena Castro, Alvaro Rabelo Ales, Amanda Germann, Amanda O'Malley, Amar Uxa, Amarachi Ojajuni, Amarino C Oliveira Jr, Amber B Hull, Ambuj Roy, Amer Zarka, Amir Janmohamed, Ammani Brown, Ammy Malinay, Amparo Martinez Monzonis, Amy J Richards, Amy Iskandrian, Amy Ollinger, Ana D Djordjevic-Dikic, Ana Fernández Martínez, Ana Gomes Almeida, Ana Paula Batista, Ana Rita Francisco, Ana S Mladenovic, Ana Santana, Anam Siddiqui, Anastasia M Kuzmina-Krutetskaya, Andras Vertes, Andre S Sousa, Andre Gabriel, André Schmidt, Andrea M Lundeen, Andrea Bartykowszki, Andrea Lorimer, Andrea Mortara, Andrea Pascual, Andreia Coelho, Andreia Rocha, Andrés García-Rincón, Andrew G Howarth, Andrew J Moriarty, Andrew Docherty, Andrew Starovoytov, Andrew Zurick, Andrzej Łabyk, Andrzej Swiatkowski, Andy Lam, Anelise Kawakami, Angela Hoye, Angela Kim, Angelique Smit, Angelo Nobre, Anil V Shah, Anja Ljubez, Anjali Anand, Ankush Sachdeva, Ann Greenberg, Ann Luyten, Ann Ostrander, Anna Di Donato, Anna Cichocka-Radwan, Anna Fojt, Anna Plachcinska, Anna Proietti, Anna Teresinska, Anne Marie Webb, Anne Cartwright, Anne Heath, Anne Mackin, Anong Amaritakomol, Anong Chaiyasri, Anoop Chauhan, Anoop Mathew, Anthony Gemignani, Anto Luigi Andres, Antonia Vega, Antonietta Hansen, Antonino Ginel Iglesias, Antonio Carlos Carvalho, Antonio Di Chiara, Antonio Serra Peñaranda, Antonio Carvalho, Antonio Colombo, Antonio Fiarresga, Anupama Rao, Aquiles Valdespino-Estrada, Araceli Boan, Areef Ishani, Ariel Diaz, Arijit Ghosh, Arintaya Prommintikul, Arline Roberts, Arnold H Seto, Arnold P Good, Arshed Quyyumi, Arthur J Labovitz, Arthur Kerner, Arturo S Campos-Santaolalla, Arunima Misra, Ashok Mukherjee, Ashok Seth, Ashraf Seedhom, Asim N Cheema, Asker Ahmed, Atul Mathur, Atul Verma, Audrey W Leong, Axel Åkerblom, Axelle Fuentes, Aynun Naher, Badhma Valaiyapathi, Baljeet Kaur, Bandula Guruge, Barbara Brzezińska, Barbara Nardi, Bartosz Czarniak, Bebek Singh, Begoña Igual, Bela Merkely, Belen Cid Alvarez, Benjamin J Spooner, Benjamin J W Chow, Benjamin Cheong, Benoy N Shah, Bernard de Bruyne, Bernardas Valecka, Bernhard Jäger, Beth A Archer, Beth Abramson, Beth Jorgenson, Bethany Harvey, Betsy O'Neal, Bev Atkinson, Bev Bozek, Bevin Lang, Bijulal Sasidharan, Bin Yang, Bin Zhang, Binoy Mannekkattukudy Kurian, Bjoern Goebel, Bob Hu, Bogdan A Popescu, Bogdan Crnokrak, Bolin Zhu, Bonnie J Kirby, Brandi D Zimbelman, Brandy Starks, Branko D Beleslin, Brenda Hart, Brian P Shapiro, Brian McCandless, Brianna Wisniewski, Brigham R Smith, Brooks Mirrer, Bruce McManus, Bruce Rutkin, Bruna Edilena Paulino, Bruna Maria Ascoli, Bryn Smith, Byron J Allen, C Michael Gibson, C Noel Bairey Merz, Calin Pop, Cameron Hague, Camila Thais de Ormundo, Candace Gopaul, Candice P Edillo, Carísi A Polanczyk, Carita Krannila, Carla Vicente, Carl-Éric Gagné, Carlo Briguori, Carlos Peña Gil, Carlos Alvarez, Carly Ohmart, Carmen C Beladan, Carmen Ginghina, Carol M Kartje, Caroline Alsweiler, Caroline Brown, Caroline Callison, Caroline Pinheiro, Caroline Rodgers, Caroline Spindler, Carolyn Corbett, Carrie Drum, Casey Riedberger, Catherine Bone, Catherine Fleming, Catherine Gordon, Catherine Jahrsdorfer, Catherine Lemay, Catherine Weick, Cathrine Patten, Cecilia Goletto, Cezary Kepka, Chandini Suvarna, Chang Xu, Chantale Mercure, Charle A Viljoen, Charlene Wiyarand, Charles Jia-Yin Hou, Charles Y Lui, Charles Cannan, Charles Cornet, Charlotte Pirro, Chataroon Rimsukcharoenchai, Chen Wang, Cheng-Ting Tsai, Chen-Yen Chien, Cheryl A Allardyce, Chester M Hedgepeth, Chetan Patel, Chiara Attanasio, Chih-Hsuan Yen, Chi-Ming Chow, Ching Min Er, Ching-Ching Ong, Cholenahally Nanjappa Manjunath, Chris Beck, Chris Buller, Christel Vassaliere, Christian Hamm, Christiano Caldeira, Christie Ballantyne, Christina Björklund, Christine R Hinton, Christine Bergeron, Christine Masson, Christine Roraff, Christine Shelley, Christophe Laure, Christophe Thuaire, Christopher Kinsey, Christopher McFarren, Christopher Spizzieri, Christopher Travill, Chun-Chieh Liu, Chung-Lieh Hung, Chunguang Li, Chun-Ho Yun, Chunli Xia, Ciarra Heard, Cidney Schultz, Clare Venn-Edmonds, Claudia P Hochberg, Claudia Wegmayr, Claudia Cortés, Claudia Escobar, Cláudia Freixo, Claudio T Mesquita, Clemens T Kadalie, Colin Berry, Constance Philander, Corine Thobois, Costantino Costantini, Courtney Page, Craig Atkinson, Craig Barr, Craig Paterson, Cristina Bare, Cynthia Baumann, Cynthia Burman, Dalisa Espinosa, Damien Collison, Dan Deleanu, Dan Elian, Dan Gao, Dana Oliver, Daniel P Vezina, Daniel O'Rourke, Daniele Komar, Danielle Schade, Darrel P Francis, Dastan Malaev, David A Bull, David E Winchester, David P Faxon, David Booth, David Cohen, David DeMets, David Foo, David Schlichting, David Taggart, David Waters, David Wohns, Davis Vo, Dawid Teodorczyk, Dawn Shelstad, Dawn Turnbull, Dayuan Li, Dean Kereiakes, Deborah O'Neill, Deborah Yip, Debra K Johnson, Debra Dees, Deepak L Bhatt, Deepika Gopal, Deepti Kumar, Deirdre Mattina, Deirdre Murphy, Delano R Small, Delsa K Rose, Dengke Jiang, Denis Carl Phaneuf, Denise Braganza, Denise Fine, Derek Cyr, Desiree Tobin, Diana Cukali, Diana Parra, Diane Camara, Diane Minshall Liu, Diego Adrián Vences, Diego Franca de Cunha, Dimitrios Stournaras, Dipti Patel, Dongze Li, Donna Exley, Dorit Grahl, Dragana Stanojevic, Duarte Cacela, Dwayne S G Conway, E Pinar Bermudez, Eapen Punnoose, Edgar L Tay, Edgar Karanjah, Edoardo Verna, Eduardo Hernandez-Rangel, Edward D Nicol, Edward O McFalls, Edward T Martin, Edyta Kaczmarska, Ekaterina I Lubinskaya, Elena A Demchenko, Elena Refoyo Salicio, Eli Feen, Elihú Durán-Cortés, Elisabeth M Janzen, Elise L Hannemann, Elise van Dongen, Elissa Restelli Piloto, Eliza Kaplan, Elizabeta Srbinovska Kostovska, Elizabeth Capasso-Gulve, Elizabeth Congdon, Elizabeth Ferguson, Elizaveta V Zbyshevskaya, Ellen Magedanz, Ellie Fridell, Ellis W Lader, Elvin Kedhi, Emanuela Racca, Emilie Tachot, Emily DeRosa, Encarnación Alonso-Álvarez, Eric Nicollet, Eric Peterson, Erick Alexánderson Rosas, Erick Donato Morales, Erin Orvis, Ermina Moga, Estelle Montpetit, Estevao Figueiredo, Eugene Passamani, Eugenia Nikolsky, Eunice Yeoh, Evgeniy I Kretov, Ewa Szczerba, Ewelina Wojtala, Expedito Eustáquio Ribeiro Silva, F Marin Ortuño, Fabio R Farias, Fabio Fimiani, Fabrizio Rolfo, Fa-Chang Yu, Fadi Hage, Fadi Matar, Fahim Haider Jafary, Fang Feng, Fang Liu, Fatima Ranjbaran, Fatima Rodriguez, Fausto J Pinto, Fauzia Rashid, Federica Ramani, Fei Wang, Fernanda Igansi, Filipa Silva, Filippo Ottani, Fiona Haines, Firas Al Solaiman, Flávia Egydio, Flavio Lyra, Florian Egger, Fran Farquharson, Frances Laube, Francesc Carreras Costa, Francesca de Micco, Francesca Bianchini, Francesca Pezzetta, Francesca Pietrucci, Francesco Orso, Francesco Pisano, Francis Burt, Francisca Patuleia Figueiras, Francisco Fernandez-Aviles, Francois Pierre Mongeon, Frans Van de Werf, Franziska Guenther, Fraser N Witherow, Fred Mohr, Frederico Dall'Orto, Fumiyuki Otsuka, G De La Morena, G Karthikeyan, Gabor Dekany, Gabor Kerecsen, Gabriel Galeote, Gabriel Grossmann, Gabriel Vorobiof, Gabriela Sanchez de Souza, Gabriela Guzman, Gabriela Zeballos, Gabriele Gabrielli, Gabriele Jakl-Kotauschek, Gail A Shammas, Gail Brandt, Gang Chen, Gary E Lane, Gary J Luckasen, Gautam Sharma, Gelmina Mikolaitiene, Gennie Yee, Georg Nickenig, George E Revtyak, George J Juang, Gerald Fletcher, Gerald Leonard, Gerard Patrick Devlin, Gerard Esposito, Gergely Ágoston, Gervasio Lamas, Geza Fontos, Ghada Mikhail, Gia Cobb, Gian Piero Perna, Gianpiero Leone, Giles Roditi, Gilles Barone-Rochette, Girish Mishra, Giuseppe Tarantini, Glenda Wong, Glenn S Hamroff, Glenn Rayos, Gong Cheng, Gonzalo Barge-Caballero, Goran Davidović, Goran Stankovic, Gordana Stevanovic, Grace Jingyan Wang, Grace M Young, Graceanne Wayser, Graciela Scaro, Graham S Hillis, Graham Wong, Grazyna Anna Szulczyk, Gregor Simonis, Gregory Kumkumian, Gretchen Ann Peichel, Grzegorz Gajos, Gudrun Steinmaurer, Guilherme G Rucatti, Guilherme Portugal, Guilhermina Cantinho Lopes, Guillem Pons Lladó, Gunnar Frostfelt, Gurpreet S Wander, Gurpreet Gulati, Gustavo Pucci, Hafidz Abd Hadi, Haibo Zhang, Haitao Wang, Halina Marciniak, Han Chen, Hanan Kerr, Hani Najm, Hanna Douglas, Hannah Phillips, Hao Dai, Haojian Dong, Haqeel Jamil, Harikrishnan Sivadasanpillai, Harry Suryapranata, Hassan Reda, Hayley Pomeroy, Heather Barrentine, Heather Golden, Heather Hurlburt, Heidi Wilson, Helen C Tucker, Helene Abergel, Hemalata Siddaram, Hermine Osseni, Herwig Schuchlenz, Hesong Zeng, Hicham Skali, Hilda Solomon, Hollie Horton, Holly Hetrick, Holly Little, Holly Park, Hongjie Chi, Hossam Mahrous, Howard A Levite, Hristo Pejkov, Huajun Li, Hugo Bloise-Adames, Hugo Marques, Hui Zhong, Hui-Min Zhang, Humayrah Hashim, Hung-I Yeh, Hussien El Fishawy, Ian Webb, Iftikhar Kullo, Igor O Grazhdankin, Ihab Hamzeh, Ikraam Hassan, Ikuko Ueda, Ileana L Pina, Ilona Tamasauskiene, Ilse Bouwhuis, Imran Arif, Ina Wenzelburger, Inês Zimbarra Cabrita, Ines Rodrigues, Inga H Robbins, Inga Soveri, Ingela Schnittger, Iqbal Karimullah, Ira M Dauber, Iram Rehman, Irena Peovska Mitevska, Irene Marthe Lang, Irina Subbotina, Irma Kalibataite-Rutkauskiene, Irni Yusnida, Isabel Estela Carvajal, Isabella C Palazzo, Isabelle Hogan, Isabelle Roy, Ishba Syed, Ishita Tejani, Ivan A Naryshkin, Ivana Jankovic, Iwona Niedzwiecka, J David Knight, Jacek Kusmierek, Jackie M White, Jackie Chow, Jacob Udell, Jacqueline E Tamis-Holland, Jacqueline Fannon, Jacquelyn A Quin, Jacquelyn Do, Jaekyeong Heo, Jakub Maksym, James E Davies, James H O'Keefe Jr, James J Jang, James Cha, James Harrison, James Hirsch, James Stafford, James Tatoulis, Jamie Rankin, Jan Henzel, Jan Orga, Jana Tancredi, Janaina Oliveira, Jane Burton, Jane Eckstein, Jane Marucci, Janet P Knight, Janet Blount, Janet Halliday, Janetta Kourzenkova, Janitha Raj, Jan-Malte Sinning, Jaqueline Pozzibon, Jaroslaw Drozdz, Jaroslaw Karwowski, Jason D Glover, Jason Loh Kwok, Jason T Call, Jason Linefsky, Jassira Gomes, Jati Anumpa, Javier J Garcia, Javier Courtis, Jay Meisner, K Jayakumar, Jayne Scales, Jean E Denaro, Jean Michel Juliard, Jean Ho, Jeanette K Stansborough, Jean-Michel Juliard, Jeanne Russo, Jeannette J M Schoep, Jeet Thambyrajah, Jeff Leimberger, Jeffery A Breall, Jeffrey A Kohn, Jeffrey C Milliken, Jeffrey Anderson, Jeffrey Blume, Jeffrey Kanters, Jeffrey Lorin, Jeffrey Moses, Jelena J Stepanovic, Jelena Celutkiene, Jelena Djokic, Jelena Stojkovic, Jenne M Jose, Jenne Manchery, Jennifer A Mull, Jennifer H Czerniak, Jennifer L Stanford, Jennifer Gillis, Jennifer Horst, Jennifer Isaacs, Jennifer Langdon, Jennifer Thomson, Jennifer Tomfohr, Jennifer White, Jen-Yuan Kuo, Jeremy Rautureau, Jerome Fleg, Jessica Berg, Jessica Rodriguez, Jessica Waldron, Jhina Patro, Jia Li, Jiajia Mao, Jiamin Liu, Jian'an Wang, Jianhua Li, Jianxin Zhang, Jie Qi, Jihyun Lyo, Jill Marcus, Jim Blankenship, Jing Zhang, Jingjing Liu, Jing-Yao Fan, Jiun-Yi Li, Jiwan Pradhan, Jiyan Chen, J M Rivera Caravaca, Jo Evans, Joan Garcia Picart, Joan Hecht, Joanna Jaroch, Joanna Zalewska, Joanne Kelly, Joanne Taaffe, João Reynaldo Abbud, João V Vitola, Joaquín V Peñafiel, Jocelyne Benatar, Jody Bindeman, Joe Sabik, Joel Klitch, Johann Christopher, Johannes Aspberg, John D Friedman, John F Beltrame, John F Heitner, John Joseph Graham, John R Davies, John Doan, John Kotter, John Kurian, John Mukai, John Pownall, Jolanta Sobolewska, Jon Kobashigawa, Jonathan L Goldberg, Jonathan W Bazeley, Jonathan Byrne, Jonathan Himmelfarb, Jonathan Leipsic, Jonean Thorsen, Jorge F Trejo Gutierrez, Jorge Escobedo, Jorik Timmer, José A Ortega-Ramírez, José Antonio Marin-Neto, Jose D Salas, Jose Enrique Castillo, Jose Francisco Saraiva, José J Cuenca-Castillo, Jose L Diez, José Luis Narro Villanueva, José Luiz da Vieira, José M Flores-Palacios, Jose Ramon Gonzalez, Jose Seijas Amigo, Jose Fragata, Josep Maria Padró, Josheph F X McGarvey Jr, Joseph Hannan, Joseph Sacco, Joseph Sweeny, Joseph Wiesel, Josephine D Abraham, Joshua P Loh, Joy Burkhardt, Joyce R White, Joyce Riestenberg-Smith, Judit Sebo, Judith L Meadows, Judith Wright, Judy Mae Foltz, Judy Hung, Judy Otis, Juergen Stumpf, Jui-Peng Tsai, Julia S Dionne, Julia de Aveiro Morata, Julie Bunke, Julie Morrow, Julio César Figal, Jun Fujita, Jun Jiang, Junhua Li, Junqing Yang, Juntima Euathrongchit, Jyotsna Garg, K Manjula Rani, K Preethi, Kaatje Goetschalckx, Kai Eggers, Kamalakar Surineni, Kanae Hirase, T R Kapilamoorthy, Karen Calfas, Karen Gratrix, Karen Hallett, Karen Hultberg, Karen Nugent, Karen Petrosyan, Karen Swan, Karolina Kryczka, Karolina Wojtczak-Soska, Karolina Wojtera, Karsten Lenk, Karthik Ramasamy, Katarzyna Łuczak, Katarzyna Malinowska, Kate Pointon, Kate Robb, Katherine Martin, Kathleen Claes, Kathryn Carruthers, Kathy E Siegel, Katia Drouin, Katie Fowler-Lehman, Kavita Rawat, Kay Rowe, Keiichi Fukuda, Keith A A Fox, Ken Mahaffey, Kendra Unterbrink, Kenneth Giedd, Kerrie Van Loo, Kerry Lee, Kerstin Bonin, Kevin R Bainey, Kevin T Harley, Kevin Anstrom, Kevin Chan, Kevin Croce, Kevin Landolfo, Kevin Marzo, Keyur Patel, Khaled Abdul-Nour, Khaled Alfakih, Khaled Dajani, Khaled Ziada, Khaula Baloch, Khrystyna Kushniriuk, Kian-Keong Poh, Kim F Ireland, Kim Holland, Kimberly Ann Byrne, Kimberly E Halverson, Kimberly Elmore, Kimberly Miller-Cox, Kiran Reddy, Kirsten J Quiles, Kirsty Abercrombie, Klaus Matschke, Konrad Szymczyk, Koo Hui Chan, Kotiboinna Preethi, Kozhaya Sokhon, Krissada Meemuk, Kristian Thygesen, Kristin M Salmi, Kristin Newby, Kristina Wippler, Kristine Arges, Kristine Teoh, Krystal Etherington, Krystyna Łoboz-Grudzień, Krzysztof W Reczuch, Krzysztof Bury, Krzysztof Drzymalski, Krzysztof Kukuła, Kuo-Tzu Sung, Kurt Huber, Ladda Douangvila, Lance Sullenberger, Larissa Miranda Trama, Laszlone Matics, Laura Drew, Laura Flint, Laura 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Luiz A Carvalho, Luyang Xiong, Lynette L Teo, Lynn M Neeson, Lynne Winstanley, M Barbara Srichai-Parsia, M Quintana Giner, M Sowjanya Reddy, M Valdés Chávarri, M Grazia Rossi, Maarten Simoons, Maayan Konigstein, Maciej Lesiak, Maciej Olsowka, Mafalda Selas, Magalie Corfias, Magdalena Madero Rovalo, Magdalena Łanocha, Magdalena Miller, Magdalena Misztal-Teodorczyk, Magdalena Rantinella, Magdy Abdelhamid, Magnolia Jimenez, Mahboob Alam, Mahevamma Mylarappa, Mahfouz El Shahawy, Mahmoud Mohamed, Mahmud Al-Bustami, Majo X Joseph, Malgorzata Frach, Małgorzta Celińska-Spodar, Malte Helm, Manas Chacko, Mandy Murphy, Manitha Vinod, Manjula Rani, Manu Dhawan, Manuela Mombelli, Marcel Weber, Marcello Galvani, Marcelo Jamus Rodrigues, Marcia F Dubin, Marcia F Werner Bayer, Marcin Szkopiak, Marco Antonio Monsalve, Marco Bizzaro Santos, Marco Magnoni, Marco Marini, Marco Sicuro, Marco Zenati, Marcos Valério Coimbra Resende, Marek Roik, Margalit Bentzvi, Margaret Gilsenan, Margaret Iraola, Margot C 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Hayes, Sebastian Sobczak, Senait Asier, Sergey A Sayganov, Seth I Sokol, Shaheen Pandie, Shaiful Azmi Yahaya, Shamir Mehta, Shao-Ping Nie, Sharad Chandra, Sharder Islam, Sharon Tai, Sheetal Rupesh Karwa, Sheri Ussery, Sheromani Bajaj, Sherron C Crook, Shigeyuki Nishimura, Shintaro Nakano, Shirin Heydari, Shiv Kumar Choudhary, Shivali Patel, Shobana Ganesan, Shruti Pandey, Shuyang Zhang, Shweta Hande, Siddharth Gadage, Sik-Yin V Tan, Silvia Zottis Poletti, Silvia Riera, Silvia Valbuena, Simon Walsh, Simona Maspoli, Simone Savaris, Si-Ting Feng, So Yang Cho, Solomon Yakubov, Songlin Zhu, Songtao Wang, Sonia Guerrero, Sonika Gupta, Sonja Salinger Martinovic, Sonya Brons, Sorin Brener, Sothinathan Gurunathan, Souheil Saba, Soundarya Nayak, Sowjanya Reddy, Srinivasa Potluri, Sriram Sudarshan, Srun Kuanprasert, Stacie Van Oosterhout, Stamatios Lerakis, Stanley E Cobos, Stefan C Bertog, Stefan M Simović, Stefan Weikl, Stefano Di Marco, Stefano Provasoli, Stephanie A Tirado, Stephanie C Boer, Stephanie M Lane, Stephanie Ferket, Stephanie Kelly, Stephanie Wasmiller, Stephen H McKellar, Stephen P Hoole, Stephen Fremes, Stephen Preston, Steve Leung, Steven A Fein, Steven J Lindsay, Steven P Sedlis, Steven Giovannone, Steven Michael, Steven Weitz, Stijn van Vugt, Subhash Banerjee, Sudhir Naik, Suellen Hosino, Sukie Desire, Sukit Yamwong, Suku T Thambar, Sulagna Mookherjee, Suman Singh, Sundeep Mishra, Sunil Kumar Verma, Supap Kulthawong, Supatchara Khwakhong, Surendra Naik, Suresh Babu, Surin Woragidpoonpol, Suryaprakash Narayanappa, Susan Derbyshire, Susan Gent, Susan Mathus, Susan Milbrandt, Susan Moore, Susan Regan, Susan Stinson, Susan Webber, Susana Silva, Susanna Stevens, Susanne Gruensfelder, Suthara Aramcharoen, Suvarna Kolhe, Suzana Tavares, Suzanne Arnold, Suzanne Welsh, Svetlana Apostolovic, Swapna Kunhunny, Ta-Chuan Hung, Taissa Zappernick, Tali Sharir, Talita Silva, Tamara Colaiácovo Soares, Tapan Umesh Pillay, Tarun K Mittal, Tatiana Trifonova, Tauane Bello Duarte, Tauqir Huk, Téodora Dutoiu, Terrance Chua, Terry Weyand, Thabitha Charles, Theodoros Kofidis, Theresa McCreary, Thierry Lefevre, Thippeekaa Arumairajah, Thitipong Tepsuwan, Thomas J Mulhearn, Thomas M Meyer, Thomas P Rocco, Thomas R Downes, Thomas Crain, Thomas Haldis, Thomas Mathew, Thomas Redick, Thounaojam Indira Devi, Thuraia Nageh, Tia Cauthren, Tiago Silva, Tiffany Little, Tijana Andric, Tina Harding, Titus Lau, Tiziana Formisano, Tiziano Moccetti, Tomasz Ciurus, Tomasz Mazurek, Tomasz Tarchalski, Toshiyuki Nagai, Tri Tran, Tricia Youn, Trish Tucker, Trudie Milner, Tuhina Bose, Tushar Kotecha, Udo Sechtem, Uma S Valeti, Umberto Cucchini, Umesh Badami, Upendra Kaul, V K Bahl, V S Narain, Valentina Casali, Valeria Godoy, Valerie Robesyn, Vamshi P Priya, Vandana Yadav, Vera McKinney, Veronica De Lenges, Veronica Tinnirello, Vicente Miro, Victor Navarro, Victoria Gumerova, Victoria Hernandez, Vidya Seeratan, Vijay Kumar, Vikentiy Y Kozulin, Viktoria Bulkley, Vilmar Veiga Jr, Vincent Setang, C P Vineeth, Virginai Pubull Nuñez, Virginia Fernández-Figares, Vitor Gomes, Viviana Gabriel, Viviane Dos Santos, Viviane Almeida, Vlad A Iliescu, Vladan Mudrenovic, Vladimir Dzavik, Vojislav L Giga, Walter Enrique Mogrovejo, Wan Xian Chan, Wanda C Marfori, Wanda Parker, Warangkana Mekara, Wassim Nona, Wayne Old, Wayne Pennachi, Weerachai Nawarawong, Wei Chen, Wei Su, Weibing Xing, Wei-Ren Lan, Wenda Crawford, Wendy L Stewart, Wendy Drewes, Wenhua Lin, William B Abernethy, William D Salerno, William F Fearon, William Vergoni, William Weintraub, Winnie C Sia, Wlodzimierz J Musial, Xacobe Flores-Ríos, Xavier Garcia-Moll Marimon, Xi Su, Xiang Ma, Xiangqiong Gu, Xiao Wang, Xiaomei Li, Xiaowei Yao, Xin Fu, Xin Su, Xin Zeng, Xinchun Yang, Xiuhong Li, Xuehua Fang, Xutong Wang, Yaming Geng, Yan Yan, Yanek Pépin-Dubois, Yanfu Wang, Yang Wang, Yanmeng Tian, Yaping Huang, Yechen Han, Yesenia Zambrano, Yi-Hsuan Yang, Ying Tung Sia, Yining Yang, Yitong Ma, Yolayfi Peralta, Yongjian Wu, Yu Kunwu, Yu Zhao, Yudong Peng, Yueh-Hung Lin, Yulan Zhao, Yumei Dong, Yunhai Zhao, Yutthaphan Wannasopha, Yvonne Taul, Zakir Sahul, Zalina Kudzoeva, Zbigniew Kalarus, Zeljko Z Markovic, Zhen Huang, Zheng Ji, Zhenyu Liu, Zhou Yue, Zhulin Zhang, Zhuxi Li, Zile Singh Meharwal, Ziliang Bai, Zixiang Yu, Zohra Huda, Zoltan Davidovits
Subjects: Male, Cardiac Catheterization, Computed Tomography Angiography, medicine.medical_treatment, Myocardial Ischemia, Coronary Disease, Coronary Artery Disease, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Coronary Angiography, ISCHEMIA Research Group, law.invention, Angina, Coronary artery disease, 0302 clinical medicine, Randomized controlled trial, law, Cardiovascular Disease, Myocardial Revascularization, 030212 general & internal medicine, Coronary Artery Bypass, 11 Medical and Health Sciences, Cardiac catheterization, General Medicine, Middle Aged, humanities, Cardiovascular Diseases, Cardiology, Female, Human, medicine.medical_specialty, Ischemia, Article, 03 medical and health sciences, Geriatric cardiology, Percutaneous Coronary Intervention, General & Internal Medicine, Internal medicine, medicine, Humans, Angina, Unstable, Aged, business.industry, Coronary Artery Bypa, Percutaneous coronary intervention, Bayes Theorem, medicine.disease, Heart failure, Quality of Life, business
Abstract: BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).
Published: 2020
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25. Autism spectrum disorder symptom expression in individuals with 3q29 deletion syndrome

Author: Rebecca M. Pollak, Jordan E. Pincus, T. Lindsey Burrell, Joseph F. Cubells, Cheryl Klaiman, Melissa M. Murphy, Celine A. Saulnier, Elaine F. Walker, Stormi Pulver White, and Jennifer G. Mulle
Subjects: Male, Social Skills, Psychiatry and Mental health, Phenotype, Developmental Neuroscience, Autism Spectrum Disorder, Surveys and Questionnaires, Humans, Female, Syndrome, Molecular Biology, Developmental Biology
Abstract: Background The 1.6 Mb 3q29 deletion is associated with neurodevelopmental and neuropsychiatric phenotypes, including a 19-fold increased risk for autism spectrum disorder (ASD). Previous work by our team identified elevated social disability in this population via parent-report questionnaires. However, clinical features of ASD in this population have not been explored in detail. Methods Thirty-one individuals with 3q29 deletion syndrome (3q29del, 61.3% male) were evaluated using two gold-standard clinical ASD evaluations: the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and the Autism Diagnostic Interview, Revised (ADI-R). Four matched comparators for each subject were ascertained from the National Database for Autism Research. Item-level scores on the ADOS-2 and ADI-R were compared between subjects with 3q29del and matched comparators. Results Subjects with 3q29del and no ASD (3q29del-ASD) had greater evidence of social disability compared to typically developing (TD) comparison subjects across the ADOS-2. Subjects with 3q29del and ASD (3q29del + ASD) were largely indistinguishable from non-syndromic ASD (nsASD) subjects on the ADOS-2. 3q29del + ASD performed significantly better on social communication on the ADI-R than nsASD (3q29 + ASD mean = 11.36; nsASD mean = 15.70; p = 0.01), and this was driven by reduced deficits in nonverbal communication (3q29 + ASD mean = 1.73; nsASD mean = 3.63; p = 0.03). 3q29del + ASD reported significantly later age at the first two-word phrase compared to nsASD (3q29del + ASD mean = 43.89 months; nsASD mean = 37.86 months; p = 0.01). However, speech delay was not related to improved nonverbal communication in 3q29del + ASD. Limitations There were not enough TD comparators with ADI-R data in NDAR to include in the present analysis. Additionally, our relatively small sample size made it difficult to assess race and ethnicity effects. Conclusions 3q29del is associated with significant social disability, irrespective of ASD diagnosis. 3q29del + ASD have similar levels of social disability to nsASD, while 3q29del-ASD have significantly increased social disability compared to TD individuals. However, social communication is reasonably well preserved in 3q29del + ASD relative to nsASD. It is critical that verbal ability and social disability be examined separately in this population to ensure equal access to ASD and social skills evaluations and services.
Published: 2022

26. Prescribing Errors With Direct Oral Anticoagulants and Their Impact on the Risk of Bleeding in Patients With Atrial Fibrillation

Author: Ilan Matok, Arthur Pollak, Yevgeni Erlichman, Mordechai Muszkat, and Bruria Hirsh Raccah
Subjects: Male, medicine.medical_specialty, Administration, Oral, Hemorrhage, Risk Factors, Atrial Fibrillation, Humans, Medication Errors, Medicine, Pharmacology (medical), In patient, Israel, Intensive care medicine, Aged, Aged, 80 and over, Pharmacology, business.industry, Anticoagulants, Atrial fibrillation, medicine.disease, Potential harm, Harm, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Introduction: Anticoagulants are associated with significant harm when used in error, but there are limited data on potential harm of inappropriate treatment with direct oral anticoagulants (DOACs). We conducted a matched case-control study among atrial fibrillation (AF) patients admitting the hospital with a chronic treatment with DOACs, in order to assess factors associated with the risk of major bleeding. Methods: Patient data were documented using hospital’s computerized provider order entry system. Patients identified with major bleeding were defined as cases and were matched with controls based on the duration of treatment with DOACs and number of chronic medications. Appropriateness of prescribing was assessed based on the relevant clinical guidelines. Conditional logistic regression was used to evaluate the potential impact of safety-relevant prescribing errors with DOACs on major bleeding. Results: A total number of 509 eligible admissions were detected during the study period, including 64 cases of major bleeding and 445 controls. The prevalence of prescribing errors with DOACs was 33%. Most prevalent prescribing errors with DOACs were “drug dose too low” (16%) and “non-recommended combination of drugs” (11%). Safety-relevant prescribing errors with DOACs were associated with major bleeding [adjusted odds ratio (aOR) 2.17, 95% confidence interval (CI) 1.14-4.12]. Conclusion: Prescribers should be aware of the potential negative impact of prescribing errors with DOACs and understand the importance of proper prescribing and regular follow-up.
Published: 2021
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27. National trends in extremity fracture hospitalizations among older adults between 2003 and 2017

Author: Andrew N. Pollak, Joseph F. Levy, Jay Magaziner, Lisa Reider, and Jennifer L. Wolff
Subjects: Male, High energy, Time Factors, Population, Arm Bones, Cohort Studies, Fractures, Bone, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Femur, Leg Bones, Longitudinal Studies, National trends, Longitudinal cohort, education, Aged, Retrospective Studies, Aged, 80 and over, 030222 orthopedics, education.field_of_study, business.industry, Incidence, Incidence (epidemiology), 030208 emergency & critical care medicine, United States, Hospitalization, Extremity fractures, Female, Geriatrics and Gerontology, Lower extremity fracture, business, Demography
Abstract: BACKGROUND Fractures in late life are highly consequential for health, services use, and spending. Little is known about trends in extremity fracture hospitalizations among older adults in the United States. DESIGN Retrospective longitudinal cohort study. SETTING The 2003-2017 National Inpatient Sample (NIS), a representative sample of U.S. community hospitals. PARTICIPANTS Hospitalized adults aged 65 and older with a diagnosis of upper or lower extremity fracture. MEASUREMENTS Incidence of extremity fracture hospitalization and mortality, using NIS discharge and trend weights, and population denominators derived from the U.S. Census Bureau. Incidence was reported separately for men and women by age, fracture diagnosis, and injury mechanism. Weighted linear regression was used to test for significant trends over time. RESULTS Incidence of extremity fracture hospitalizations declined in both women (15.7%, p trend
Published: 2021
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28. Sex Differences in the Impact of Aortic Valve Calcium Score on Mortality After Transcatheter Aortic Valve Replacement

Author: Parth P. Patel, Abdallah El Sabbagh, Patrick W. Johnson, Rayan Suliman, Najiyah Salwa, Andrea Carolina Morales-Lara, Peter Pollak, Mohamad Yamani, Pragnesh Parikh, Sushilkumar K. Sonavane, Carolyn Landolfo, Mohamad Adnan Alkhouli, Mackram F. Eleid, Mayra Guerrero, F. David Fortuin, John Sweeney, Peter A. Noseworthy, Rickey E. Carter, and Demilade Adedinsewo
Subjects: Aged, 80 and over, Male, Sex Characteristics, Aortic Valve Stenosis, Transcatheter Aortic Valve Replacement, Treatment Outcome, Risk Factors, Aortic Valve, Heart Valve Prosthesis, Humans, Calcium, Female, Radiology, Nuclear Medicine and imaging, Cardiology and Cardiovascular Medicine
Abstract: Background: Transcatheter aortic valve replacement (TAVR) is now an approved alternative to surgical aortic valve replacement for the treatment of severe aortic stenosis. As the clinical adoption of TAVR expands, it remains important to identify predictors of mortality after TAVR. We aimed to evaluate the impact of sex differences in aortic valve calcium score (AVCS) on long-term mortality following TAVR in a large patient sample. Methods: We included consecutive patients who successfully underwent TAVR for treatment of severe native aortic valve stenosis from June 2010 to May 2021 across all US Mayo Clinic sites with follow-up through July 2021. AVCS values were obtained from preoperative computed tomography of the chest. Additional clinical data were abstracted from medical records. Kaplan-Meier curves and Cox-proportional hazard regression models were employed to evaluate the effect of AVCS on long-term mortality. Results: A total of 2543 patients were evaluated in the final analysis. Forty-one percent were women, median age was 82 years (Q1: 76, Q3: 86), 18.4% received a permanent pacemaker following TAVR, and 88.5% received a balloon expandable valve. We demonstrate an increase in mortality risk with higher AVCS after multivariable adjustment ( P Conclusions: We demonstrate a notable sex difference in the association between AVCS and long-term mortality in a large TAVR patient sample. This study highlights the potential value of AVCS in preprocedural risk stratification, specifically among women undergoing TAVR. Additional studies are needed to validate this finding.
Published: 2022
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29. Aqueous skin antisepsis before surgical fixation of open fractures (Aqueous-PREP): a multiple-period, cluster-randomised, crossover trial

Author: Gerard P. Slobogean, Sheila Sprague, Jeffrey L. Wells, Mohit Bhandari, Anthony D. Harris, C. Daniel Mullins, Lehana Thabane, Amber Wood, Gregory J. Della Rocca, Joan N. Hebden, Kyle J. Jeray, Lucas S. Marchand, Lyndsay M. O'Hara, Robert D. Zura, Christopher Lee, Joseph T. Patterson, Michael J. Gardner, Jenna Blasman, Jonah Davies, Stephen Liang, Monica Taljaard, PJ Devereaux, Gordon Guyatt, Diane Heels-Ansdell, Debra Marvel, Jana E. Palmer, Jeff Friedrich, Nathan N. O'Hara, Frances Grissom, I. Leah Gitajn, Saam Morshed, Robert V. O'Toole, Bradley Petrisor, Franca Mossuto, Manjari G. Joshi, Jean-Claude G. D'Alleyrand, Justin Fowler, Jessica C. Rivera, Max Talbot, David Pogorzelski, Shannon Dodds, Silvia Li, Gina Del Fabbro, Olivia Paige Szasz, Sofia Bzovsky, Paula McKay, Alexandra Minea, Kevin Murphy, Andrea L. Howe, Haley K. Demyanovich, Wayne Hoskins, Michelle Medeiros, Genevieve Polk, Eric Kettering, Nirmen Mahal, Andrew Eglseder, Aaron Johnson, Christopher Langhammer, Christopher Lebrun, Jason Nascone, Raymond Pensy, Andrew Pollak, Marcus Sciadini, Yasmin Degani, Heather Phipps, Eric Hempen, Herman Johal, Bill Ristevski, Dale Williams, Matthew Denkers, Krishan Rajaratnam, Jamal Al-Asiri, Jodi L. Gallant, Kaitlyn Pusztai, Sarah MacRae, Sara Renaud, John D. Adams, Michael L. Beckish, Christopher C. Bray, Timothy R. Brown, Andrew W. Cross, Timothy Dew, Gregory K. Faucher, Richard W. Gurich Jr, David E. Lazarus, S. John Millon, M. Christian Moody, M. Jason Palmer, Scott E. Porter, Thomas M. Schaller, Michael S. Sridhar, John L. Sanders, L. Edwin Rudisill Jr, Michael J. Garitty, Andrew S. Poole, Michael L. Sims, Clark M. Walker, Robert Carlisle, Erin A. Hofer, Brandon Huggins, Michael Hunter, William Marshall, Shea B. Ray, Cory Smith, Kyle M. Altman, Erin R. Pichiotino, Julia C. Quirion, Markus F. Loeffler, Austin A. Cole, Ethan J. Maltz, Wesley Parker, T. Bennett Ramsey, Alex Burnikel, Michael Colello, Russell Stewart, Jeremy Wise, Matthew Anderson, Joshua Eskew, Benjamin Judkins, James M. Miller, Stephanie L. Tanner, Rebecca G. Snider, Christine E. Townsend, Kayla H. Pham, Abigail Martin, Emily Robertson, Emily Bray, J. Wilson Sykes, Krystina Yoder, Kelsey Conner, Harper Abbott, Roman M. Natoli, Todd O. McKinley, Walter W. Virkus, Anthony T. Sorkin, Jan P. Szatkowski, Brian H. Mullis, Yohan Jang, Luke A. Lopas, Lauren C. Hill, Courteney L. Fentz, Maricela M. Diaz, Krista Brown, Katelyn M. Garst, Emma W. Denari, Patrick Osborn, Sarah N. Pierrie, Bradley Kessler, Maria Herrera, Theodore Miclau, Meir T. Marmor, Amir Matityahu, R. Trigg McClellan, David Shearer, Paul Toogood, Anthony Ding, Jothi Murali, Ashraf El Naga, Jennifer Tangtiphaiboontana, Tigist Belaye, Eleni Berhaneselase, Dmitry Pokhvashchev, William T. Obremskey, Amir Alex Jahangir, Manish Sethi, Robert Boyce, Daniel J. Stinner, Phillip P. Mitchell, Karen Trochez, Elsa Rodriguez, Charles Pritchett, Natalie Hogan, A. Fidel Moreno, Jennifer E. Hagen, Matthew Patrick, Richard Vlasak, Thomas Krupko, Michael Talerico, Marybeth Horodyski, Marissa Pazik, Elizabeth Lossada-Soto, Joshua L. Gary, Stephen J. Warner, John W. Munz, Andrew M. Choo, Timothy S. Achor, Milton L. 'Chip' Routt, Michael Kutzler, Sterling Boutte, Ryan J. Warth, Michael J. Prayson, Indresh Venkatarayappa, Brandon Horne, Jennifer Jerele, Linda Clark, Christina Boulton, Jason Lowe, John T. Ruth, Brad Askam, Andrea Seach, Alejandro Cruz, Breanna Featherston, Robin Carlson, Iliana Romero, Isaac Zarif, Niloofar Dehghan, Michael McKee, Clifford B. Jones, Debra L. Sietsema, Alyse Williams, Tayler Dykes, Ernesto Guerra-Farfan, Jordi Tomas-Hernandez, Jordi Teixidor-Serra, Vicente Molero-Garcia, Jordi Selga-Marsa, Juan Antonio Porcel-Vazquez, Jose Vicente Andres-Peiro, Ignacio Esteban-Feliu, Nuria Vidal-Tarrason, Jordi Serracanta, Jorge Nuñez-Camarena, Maria del Mar Villar-Casares, Jaume Mestre-Torres, Pilar Lalueza-Broto, Felipe Moreira-Borim, Yaiza Garcia-Sanchez, Francesc Marcano-Fernández, Laia Martínez-Carreres, David Martí-Garín, Jorge Serrano-Sanz, Joel Sánchez-Fernández, Matsuyama Sanz-Molero, Alejandro Carballo, Xavier Pelfort, Francesc Acerboni-Flores, Anna Alavedra-Massana, Neus Anglada-Torres, Alexandre Berenguer, Jaume Cámara-Cabrera, Ariadna Caparros-García, Ferran Fillat-Gomà, Ruben Fuentes-López, Ramona Garcia-Rodriguez, Nuria Gimeno-Calavia, Marta Martínez-Álvarez, Patricia Martínez-Grau, Raúl Pellejero-García, Ona Ràfols-Perramon, Juan Manuel Peñalver, Mònica Salomó Domènech, Albert Soler-Cano, Aldo Velasco-Barrera, Christian Yela-Verdú, Mercedes Bueno-Ruiz, Estrella Sánchez-Palomino, Vito Andriola, Matilde Molina-Corbacho, Yeray Maldonado-Sotoca, Alfons Gasset-Teixidor, Jorge Blasco-Moreu, Núria Fernández-Poch, Josep Rodoreda-Puigdemasa, Arnau Verdaguer-Figuerola, Heber Enrique Cueva-Sevieri, Santiago Garcia-Gimenez, Darius G. Viskontas, Kelly L. Apostle, Dory S. Boyer, Farhad O. Moola, Bertrand H. Perey, Trevor B. Stone, H. Michael Lemke, Ella Spicer, Kyrsten Payne, Robert A. Hymes, Cary C. Schwartzbach, Jeff E. Schulman, A. Stephen Malekzadeh, Michael A. Holzman, Greg E. Gaski, Jonathan Wills, Holly Pilson, Eben A. Carroll, Jason J. Halvorson, Sharon Babcock, J. Brett Goodman, Martha B. Holden, Wendy Williams, Taylor Hill, Ariel Brotherton, Nicholas M. Romeo, Heather A. Vallier, Anna Vergon, Thomas F. Higgins, Justin M. Haller, David L. Rothberg, Zachary M. Olsen, Abby V. McGowan, Sophia Hill, Morgan K. Dauk, Patrick F. Bergin, George V. Russell, Matthew L. Graves, John Morellato, Sheketha L. McGee, Eldrin L. Bhanat, Ugur Yener, Rajinder Khanna, Priyanka Nehete, David Potter, Robert VanDemark III, Kyle Seabold, Nicholas Staudenmier, Marcus Coe, Kevin Dwyer, Devin S. Mullin, Theresa A. Chockbengboun, Peter A. DePalo Sr., Kevin Phelps, Michael Bosse, Madhav Karunakar, Laurence Kempton, Stephen Sims, Joseph Hsu, Rachel Seymour, Christine Churchill, Ada Mayfield, Juliette Sweeney, Todd Jaeblon, Robert Beer, Brent Bauer, Sean Meredith, Sneh Talwar, Christopher M. Domes, Mark J. Gage, Rachel M. Reilly, Ariana Paniagua, JaNell Dupree, Michael J. Weaver, Arvind G. von Keudell, Abigail E. Sagona, Samir Mehta, Derek Donegan, Annamarie Horan, Mary Dooley, Marilyn Heng, Mitchel B. Harris, David W. Lhowe, John G. Esposito, Ahmad Alnasser, Steven F. Shannon, Alesha N. Scott, Bobbi Clinch, Becky Weber, Michael J. Beltran, Michael T. Archdeacon, Henry Claude Sagi, John D. Wyrick, Theodore Toan Le, Richard T. Laughlin, Cameron G. Thomson, Kimberly Hasselfeld, Carol A. Lin, Mark S. Vrahas, Charles N. Moon, Milton T. Little, Geoffrey S. Marecek, Denice M. Dubuclet, John A. Scolaro, James R. Learned, Philip K. Lim, Susan Demas, Arya Amirhekmat, and Yan Marco Dela Cruz
Subjects: Adult, Male, Canada, Cross-Over Studies, Chlorhexidine, General Medicine, Antisepsis, Middle Aged, Fractures, Open, Anti-Infective Agents, Local, Humans, Surgical Wound Infection, Female, Povidone-Iodine
Abstract: Chlorhexidine skin antisepsis is frequently recommended for most surgical procedures; however, it is unclear if these recommendations should apply to surgery involving traumatic contaminated wounds where povidone-iodine has previously been preferred. We aimed to compare the effect of aqueous 10% povidone-iodine versus aqueous 4% chlorhexidine gluconate on the risk of surgical site infection in patients who required surgery for an open fracture.We conducted a multiple-period, cluster-randomised, crossover trial (Aqueous-PREP) at 14 hospitals in Canada, Spain, and the USA. Eligible patients were adults aged 18 years or older with an open extremity fracture treated with a surgical fixation implant. For inclusion, the open fracture required formal surgical debridement within 72 h of the injury. Participating sites were randomly assigned (1:1) to use either aqueous 10% povidone-iodine or aqueous 4% chlorhexidine gluconate immediately before surgical incision; sites then alternated between the study interventions every 2 months. Participants, health-care providers, and study personnel were aware of the treatment assignment due to the colour of the solutions. The outcome adjudicators and data analysts were masked to treatment allocation. The primary outcome was surgical site infection, guided by the 2017 US Centers for Disease Control and Prevention National Healthcare Safety Network reporting criteria, which included superficial incisional infection within 30 days or deep incisional or organ space infection within 90 days of surgery. The primary analyses followed the intention-to-treat principle and included all participants in the groups to which they were randomly assigned. This study is registered with ClinicalTrials.gov, NCT03385304.Between April 8, 2018, and June 8, 2021, 3619 patients were assessed for eligibility and 1683 were enrolled and randomly assigned to povidone-iodine (n=847) or chlorhexidine gluconate (n=836). The trial's adjudication committee determined that 45 participants were ineligible, leaving 1638 participants in the primary analysis, with 828 in the povidone-iodine group and 810 in the chlorhexidine gluconate group (mean age 44·9 years [SD 18·0]; 629 [38%] were female and 1009 [62%] were male). Among 1571 participants in whom the primary outcome was known, a surgical site infection occurred in 59 (7%) of 787 participants in the povidone-iodine group and 58 (7%) of 784 in the chlorhexidine gluconate group (odds ratio 1·11, 95% CI 0·74 to 1·65; p=0·61; risk difference 0·6%, 95% CI -1·4 to 3·4).For patients who require surgical fixation of an open fracture, either aqueous 10% povidone-iodine or aqueous 4% chlorhexidine gluconate can be selected for skin antisepsis on the basis of solution availability, patient contraindications, or product cost. These findings might also have implications for antisepsis of other traumatic wounds.US Department of Defense, Canadian Institutes of Health Research, McMaster University Surgical Associates, PSI Foundation.
Published: 2022

30. Multimodal Investigation of Neuroinflammation in Aviremic Patients With HIV on Antiretroviral Therapy and HIV Elite Controllers

Author: Hasan, Sari, Riccardo, Galbusera, Guillaume, Bonnier, Yang, Lin, Zeynab, Alshelh, Angel, Torrado-Carvajal, Shibani S, Mukerji, Eva M, Ratai, Rajesh T, Gandhi, Jacqueline T, Chu, Oluwaseun, Akeju, Vwaire, Orhurhu, Andrew N, Salvatore, Janet, Sherman, Douglas S, Kwon, Bruce, Walker, Bruce, Rosen, Julie C, Price, Lauren E, Pollak, Marco, Loggia, and Cristina, Granziera
Subjects: Male, Brain Diseases, Correction & Replacement, HIV Infections, Neuroimaging, Middle Aged, Magnetic Resonance Imaging, Multimodal Imaging, Neurology, Anti-Retroviral Agents, Positron-Emission Tomography, Neuroinflammatory Diseases, HIV Non-Progressors, Humans, Cognitive Dysfunction, Female, Neurology (clinical), Aged
Abstract: The presence of HIV in the CNS has been related to chronic immune activation and cognitive dysfunction. The aim of this work was to investigate (1) the presence of neuroinflammation in aviremic people with HIV (PWH) on therapy and in nontreated aviremic PWH (elite controllers [ECs]) using a translocator protein 18 kDa radioligand; (2) the relationship between neuroinflammation and cognitive function in aviremic PWH; and (3) the relationship between [[In region of interest analyses, ECs exhibited significantly lower [This study casts a new light onto the role of neuroinflammation and related microstructural alterations of HIV infection in the CNS and shows that ECs suppress neuroinflammation more effectively than PWH on therapy.
Published: 2022

31. Decision-making and Risky Behavior in Individuals with Attention-Deficit/Hyperactivity Disorder: A 10-year Longitudinal Study

Author: Stian Orm, Yehuda Pollak, Ingrid Nesdal Fossum, Per Normann Andersen, Merete Glenne Øie, and Erik Winther Skogli
Subjects: Male, Attention-Deficit, Decision Making, Neuropsychology and Physiological Psychology, Risk-Taking, children, Attention Deficit Disorder with Hyperactivity, Gambling, Developmental and Educational Psychology, Hyperactivity Disorder, ADHD, VDP::Samfunnsvitenskap: 200, Humans, Female, Longitudinal Studies
Abstract: We assessed 85 children with Attention-Deficit/Hyperactivity Disorder (ADHD) and 50 typically developing children (TD) (Mage = 11.59, 57.8% boys) with the Hungry Donkey Task (HDT) at baseline and 2-year follow-up, and the Iowa Gambling Task at 10-year follow-up (75% retention). Improvement in the proportion of advantageous choices was observed from two- to 10-year follow-up, but the ADHD group improved less and was outperformed by the TD group at the 10-year follow-up. More advantageous choices on the HDT at baseline predicted less risky behaviour at 10-year follow-up. Male sex and more inattentive or externalizing symptoms at base line predicted more risky behaviour.
Published: 2022

32. Learning from the past and expecting the future in Parkinsonism: Dopaminergic influence on predictions about the timing of future events

Author: Alessandro Tomassini, Mark J. Edwards, Sven Bestmann, Thomas A Pollak, Pollak, Thomas A [0000-0002-6171-0810], Edwards, Mark J [0000-0002-8283-9015], Bestmann, Sven [0000-0002-6867-9545], and Apollo - University of Cambridge Repository
Subjects: Male, Visual perception, Parkinson's disease, Dopamine, Cognitive Neuroscience, Decision Making, Experimental and Cognitive Psychology, Stimulus (physiology), Article, 050105 experimental psychology, 03 medical and health sciences, Behavioral Neuroscience, Cognition, 0302 clinical medicine, Parkinsonian Disorders, Reaction Time, medicine, Humans, 0501 psychology and cognitive sciences, Predictability, Aged, Motor preparation, Parkinson's Disease, Parkinsonism, 05 social sciences, Dopaminergic, Uncertainty, Temporal expectation, Middle Aged, Anticipation, Psychological, medicine.disease, Temporal processing, Drift-diffusion model, Female, Psychology, Neuroscience, Photic Stimulation, Psychomotor Performance, 030217 neurology & neurosurgery, medicine.drug
Abstract: The prolonged reaction times seen in Parkinson's disease (PD) have been linked to a dopaminergic-dependent deficit in using prior information to prepare responses, but also have been explained by an altered temporal processing. However, an underlying cognitive mechanism linking dopamine, temporal processing and response preparation remains elusive. To address this, we studied PD patients, with or without medication, and age-matched healthy individuals using a variable foreperiod task requiring speeded responses to a visual stimulus occurring at variable onset-times, with block-wise changes in the temporal predictability of visual stimuli. Compared with controls, unmedicated patients showed impaired use of prior information to prepare their responses, as reflected by slower reaction times, regardless of the level of temporal predictability. Crucially, after dopamine administration normal performance was restored, with faster responses for high temporal predictability. Using Bayesian hierarchical drift-diffusion modelling, we estimated the parameters that determine temporal preparation. In this theoretical framework, impaired temporal preparation under dopaminergic depletion was driven by inflexibly high decision boundaries (i.e. participants were always extremely cautious). This indexes high levels of uncertainty about temporal predictions irrespectively of stimulus onset predictability. Our results suggest that dopaminergic depletion in PD affects the uncertainty of predictions about the timing of future events (temporal predictions), which are crucial for the anticipatory preparation of responses. Dopamine, which is affected in PD, controls the ability to predict the timing of future events., Highlights • Parkinson’s patients cannot use prior temporal information to prepare motor responses. • Temporal preparation is restored to normality by dopamine administration. • Temporal preparation declines with increasing uncertainty about temporal predictions. • Dopaminergic depletion linked to inflexibly high uncertainty in temporal predictions. • Dopamine regulates the uncertainty of predictions about the timing of future events.
Published: 2019
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33. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Author: Verena Klämbt, Youying Mao, Vimla Aggarwal, Arang Kim, Friedhelm Hildebrandt, Mohamad A. Mikati, Vandana Shashi, Anne H. O’Donnell-Luria, Vaidehi Jobanputra, Jeremiah Martino, Vivette D. D'Agati, Minxian Wang, Marcus R. Benz, Shoji Yano, Janine Altmüller, Ali G. Gharavi, Florian Buerger, Enrico Fiaccadori, Richard P. Lifton, Bodo B. Beck, Amy Kolb, Mordi Muorah, David Goldstein, Nina Mann, Martin R. Pollak, Dina Ahram, Heidi Cope, Gian Marco Ghiggeri, Jillian S. Parboosingh, Asmaa S. AbuMaziad, Kamal Khan, Ana C. Onuchic-Whitford, Louise Bier, Emma Pierce-Hoffman, Jonathan E. Zuckerman, Shrikant Mane, Moin A. Saleem, Amar J. Majmundar, Heidi L. Rehm, Ora Yadin, Erin L. Heinzen, Gina Y. Jin, Christelle Moufawad El Achkar, Konstantin Deutsch, Julia Hoefele, Ania Koziell, Gianluca Caridi, Talha Gunduz, Agnieszka Bierzynska, Korbinian M. Riedhammer, Monica Bodria, Ronen Schneider, Julian A. Martinez-Agosto, Thomas M. Kitzler, Shirlee Shril, Ulrike John-Kroegel, Howard Trachtman, Adele Mitrotti, Eleanor G. Seaby, Amanda V. Tyndall, Isabella Pisani, Patricia L. Weng, Tze Y Lim, A. Micheil Innes, John Musgrove, Simone Sanna-Cherchi, and Erica E. Davis
Subjects: Adult, Male, 0301 basic medicine, Proband, medicine.medical_specialty, Nephrotic Syndrome, Developmental Disabilities, 030232 urology & nephrology, Neurogenetics, Nerve Tissue Proteins, Biology, Kidney, Cell Line, Mice, 03 medical and health sciences, Exon, 0302 clinical medicine, Focal segmental glomerulosclerosis, Report, Exome Sequencing, Genetics, medicine, Animals, Humans, Child, Exome, Genetics (clinical), Exome sequencing, Epilepsy, Glomerulosclerosis, Focal Segmental, Podocytes, medicine.disease, 3. Good health, Phenotype, 030104 developmental biology, Codon, Nonsense, Child, Preschool, Mutation, Medical genetics, Female, Intranuclear Space, Carrier Proteins, Nephrotic syndrome
Abstract: Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10(−11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10(−15)). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.
Published: 2021
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34. Evidence for multi-copy Mega-NUMTsin the human genome

Author: Matthias Schmuth, Sandra Carina Weiß, Thomas Liehr, Jana Naue, Stefan Pollak, Timo Sänger, Fengtang Yang, Jodi A. Irwin, Peter Lichter, Cordula Berger, Pidder Jansen-Dürr, Erica L. Romsos, Marianne Volleth, Thomas J. Parsons, René Pflugradt, Rafal Koziel, Christina Strobl, Sabine Lutz-Bonengel, Catarina Xavier, Gabriela Huber, Peter M. Vallone, Walther Parson, Harald Niederstätter, and Gudrun Ratzinger
Subjects: Male, Mitochondrial DNA, DNA Copy Number Variations, AcademicSubjects/SCI00010, Mitochondrial disease, Biology, DNA, Mitochondrial, Genome, Haplogroup, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, 030216 legal & forensic medicine, 030304 developmental biology, Cell Nucleus, 0303 health sciences, Massive parallel sequencing, Genome, Human, Sequence Analysis, DNA, Genomics, medicine.disease, Human genetics, Pedigree, Nuclear DNA, Female, Human genome
Abstract: The maternal mode of mitochondrial DNA (mtDNA) inheritance is central to human genetics. Recently, evidence for bi-parental inheritance of mtDNA was claimed for individuals of three pedigrees that suffered mitochondrial disorders. We sequenced mtDNA using both direct Sanger and Massively Parallel Sequencing in several tissues of eleven maternally related and other affiliated healthy individuals of a family pedigree and observed mixed mitotypes in eight individuals. Cells without nuclear DNA, i.e. thrombocytes and hair shafts, only showed the mitotype of haplogroup (hg) V. Skin biopsies were prepared to generate ρ° cells void of mtDNA, sequencing of which resulted in a hg U4c1 mitotype. The position of the Mega-NUMT sequence was determined by fluorescence in situ hybridization and two different quantitative PCR assays were used to determine the number of contributing mtDNA copies. Thus, evidence for the presence of repetitive, full mitogenome Mega-NUMTs matching haplogroup U4c1 in various tissues of eight maternally related individuals was provided. Multi-copy Mega-NUMTs mimic mixtures of mtDNA that cannot be experimentally avoided and thus may appear in diverse fields of mtDNA research and diagnostics. We demonstrate that hair shaft mtDNA sequencing provides a simple but reliable approach to exclude NUMTs as source of misleading results.
Published: 2021
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35. Clozapine Response in Schizophrenia and Hematological Changes

Author: Robert Stewart, James H. MacCabe, Alexis E. Cullen, Jonathan Rogers, Matthew M. Nour, Kira Griffiths, Jenny E. L. Lisshammar, Anthony S. David, Thomas A Pollak, Rayyan Zafar, Graham Blackman, Megan Pritchard, Philip McGuire, and Ben Carter
Subjects: Adult, Male, medicine.medical_specialty, Treatment response, Original Contributions, Young Adult, 03 medical and health sciences, 0302 clinical medicine, White blood cell, Internal medicine, medicine, Humans, Pharmacology (medical), Platelet, psychosis, Young adult, Clozapine, Retrospective Studies, Hematologic Tests, clozapine, hematology, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, medicine.anatomical_structure, inflammation, Schizophrenia, Female, Drug Monitoring, business, Early phase, 030217 neurology & neurosurgery, Antipsychotic Agents, medicine.drug
Abstract: Background Clozapine is the only effective medication for treatment-resistant schizophrenia; however, its mechanism of action remains unclear. The present study explored whether its effectiveness is related to changes in hematological measures after clozapine initiation. Methods Patients with treatment-resistant schizophrenia commenced on clozapine between January 2007 and December 2014 by the United Kingdom’s largest mental health trust were identified from electronic patient records. Hematological data from these patients were obtained from a monitoring registry. White blood cell, neutrophil, and platelet count were assessed at baseline and during the early phase of clozapine treatment. Clozapine response at 3 months was defined as “much,” or “very much” improved on the seven-point Clinical Global Impression—Improvement (CGI-I) subscale. Results In the total sample (n = 188), clozapine initiation was associated with a significant transient increase (peaking in weeks 3 to 4) in white blood cell, neutrophil, and platelet count (P < 0.001). There were 112 (59.6%) patients that responded to treatment; however, none of the hematological factors assessed at baseline, nor changes in these factors, were directly associated with treatment response. Implications Clozapine treatment is associated with transient hematological changes during the first month of treatment; however, there was no evidence that these were related to the therapeutic response.
Published: 2020
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36. Unconventional Natural Gas Development and Hospitalization for Heart Failure in Pennsylvania

Author: Brian S. Schwartz, Erin D. Michos, Jonathan Pollak, John W. McEvoy, Tara McAlexander, Jessie P. Buckley, and Karen Bandeen-Roche
Subjects: Adult, Male, medicine.medical_specialty, Natural Gas, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, 0302 clinical medicine, Older patients, Internal medicine, medicine, Humans, Petroleum Pollution, 030212 general & internal medicine, Aged, Aged, 80 and over, Heart Failure, Ejection fraction, Hydraulic Fracking, business.industry, Mean age, Environmental Exposure, Odds ratio, Middle Aged, Pennsylvania, medicine.disease, Confidence interval, Hospitalization, Quartile, Control selection, Case-Control Studies, Heart failure, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Background Growing literature linking unconventional natural gas development (UNGD) to adverse health has implicated air pollution and stress pathways. Persons with heart failure (HF) are susceptible to these stressors. Objectives This study sought to evaluate associations between UNGD activity and hospitalization among HF patients, stratified by both ejection fraction (EF) status (reduced [HFrEF], preserved [HFpEF], not classifiable) and HF severity. Methods We evaluated the odds of hospitalization among patients with HF seen at Geisinger from 2008 to 2015 using electronic health records. We assigned metrics of UNGD activity by phase (pad preparation, drilling, stimulation, and production) 30 days before hospitalization or a frequency-matched control selection date. We assigned phenotype status using a validated algorithm. Results We identified 9,054 patients with HF with 5,839 hospitalizations (mean age 71.1 ± 12.7 years; 47.7% female). Comparing 4th to 1st quartiles, adjusted odds ratios (95% confidence interval) for hospitalization were 1.70 (1.35 to 2.13), 0.97 (0.75 to 1.27), 1.80 (1.35 to 2.40), and 1.62 (1.07 to 2.45) for pad preparation, drilling, stimulation, and production metrics, respectively. We did not find effect modification by HFrEF or HFpEF status. Associations of most UNGD metrics with hospitalization were stronger among those with more severe HF at baseline. Conclusions Three of 4 phases of UNGD activity were associated with hospitalization for HF in a large sample of patients with HF in an area of active UNGD, with similar findings by HFrEF versus HFpEF status. Older patients with HF seem particularly vulnerable to adverse health impacts from UNGD activity.
Published: 2020
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37. Resting Cardiac Efficiency Affects Survival Following Transcatheter Aortic Valve Replacement

Author: Floyd David Fortuin, Kevin L. Greason, Panwen Wang, Peter M. Pollak, Hasan Ashraf, Mackram F. Eleid, John P. Sweeney, Nithin R. Venepally, Farouk Mookadam, Sai Harika Pujari, Nirat Beohar, Mohamed Allam, Reza Arsanjani, and Pradyumna Agasthi
Subjects: Male, medicine.medical_specialty, Cardiac output, medicine.medical_treatment, 030204 cardiovascular system & hematology, Doppler echocardiography, Severity of Illness Index, Transcatheter Aortic Valve Replacement, 03 medical and health sciences, 0302 clinical medicine, Valve replacement, Aortic valve replacement, Risk Factors, Internal medicine, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Retrospective Studies, Framingham Risk Score, medicine.diagnostic_test, business.industry, Atrial fibrillation, Aortic Valve Stenosis, General Medicine, medicine.disease, Treatment Outcome, Blood pressure, Aortic Valve, cardiovascular system, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Cardiac power to left ventricular mass (LVM) ratio, also termed cardiac efficiency (CE), reflects the rate of cardiac work delivered to the potential energy stored in LVM. We sought to assess the association between baseline resting CE and survival post transcatheter aortic valve replacement (TAVR).We retrospectively extracted data of patients who received TAVR in the Mayo Clinic Foundation with follow up data available at 1 year. Cardiac output was measured using Doppler echocardiography at baseline. CE was calculated using the formula, (cardiac output × mean arterial blood pressure)/(451 × LVM × 100) W/100 g. Survival score analysis was performed to identify cut off value for CE to identify the maximum difference in mortality in the study cohort. Patients were subsequently divided into 2 groups CE 0.38 W/100 g and CE ≥ 0.38 W/100 g. Survival was determined using Kaplan-Meier method.We included 954 patients in the final analysis. CE in group1 vs group 2 was 0.31 ± 0.05 W/100 g vs 0.59 ± 0.18 W/100 g. Patients in group1 were more likely to be male, had a higher prevalence of atrial fibrillation, prior myocardial infarction, mitral and tricuspid regurgitation. They also had a higher STS risk score, NYHA functional class, and lower aortic valve area. The remainder of the baseline characteristics was similar in both groups. A lower CE was associated with higher 1-year mortality following TAVR based on multivariate analysis. (Group1: 22.18% vs Group 2: 9.89%, p .0001).In our cohort, a low baseline CE (0.38 W/100 g) conferred higher mortality risk following TAVR.
Published: 2020
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38. Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020

Author: Lilian M. Abbo, Shuba Balan, Julie Hand, Sapna Bamrah Morris, Ermias D. Belay, Daniel P. Eiras, Sharon E. Fox, Emer Smith, Aaron Kofman, Vennus Ballen, Zachary Ende, Marie Dorsinville, Bobbi Bryant, Pragna Patel, Rachel Paneth-Pollak, Gillian Richardson, Ellen H. Lee, Anita Geevarughese, Noah G. Schwartz, Sarah Lim, Maura K. Lash, Nora T. Oliver, Shana Godfred-Cato, Patricia Stogsdill, Christopher Newton-Cheh, Laura Beauchamps, Deblina Datta, and Sara Robinson
Subjects: Adult, Male, medicine.medical_specialty, Abdominal pain, Health (social science), Epidemiology, Health, Toxicology and Mutagenesis, Pneumonia, Viral, 01 natural sciences, Virus, Pathogenesis, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Health Information Management, Internal medicine, Pandemic, medicine, Humans, 030212 general & internal medicine, Full Report, 0101 mathematics, Young adult, Pandemics, biology, business.industry, 010102 general mathematics, COVID-19, General Medicine, Middle Aged, medicine.disease, Systemic Inflammatory Response Syndrome, United Kingdom, United States, Systemic inflammatory response syndrome, Pneumonia, biology.protein, Female, medicine.symptom, Antibody, business, Coronavirus Infections
Abstract: During the course of the coronavirus disease 2019 (COVID-19) pandemic, reports of a new multisystem inflammatory syndrome in children (MIS-C) have been increasing in Europe and the United States (1-3). Clinical features in children have varied but predominantly include shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers, including C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 (1). Since June 2020, several case reports have described a similar syndrome in adults; this review describes in detail nine patients reported to CDC, seven from published case reports, and summarizes the findings in 11 patients described in three case series in peer-reviewed journals (4-6). These 27 patients had cardiovascular, gastrointestinal, dermatologic, and neurologic symptoms without severe respiratory illness and concurrently received positive test results for SARS-CoV-2, the virus that causes COVID-19, by polymerase chain reaction (PCR) or antibody assays indicating recent infection. Reports of these patients highlight the recognition of an illness referred to here as multisystem inflammatory syndrome in adults (MIS-A), the heterogeneity of clinical signs and symptoms, and the role for antibody testing in identifying similar cases among adults. Clinicians and health departments should consider MIS-A in adults with compatible signs and symptoms. These patients might not have positive SARS-CoV-2 PCR or antigen test results, and antibody testing might be needed to confirm previous SARS-CoV-2 infection. Because of the temporal association between MIS-A and SARS-CoV-2 infections, interventions that prevent COVID-19 might prevent MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition.
Published: 2020

39. Circulating testican-2 is a podocyte-derived marker of kidney health

Author: Michelle J. Keyes, Sumita Sinha, James G. Wilson, Dongxiao Shen, Thomas J. Wang, Robert E. Gerszten, Bessie A. Young, Donghai Wen, Benjamin D. Humphreys, Yan Gao, Sammy Elmariah, Adolfo Correa, Martin G. Larson, Qiong Yang, Daniel H. Katz, Erika R. Drury, J. Gustav Smith, Debby Ngo, Laurie A. Farrell, David J. Friedman, Martin R. Pollak, Bennet Peterson, Eugene P. Rhee, Mark D. Benson, and Ramachandran S. Vasan
Subjects: Male, Proteomics, medicine.medical_specialty, Kidney Disease, 1.1 Normal biological development and functioning, Kidney Glomerulus, Renal and urogenital, Renal function, Type 2 diabetes, Cardiovascular, Kidney, Kidney Function Tests, Aptamers, testican-2, Podocyte, Framingham Heart Study, Clinical Research, Underpinning research, Internal medicine, Humans, Medicine, Tube formation, Multidisciplinary, Podocytes, business.industry, Middle Aged, Biological Sciences, medicine.disease, Black or African American, medicine.anatomical_structure, Endocrinology, Peptide, Hypertension, Albuminuria, Biomarker (medicine), Female, Proteoglycans, medicine.symptom, business, chronic kidney disease, Aptamers, Peptide, Biomarkers, Glomerular Filtration Rate
Abstract: In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.
Published: 2020
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40. Clinical Outcomes following Left Atrial Appendage Occlusion: A Single-Center Experience

Author: K.L. Venkatachalam, Jeffery Winder, Pragnesh Parikh, Demilade Adedinsewo, Susie Sennhauser, Elizabeth R. Lesser, Carolyn Landolfo, Najiyah Salwa, Launia J. White, Peter M. Pollak, and Salman Farhat
Subjects: Male, Gastrointestinal bleeding, medicine.medical_specialty, Percutaneous, medicine.medical_treatment, Single Center, Left atrial appendage occlusion, Antithrombotic, medicine, Humans, Atrial Appendage, Pharmacology (medical), Stroke, Aged, Retrospective Studies, business.industry, Anticoagulants, Atrial fibrillation, medicine.disease, Surgery, Treatment Outcome, Female, Observational study, Cardiology and Cardiovascular Medicine, business
Abstract: Introduction: Percutaneous left atrial appendage closure is an established alternative to anticoagulation therapy for stroke prophylaxis among patients with nonvalvular atrial fibrillation. There are currently no guidelines on the choice of antithrombotic therapy following placement of the Watchman® device, the optimal time to discontinue anticoagulation or the duration of follow-up imaging after device deployment. Our main objective was to evaluate clinical outcomes among these patients. Methods: We conducted a retrospective review of patients who received a Watchman® device at Mayo Clinic sites between January 2010 and December 2018. We constructed Cox-proportional hazard models to evaluate the effect of specific variables on clinical outcomes. Results: 231 patients were identified (33% female), median age was 77 years, CHA2DS2-VASc score was 5 and HASBLED score was 4. We found no difference in clinically significant bleeding based on initial antithrombotic choice. However, patients with prior gastrointestinal bleeding were more likely to have a bleeding event in the first 6 weeks following Watchman® implantation (HR 9.40, 95% CI 2.15–41.09). Device sizes of 24–27 mm were significantly associated with a decreased risk of thromboembolic events (HR 0.15, 95% CI 0.04–0.55) compared to 21-mm devices. Peridevice leak (PDL) sizes appeared to either remain the same or increase on follow-up imaging. Discussion/Conclusions: This observational study showed no statistically significant difference in bleeding risk related to initial antithrombotic choice. Smaller device sizes were associated with thromboembolic events, and longitudinal PDL assessment using transesophageal echocardiography showed these frequently do not decrease in size. Larger studies are needed.
Published: 2020
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41. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictors of tumor response in hepatocellular carcinoma after DEB-TACE

Author: MingDe Lin, Todd Schlachter, Lynn Jeanette Savic, Isabel Schobert, Evan M. Chen, Jonathan Tefera, Nariman Nezami, Khaled Bousabarah, Jeffrey Pollak, Fabian Laage-Gaupp, and Julius Chapiro
Subjects: Blood Platelets, Male, Oncology, medicine.medical_specialty, Carcinoma, Hepatocellular, Neutrophils, Lymphocyte, Kaplan-Meier Estimate, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Bayesian multivariate linear regression, medicine, Humans, Radiology, Nuclear Medicine and imaging, Lymphocytes, Chemoembolization, Therapeutic, Aged, Proportional Hazards Models, Retrospective Studies, Neuroradiology, Inflammation, medicine.diagnostic_test, Proportional hazards model, business.industry, Liver Neoplasms, Magnetic resonance imaging, Retrospective cohort study, General Medicine, Middle Aged, Prognosis, medicine.disease, Magnetic Resonance Imaging, Progression-Free Survival, Treatment Outcome, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Multivariate Analysis, Female, Liver function, Radiology, business
Abstract: To investigate the predictive value of quantifiable imaging and inflammatory biomarkers in patients with hepatocellular carcinoma (HCC) for the clinical outcome after drug-eluting bead transarterial chemoembolization (DEB-TACE) measured as volumetric tumor response and progression-free survival (PFS). This retrospective study included 46 patients with treatment-naive HCC who received DEB-TACE. Laboratory work-up prior to treatment included complete and differential blood count, liver function, and alpha-fetoprotein levels. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were correlated with radiomic features extracted from pretreatment contrast-enhanced magnetic resonance imaging (MRI) and with tumor response according to quantitative European Association for the Study of the Liver (qEASL) criteria and progression-free survival (PFS) after DEB-TACE. Radiomic features included single nodular tumor growth measured as sphericity, dynamic contrast uptake behavior, arterial hyperenhancement, and homogeneity of contrast uptake. Statistics included univariate and multivariate linear regression, Cox regression, and Kaplan–Meier analysis. Accounting for laboratory and clinical parameters, high baseline NLR and PLR were predictive of poorer tumor response (p = 0.014 and p = 0.004) and shorter PFS (p = 0.002 and p
Published: 2020
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42. Prospective Association of Energy Balance Scores Based on Metabolic Biomarkers with Colorectal Cancer Risk

Author: Ying Wang, Michael Pollak, W. Dana Flanders, Mark A. Guinter, Kassandra I. Alcaraz, Marjorie L. McCullough, Erika Rees-Punia, Peter T. Campbell, and Susan M. Gapstur
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Colorectal cancer, Risk Assessment, Body Mass Index, Food group, 03 medical and health sciences, 0302 clinical medicine, Hyperinsulinism, Internal medicine, Humans, Medicine, Prospective Studies, Receptors, Immunologic, Exercise, Aged, Glycated Hemoglobin, Inflammation, Cancer prevention, C-Peptide, business.industry, Incidence, Incidence (epidemiology), Feeding Behavior, Middle Aged, medicine.disease, Confidence interval, 030104 developmental biology, Quartile, Hyperglycemia, 030220 oncology & carcinogenesis, Cohort, Female, Colorectal Neoplasms, Energy Metabolism, business, Body mass index, Biomarkers, Follow-Up Studies
Abstract: Background: Energy balance–related factors, such as body mass index (BMI), diet, and physical activity, may influence colorectal cancer etiology through interconnected metabolic pathways, but their combined influence is less clear. Methods: We used reduced rank regression to derive three energy balance scores that associate lifestyle factors with combinations of prediagnostic, circulating levels of high-sensitivity C-reactive protein (hsCRP), C-peptide, and hemoglobin A1c (HbA1c) among 2,498 participants in the Cancer Prevention Study-II Nutrition Cohort. Among 114,989 participants, we verified 2,228 colorectal cancer cases. We assessed associations of each score with colorectal cancer incidence and by tumor molecular phenotypes using Cox proportional hazards regression. Results: The derived scores comprised BMI, physical activity, screen time, and 14 food groups, and explained 5.1% to 10.5% of the variation in biomarkers. The HR and 95% confidence interval (CI) for quartile 4 versus 1 of the HbA1c+C peptide–based score and colorectal cancer was 1.30 (1.15–1.47), the hsCRP-based score was 1.35 (1.19–1.53), and the hsCRP, C-peptide, and HbA1c-based score was 1.35 (1.19–1.52). The latter score was associated with non-CIMP tumors (HRQ4vsQ1: 1.59; 95% CI: 1.17–2.16), but not CIMP-positive tumors (Pheterogeneity = 0.04). Conclusions: These results further support hypotheses that systemic biomarkers of metabolic health—inflammation and abnormal glucose homeostasis—mediate part of the relationship between several energy balance–related modifiable factors and colorectal cancer risk. Impact: Results support cancer prevention guidelines for maintaining a healthful body weight, consuming a healthful diet, and being physically active. More research is needed on these clusters of exposures with molecular phenotypes of tumors.
Published: 2020
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43. Cancer Immunoprevention: A Case Report Raising the Possibility of 'Immuno-interception'

Author: Michael Pollak, William D. Foulkes, and Jessica G. Mancuso
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Cancer immunoprevention, medicine.medical_treatment, Pembrolizumab, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Internal medicine, medicine, Humans, Cancer prevention, Bladder cancer, business.industry, Immunotherapy, Middle Aged, Prognosis, medicine.disease, Immune checkpoint, Lynch syndrome, 030104 developmental biology, Muir-Torre Syndrome, 030220 oncology & carcinogenesis, DNA mismatch repair, business
Abstract: Immune checkpoint blockade therapy provides substantial benefits for subsets of patients with advanced cancer, but its utility for cancer prevention is unknown. Lynch syndrome (MIM 120435) is characterized by defective DNA mismatch repair and predisposition to multiple cancers. A variant of Lynch syndrome, Muir–Torre syndrome (MIM 158320), is characterized by frequent gastrointestinal tumors and hyperplastic or neoplastic skin tumors. We report the case of a man with Muir–Torre syndrome who had 136 cutaneous or visceral hyperplastic or neoplastic lesions over a period of 19 years (mean 7.5 neoplasms/year, range 2–26) prior to receiving pembrolizumab immunotherapy as part of multi-modality treatment for invasive bladder cancer. He not only had a complete response of the bladder cancer, but also was noted to have an absence of new cancers during a 22-month follow-up period. This case adds to the rationale for exploring the utility of immune checkpoint blockade for cancer prevention, particularly for patients with DNA repair deficits.
Published: 2020
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44. Quantification of contrast-uptake as imaging biomarker for disease progression of renal cell carcinoma after tumor ablation

Author: Bernhard Gebauer, Jeffrey Pollak, Lynn Jeanette Savic, Steffen Huber, Julius Chapiro, MingDe Lin, and Bruno R Tegel
Subjects: Ablation Techniques, Adult, Male, Pathology, medicine.medical_specialty, Imaging biomarker, Contrast Media, Radiography, Interventional, Sensitivity and Specificity, Article, Tumor ablation, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Imaging, Three-Dimensional, 0302 clinical medicine, Renal cell carcinoma, Biomarkers, Tumor, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Carcinoma, Renal Cell, Ultrasonography, Interventional, Aged, Neoplasm Staging, Retrospective Studies, Aged, 80 and over, Radiological and Ultrasound Technology, business.industry, Disease progression, General Medicine, Middle Aged, medicine.disease, Kidney Neoplasms, Tumor Burden, 030220 oncology & carcinogenesis, Disease Progression, Female, business
Abstract: Background The prognosis of patients with renal cell carcinoma (RCC) depends greatly on the presence of extra-renal metastases. Purpose To investigate the value of total tumor volume (TTV) and enhancing tumor volume (ETV) as three-dimensional (3D) quantitative imaging biomarkers for disease aggressiveness in patients with RCC. Material and Methods Retrospective, HIPAA-compliant, IRB-approved study including 37 patients with RCC treated with image-guided thermal ablation during 2007–2015. TNM stage, RENAL Nephrometry Score, largest tumor diameter, TTV, and ETV were assessed on cross-sectional imaging at baseline and correlated with outcome measurements. The primary outcome was time-to-occurrence of extra-renal metastases and the secondary outcome was progression-free survival (PFS). Correlation was assessed using a Cox regression model and differences in outcomes were shown by Kaplan–Meier plots with significance and odds ratios (OR) calculated by Log-rank test/generalized Wilcoxon and continuity-corrected Woolf logit method. Results Patients with a TTV or ETV > 5 cm3 were more likely to develop distant metastases compared to patients with TTV (OR 6.69, 95% confidence interval [CI] 0.33–134.4, P=0.022) or ETV (OR 8.48, 95% CI 0.42–170.1, P=0.016) 3. Additionally, PFS was significantly worse in patients with larger ETV ( P = 0.039; median PFS 51.87 months vs. 69.97 months). In contrast, stratification by median value of the established, caliper-based measurements showed no significant correlation with outcome parameters. Conclusion ETV, as surrogate of lesion vascularity, is a sensitive imaging biomarker for occurrence of extra-renal metastatic disease and PFS in patients with RCC.
Published: 2020
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45. AP4B1-associated hereditary spastic paraplegia: expansion of phenotypic spectrum related to homozygous p.Thr387fs variant

Author: Piotr Stawiński, Małgorzata Rydzanicz, Rafał Płoski, Anna Biernacka, Robert Śmigiel, Agnieszka Pollak, Hanna Mierzewska, Agnieszka Koppolu, Krzysztof Szczałuba, and Joanna Kosińska
Subjects: Exome sequencing, Male, 0301 basic medicine, Microcephaly, Adolescent, Hereditary spastic paraplegia, Adaptor Protein Complex 4, 030105 genetics & heredity, Biology, AP4B1, 03 medical and health sciences, Epilepsy, Human Genetics • Original Paper, Neurodevelopmental disorder, Intellectual Disability, Genetics, medicine, Spastic, Humans, Adaptor Protein Complex beta Subunits, Genetic Predisposition to Disease, Global developmental delay, Child, Spastic Paraplegia, Hereditary, Homozygote, Genetic Variation, Infant, General Medicine, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Mutation, Female, medicine.symptom
Abstract: Biallelic mutations in the AP4B1 gene, encoding adaptor-related protein complex 4 beta-1 subunit, have been recognized as an important cause of a group of conditions leading to adaptor-related protein complex 4 (AP4)-associated hereditary spastic paraplegia (SPG47). We describe a homozygous, known variant c.1160_1161delCA (p.Thr387fs) that was found in the largest ever group of patients coming from four families. The patients exhibited early hypotonia progressing to spastic paraplegia, microcephaly, epilepsy, and central nervous system (CNS) defects and global developmental delay that are consistent with the nature of SPG47. Our findings expand phenotypic spectrum of SPG47 to include polymorphic seizures, mild/moderate intellectual disability, and intracerebral cysts as well as point to founder mutation in AP4 deficiency disorders in apparently non-consanguineous Polish families without shared ancestry. Electronic supplementary material The online version of this article (10.1007/s13353-020-00552-w) contains supplementary material, which is available to authorized users.
Published: 2020
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46. New phenotypes associated with 3q29 duplication syndrome: Results from the 3q29 registry

Author: Rebecca M Pollak, Emory q, Michael E. Zwick, Michael C Zinsmeister, Jennifer G. Mulle, and Melissa M. Murphy
Subjects: Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, Developmental Disabilities, Population, 030105 genetics & heredity, Article, Young Adult, 03 medical and health sciences, Intellectual Disability, Chromosome Duplication, Intellectual disability, Genetics, medicine, Humans, Registries, Child, Child Behavior Checklist, education, Genetics (clinical), education.field_of_study, business.industry, Middle Aged, medicine.disease, Checklist, Hypotonia, Phenotype, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Cohort, Autism, Female, Chromosomes, Human, Pair 3, Chromosome Deletion, medicine.symptom, business
Abstract: 3q29 duplication syndrome (3q29dup) is a rare genomic disorder caused by a 1.6 Mb duplication (GRCh38 chr3:195,998,000-197,623,000). Case reports indicate the 3q29dup is likely to be pathogenic, but the full range of manifestations is not well understood. We used the 3q29 registry (https://3q29.com) to ascertain 31 individuals with 3q29dup, the largest cohort ever surveyed in a systematic way. For comparison, we ascertained 117 individuals with the reciprocal 3q29 deletion and 64 typically developing controls. We used a custom medical and demographic questionnaire to assess physical and developmental phenotypes, and two standardized instruments, the Social Responsiveness Scale and Child Behavior Checklist/Adult Behavior Checklist, to assess social disability. Participants with 3q29dup report a high rate of problems in the first year of life (80.6%), including feeding problems (55%), failure to gain weight (42%), hypotonia (39%), and respiratory distress (29%). In early childhood, learning problems (71.0%) and seizures (25.8%) are common. Additionally, the rate of self-reported autism spectrum disorder diagnoses (39%) is substantially elevated compared to the general population, suggesting that the 3q29 duplication may be an autism susceptibility locus. This is the most comprehensive description of 3q29dup to date. Our findings can be used to develop evidence-based strategies for early intervention and management of 3q29dup.
Published: 2020
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47. Prognostic significance of the frontal QRS-T angle in patients with AL cardiac amyloidosis

Author: Mony Shuvy, Israel Gotsman, Anna Turyan Medvedovsky, and Arthur Pollak
Subjects: Male, medicine.medical_specialty, 030204 cardiovascular system & hematology, Pericardial effusion, Electrocardiography, 03 medical and health sciences, Amyloid disease, 0302 clinical medicine, Median follow-up, Interquartile range, Internal medicine, medicine, AL amyloidosis, Humans, Immunoglobulin Light-chain Amyloidosis, cardiovascular diseases, 030212 general & internal medicine, business.industry, Amyloidosis, Middle Aged, Prognosis, medicine.disease, Cardiac amyloidosis, Heart failure, cardiovascular system, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies
Abstract: Introduction Cardiac involvement is a leading cause of morbidity and mortality in primary light chain (AL) amyloidosis. The electrocardiographic spatial QRS-T angle reflects changes in the direction of the repolarization sequence and is a powerful predictor of outcome in patients with heart failure. We examined the significance of the frontal QRS-T angle in predicting the clinical outcome in patients with AL cardiac amyloidosis. Methods Forty-three consecutive patients with cardiac involvement of AL amyloidosis were studied. Patients were followed for survival. Results Patient median age was 62 years, 56% were males. After a median follow up of 56 months, 16 out of 43 patients had died (37%). The median QRS-T angle was 102° (interquartile range 35–148). QRS-T angle>102° was associated with increased prevalence of lambda free light chain disease and the presence of a pleural effusion. It was also associated with increased interventricular septum thickness, smaller left ventricle end-diastolic diameter, echocardiographic myocardial sparkling texture, pericardial effusion, elevated NT-Pro-BNP and increased restrictive physiology evident by increased E/A and E/e`. A QRS-T angle>102° was a significant predictor of increased mortality by Kaplan-Meier survival analysis (71.6 ± 11.1% vs. 45.7 ± 11.1%, P = .02). A QRS-T angle>102° was an independent predictor of mortality by Cox regression analysis (HR 3.00, 95% CI 1.01–8.89, P Conclusions The QRS-T angle is associated with indices of advanced amyloid disease and is an independent predictor of survival.
Published: 2020
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48. Outcomes of Radial Versus Femoral Access in Patients With Severe Aortic Stenosis Undergoing Percutaneous Coronary Intervention Prior to Transcatheter Aortic Valve Replacement

Author: Salman, Farhat, Abdallah, El Sabbagh, Mohammed, Al-Hijji, Keniel, Pierre, Nahyr S, Lugo-Fagundo, Yader, Sandoval, Michael S, Gharacholou, Peter M, Pollak, Mandeep, Singh, Mackram F, Eleid, Mohammed, Al-Khouli, David R, Holmes, Mayra, Guerrero, Rajiv, Gulati, Malcolm, Bell, and Charanjit S, Rihal
Subjects: Aged, 80 and over, Male, Stroke, Transcatheter Aortic Valve Replacement, Percutaneous Coronary Intervention, Treatment Outcome, Fluoroscopy, Humans, Female, Aortic Valve Stenosis
Abstract: The safety and feasibility of radial access in patients undergoing percutaneous coronary intervention (PCI) prior to transcatheter aortic valve replacement (TAVR) has not been studied.This study included consecutive patients who underwent PCI within 30 days before TAVR at Mayo Clinic. Vascular access was left to the discretion of the operator. Baseline demographics, procedural data, PCI outcomes, and subsequent transfemoral TAVR outcomes were extracted from patient charts.A total of 331 patients were included in this study, with 107 patients undergoing PCI via radial access (rPCI), and 224 via femoral access (fPCI). Mean age was 80.6 years and 35.6% were females (35.5% rPCI vs 35.3% fPCI). More patients in the fPCI group had previous coronary artery bypass graft surgery (13.1% rPCI vs 34.4% fPCI; P.001). Fluoroscopy time (13.36 minutes vs 18.86 minutes; P.001) and contrast use (115 mL vs 140 mL; P.01) were lower in the rPCI group than in the fPCI group. Crossover rate from radial to femoral was 6.5%. There were more access-site hematomas in the fPCI group (2.8% rPCI vs 14.3% fPCI; P.001), with no statistically significant rate of other access-related complications. There was no difference in stroke, myocardial infarction, cardiac arrest, or unplanned surgery. There was no difference in bleeding or stroke between both groups during subsequent transfemoral TAVR.Radial access for pre-TAVR PCI is feasible and safe and is associated with a lower rate of access-site hematoma. This study supports the increased use of transradial access for pre-TAVR PCI.
Published: 2022

49. Social determinants of health Z-codes and postoperative outcomes after colorectal surgery: A national population-based study

Author: Yolana L.E. Pollak, Jennifer Y. Lee, Syed I. Khalid, Christopher T. Aquina, Dana M. Hayden, and Adán Z. Becerra
Subjects: Male, Postoperative Complications, Social Determinants of Health, Humans, Surgery, Female, General Medicine, Middle Aged, Colorectal Surgery, Colectomy, Retrospective Studies
Abstract: We sought to evaluate the impact of social determinants of health (SDOH) on postoperative outcomes following colorectal surgery.This retrospective cohort study used PearlDiver-Mariner, an all-payer insurance claims database. Patients who underwent colectomy or proctectomy between 2010 and 2020 were included. SDOH were identified using International Classification of Diseases diagnosis codes. Outcomes were compared using multivariable regression models.The 30-day postoperative complication rate among 333,387 patients (mean age, 59 years; 58% female) was 27%. Approximately 5% of patients reported at least one SDOH at baseline. SDOH were not associated with length of stay but were associated with higher odds of 30-day postoperative complications (OR:1.16, 95% CI:1.12-1.20), including urinary tract infection (OR:1.27, 95% CI:1.20-1.35) anastomotic leak (OR:1.22, 95% CI:1.16-1.28), pneumonia (OR:1.19, 95% CI:1.11-1.27), deep vein thrombosis (OR:1.13, 95% CI:1.02-1.23), sepsis (OR:1.12, 95% CI:1.07-1.18), disruption of wound (OR:1.12, 95% CI:1.03-1.21), and acute kidney injury (OR:1.04, 95% CI:0.99-1.10).SDOH Z-codes were associated with worse postoperative complications following colorectal surgery and may help target high-risk patients.
Published: 2022

50. Effects of Testing and Disclosing Ancestry-Specific Genetic Risk for Kidney Failure on Patients and Health Care Professionals: A Randomized Clinical Trial

Author: Girish N. Nadkarni, Kezhen Fei, Michelle A. Ramos, Diane Hauser, Emilia Bagiella, Stephen B. Ellis, Saskia Sanderson, Stuart A. Scott, Tatiana Sabin, Ebony Madden, Richard Cooper, Martin Pollak, Neil Calman, Erwin P. Bottinger, and Carol R. Horowitz
Subjects: Adult, Male, Health Personnel, General Medicine, Disclosure, Middle Aged, Apolipoprotein L1, Black or African American, Hypertension, Humans, Female, Genetic Predisposition to Disease, Genetic Testing, Renal Insufficiency, Chronic
Abstract: Risk variants in the apolipoprotein L1 (APOL1 [OMIM 603743]) gene on chromosome 22 are common in individuals of West African ancestry and confer increased risk of kidney failure for people with African ancestry and hypertension. Whether disclosing APOL1 genetic testing results to patients of African ancestry and their clinicians affects blood pressure, kidney disease screening, or patient behaviors is unknown.To determine the effects of testing and disclosing APOL1 genetic results to patients of African ancestry with hypertension and their clinicians.This pragmatic randomized clinical trial randomly assigned 2050 adults of African ancestry with hypertension and without existing chronic kidney disease in 2 US health care systems from November 1, 2014, through November 28, 2016; the final date of follow-up was January 16, 2018. Patients were randomly assigned to undergo immediate (intervention) or delayed (waiting list control group) APOL1 testing in a 7:1 ratio. Statistical analysis was performed from May 1, 2018, to July 31, 2020.Patients randomly assigned to the intervention group received APOL1 genetic testing results from trained staff; their clinicians received results through clinical decision support in electronic health records. Waiting list control patients received the results after their 12-month follow-up visit.Coprimary outcomes were the change in 3-month systolic blood pressure and 12-month urine kidney disease screening comparing intervention patients with high-risk APOL1 genotypes and those with low-risk APOL1 genotypes. Secondary outcomes compared these outcomes between intervention group patients with high-risk APOL1 genotypes and controls. Exploratory analyses included psychobehavioral factors.Among 2050 randomly assigned patients (1360 women [66%]; mean [SD] age, 53 [10] years), the baseline mean (SD) systolic blood pressure was significantly higher in patients with high-risk APOL1 genotypes vs those with low-risk APOL1 genotypes and controls (137 [21] vs 134 [19] vs 133 [19] mm Hg; P = .003 for high-risk vs low-risk APOL1 genotypes; P = .001 for high-risk APOL1 genotypes vs controls). At 3 months, the mean (SD) change in systolic blood pressure was significantly greater in patients with high-risk APOL1 genotypes vs those with low-risk APOL1 genotypes (6 [18] vs 3 [18] mm Hg; P = .004) and controls (6 [18] vs 3 [19] mm Hg; P = .01). At 12 months, there was a 12% increase in urine kidney disease testing among patients with high-risk APOL1 genotypes (from 39 of 234 [17%] to 68 of 234 [29%]) vs a 6% increase among those with low-risk APOL1 genotypes (from 278 of 1561 [18%] to 377 of 1561 [24%]; P = .10) and a 7% increase among controls (from 33 of 255 [13%] to 50 of 255 [20%]; P = .01). In response to testing, patients with high-risk APOL1 genotypes reported more changes in lifestyle (a subjective measure that included better dietary and exercise habits; 129 of 218 [59%] vs 547 of 1468 [37%]; P .001) and increased blood pressure medication use (21 of 218 [10%] vs 68 of 1468 [5%]; P = .005) vs those with low-risk APOL1 genotypes; 1631 of 1686 (97%) declared they would get tested again.In this randomized clinical trial, disclosing APOL1 genetic testing results to patients of African ancestry with hypertension and their clinicians was associated with a greater reduction in systolic blood pressure, increased kidney disease screening, and positive self-reported behavior changes in those with high-risk genotypes.ClinicalTrials.gov Identifier: NCT02234063.
Published: 2022

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