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1. Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases.

Author

Rosain, Jérémie, Le Voyer, Tom, Liu, Xian, Gervais, Adrian, Polivka, Laura, Cederholm, Axel, Berteloot, Laureline, Parent, Audrey, Pescatore, Alessandra, Spinosa, Ezia, Minic, Snezana, Kiszewski, Ana, Tsumura, Miyuki, Thibault, Chloé, Esnaola Azcoiti, Maria, Martinovic, Jelena, Philippot, Quentin, Khan, Taushif, Marchal, Astrid, Charmeteau-De Muylder, Bénédicte, Bizien, Lucy, Deswarte, Caroline, Hadjem, Lillia, Fauvarque, Marie-Odile, Dorgham, Karim, Eriksson, Daniel, Falcone, Emilia, Puel, Mathilde, Ünal, Sinem, Geraldo, Amyrath, Le Floch, Corentin, Li, Hailun, Rheault, Sylvie, Muti, Christine, Bobrie-Moyrand, Claire, Welfringer-Morin, Anne, Fuleihan, Ramsay, Lévy, Romain, Roelens, Marie, Gao, Liwei, Materna, Marie, Pellegrini, Silvia, Piemonti, Lorenzo, Catherinot, Emilie, Goffard, Jean-Christophe, Fekkar, Arnaud, Sacko-Sow, Aissata, Soudée, Camille, Boucherit, Soraya, Neehus, Anna-Lena, Has, Cristina, Hübner, Stefanie, Blanchard-Rohner, Géraldine, Amador-Borrero, Blanca, Utsumi, Takanori, Taniguchi, Maki, Tani, Hiroo, Izawa, Kazushi, Yasumi, Takahiro, Kanai, Sotaro, Migaud, Mélanie, Aubart, Mélodie, Lambert, Nathalie, Gorochov, Guy, Picard, Capucine, Soudais, Claire, LHonneur, Anne-Sophie, Rozenberg, Flore, Milner, Joshua, Zhang, Shen-Ying, Vabres, Pierre, Trpinac, Dusan, Marr, Nico, Boddaert, Nathalie, Desguerre, Isabelle, Pasparakis, Manolis, Miller, Corey, Poziomczyk, Cláudia, Abel, Laurent, Okada, Satoshi, Jouanguy, Emmanuelle, Cheynier, Rémi, Zhang, Qian, Cobat, Aurélie, Béziat, Vivien, Boisson, Bertrand, Steffann, Julie, Fusco, Francesca, Ursini, Matilde, Hadj-Rabia, Smail, Bodemer, Christine, Bustamante, Jacinta, Luche, Hervé, Puel, Anne, Courtois, Gilles, Bastard, Paul, Landegren, Nils, Anderson, Mark, and Casanova, Jean-Laurent

Subjects
Humans, Interferon Type I, Female, Autoantibodies, Thymus Gland, Child, Incontinentia Pigmenti, Child, Preschool, I-kappa B Kinase, Virus Diseases, Infant, Adult, Adolescent, Young Adult
Abstract

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

Published
2024

2. Machine learning models for predicting blood pressure phenotypes by combining multiple polygenic risk scores.

Author

Hrytsenko, Yana, Shea, Benjamin, Elgart, Michael, Kurniansyah, Nuzulul, Lyons, Genevieve, Morrison, Alanna, Carson, April, Haring, Bernhard, Mitchell, Braxton, Psaty, Bruce, Jaeger, Byron, Gu, C, Kooperberg, Charles, Levy, Daniel, Lloyd-Jones, Donald, Choi, Eunhee, Brody, Jennifer, Smith, Jennifer, Rotter, Jerome, Moll, Matthew, Fornage, Myriam, Simon, Noah, Castaldi, Peter, Casanova, Ramon, Chung, Ren-Hua, Kaplan, Robert, Loos, Ruth, Kardia, Sharon, Rich, Stephen, Redline, Susan, Kelly, Tanika, OConnor, Timothy, Zhao, Wei, Kim, Wonji, Guo, Xiuqing, Ida Chen, Yii-Der, and Sofer, Tamar

Subjects
Humans, Machine Learning, Blood Pressure, Multifactorial Inheritance, Phenotype, Genome-Wide Association Study, Risk Factors, Male, Female, Genetic Predisposition to Disease, Models, Genetic, Hypertension, Middle Aged, Genetic Risk Score
Abstract

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble models performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.

Published
2024

3. The relationship between optimism, MCI, and dementia among postmenopausal women.

Author

Shumaker, Sally, Wactawski-Wende, Jean, Wells, Gretchen, Hayden, Kathleen, Sachs, Bonnie, Gaussoin, Sarah, Brenes, Gretchen, Casanova, Ramon, Chlebowski, Rowan, Chen, Jiu-Chiuan, Luo, Juhua, Rapp, Stephen, and Shadyab, Aladdin

Subjects
LOT-R, MCI, dementia, optimism, pessimism, Humans, Female, Aged, Postmenopause, Cognitive Dysfunction, Cognition Disorders, Optimism, Dementia, Vascular Diseases
Abstract

OBJECTIVES: The relationship between optimism and cognitive functioning is not fully understood. We examined the association of optimism with risk of mild cognitive impairment (MCI) and dementia in the Womens Health Initiative Memory Study (WHIMS). METHODS: Optimism was measured by the Life Orientation Test-Revised (LOT-R) total score, and optimism and pessimism subscales. A panel of experts adjudicated cognitive endpoints based on annual cognitive assessments. We used cox proportional hazard regression models to examine the association of LOT-R total score and optimism and pessimism sub-scores with MCI/dementia. We also examined the relationship between vascular disease, LOT-R total score, optimism and pessimism, and cognition. RESULTS: Mean age was 70.5 (SD = 3.9) years. The sample (N = 7249) was 87% white, and 29.8% of participants had < 12 years of education. Total LOT-R score (HR = 0.96, 95% CI: 0.94, 0.98, p

Published
2023

4. Associations of Accelerometer-Measured Physical Activity and Sedentary Time With All-Cause Mortality by Genetic Predisposition for Longevity.

Author

Posis, Alexander Ivan B, Bellettiere, John, Salem, Rany M, LaMonte, Michael J, Manson, JoAnn E, Casanova, Ramon, LaCroix, Andrea Z, and Shadyab, Aladdin H

Subjects
Public Health, Health Sciences, Behavioral and Social Science, Aging, Basic Behavioral and Social Science, Clinical Research, Prevention, Cardiovascular, Metabolic and endocrine, Good Health and Well Being, Humans, Female, Aged, Longevity, Sedentary Behavior, Genetic Predisposition to Disease, Accelerometry, Exercise, healthy aging, sedentary behavior, women?s health, women’s health, Human Movement and Sports Sciences, Gerontology, Public health, Sports science and exercise, Applied and developmental psychology
Abstract

The goal of this study was to examine associations between accelerometer-measured physical activity (PA) and sedentary time (ST) with mortality by a genetic risk score (GRS) for longevity. Among 5,446 women, (mean [SD]: age, 78.2 [6.6] years), 1,022 deaths were observed during 33,350 person-years of follow-up. Using multivariable Cox proportional hazards models, higher light PA and moderate to vigorous PA were associated with lower mortality across all GRS for longevity categories (low/medium/high; all ptrend < .001). Higher ST was associated with higher mortality (ptrend across all GRS categories < .001). Interaction tests for PA and ST with the GRS were not statistically significant. Findings support the importance of higher PA and lower ST for reducing mortality risk in older women, regardless of genetic predisposition for longevity.

Published
2023

5. Symblepharon in kittens: a retrospective study of 40 kittens and 54 eyes (2002-2022).

Author

Shiraishi, Hikaru, Vernau, Karen, Kim, Soohyun, Good, Kathryn, Hollingsworth, Steven, Sebbag, Lionel, Montgomery, Elizabeth, Surmick, Jennifer, Freeman, Kate, Choi, April, Casanova, M, and Maggs, David

Subjects
Feline herpesvirus, adhesions, conjunctival ulcer, corneal ulcer, ophthalmology, surgery, Cats, Animals, Female, Retrospective Studies, Conjunctiva, Pterygium, Eyelid Diseases, Cat Diseases
Abstract

OBJECTIVES: The aim of this study was to retrospectively evaluate the signalment, treatment, surgical technique and outcomes for feline symblepharon. METHODS: A retrospective medical record review and standardized grading of clinical descriptions and photographs was undertaken. RESULTS: Forty kittens (54 eyes) aged 3-46 weeks had symblepharon of five types in various combinations: eyelid deformation (24 kittens; 32 eyes); ankyloblepharon (four kittens; four eyes); conjunctiva-to-conjunctiva (11 kittens; 12 eyes); third eyelid-to-conjunctiva (24 kittens; 29 eyes); and corneoconjunctival adhesions (14 kittens; 16 eyes). At initial presentation, 23 (43%) eyes were affected by one type of symblepharon, 25 (46%) eyes by two types and six (11%) eyes by three types; 11 (20%) corneas were ulcerated. Twenty-four (44%) eyes of 18 (45%) kittens were managed medically. Surgery was performed under general anesthesia/sedation (30 occasions) or topical anesthesia (21 occasions) on 30 (56%) eyes of 22 kittens; 12 eyes (40%) underwent multiple surgeries. Four techniques were commonly employed: separation of conjunctival-to-conjunctival adhesions ± eyelid margins (14 eyes); resection of third eyelid adhesions ± temporary tacking of the third eyelid (modified Arlts pterygium technique; 18 eyes); en bloc resection of the third eyelid (two eyes); and separation of corneoconjunctival adhesions (14 eyes). Median duration of follow-up was 55 days (range 1-1051). Median symblepharon grade in kittens treated surgically improved for all types except corneoconjunctival symblepharon. Median symblepharon grade in kittens receiving medical management remained the same or improved. Corneoconjunctival symblepharon opacity decreased for eyes treated surgically but increased for eyes treated medically. Three eyes were enucleated due to complications of corneoconjunctival symblepharon. At final presentation, symblepharon persisted in 46 (85%) eyes; however, menace response was evident in 13/16 eyes and dazzle reflex in 23/23 eyes. CONCLUSIONS AND RELEVANCE: Symblepharon is a heterogeneous group of conditions with diverse anatomic involvement, clinical appearance and impact, optimal treatment and prognosis for vision.

Published
2023

6. Imagining Improved Interactions: Patients Designs To Address Implicit Bias.

Author

Yang, Connie, Coney, Leslie, Mohanraj, Deepthi, Casanova-Perez, Reggie, Bascom, Emily, Efrem, Niyat, Garcia, Joseph, Sabin, Janice, Pratt, Wanda, Weibel, Nadir, and Hartzler, Andrea

Subjects
Female, Humans, Bias, Implicit, Sexual and Gender Minorities, Delivery of Health Care, Sexual Behavior, Gender Identity
Abstract

Implicit biases may negatively influence healthcare providers behaviors toward patients from historically marginalized communities, impacting providers communication style, clinical decision-making, and delivery of quality care. Existing interventions to mitigate negative experiences of implicit biases are primarily designed to increase recognition and management of stereotypes and prejudices through provider-facing tools and resources. However, there is a gap in understanding and designing interventions from patient perspectives. We conducted seven participatory co-design workshops with 32 Black, Indigenous, People of Color (BIPOC), Lesbian, Gay, Bisexual, Transgender, Queer/Questioning (LGBTQ+), and Queer, Transgender, Black, Indigenous, People of Color (QTBIPOC) individuals to design patient-centered interventions that help them address and recover from provider implicit biases in primary care. Participants designed four types of solutions: accountability measures, real-time correction, patient enablement tools, and provider resources. These informatics interventions extend the research on implicit biases in healthcare through inclusion of valuable, firsthand patient perspectives and experiences.

Published
2023

7. Maybe they had a bad day: how LGBTQ and BIPOC patients react to bias in healthcare and struggle to speak out.

Author

Apodaca, Calvin, Casanova-Perez, Reggie, Bascom, Emily, Mohanraj, Deepthi, Lane, Cezanne, Vidyarthi, Drishti, Beneteau, Erin, Sabin, Janice, Pratt, Wanda, Weibel, Nadir, and Hartzler, Andrea

Subjects
bias, implicit, interview, patient harm, perceived discrimination, sexism, sexual and gender minorities, Humans, Female, Male, Healthcare Disparities, Health Promotion, Sexual and Gender Minorities, Gender Identity, Sexual Behavior
Abstract

OBJECTIVE: People who experience marginalization, including Black, Indigenous, People of Color (BIPOC) and Lesbian, Gay, Bisexual, Transgender, Queer, Plus (ie, all other marginalized genders and sexual orientations) people (LGBTQ+) experience discrimination during healthcare interactions, which negatively impacts patient-provider communication and care. Yet, scarce research examines the lived experience of unfair treatment among patients from marginalized groups to guide patient-centered tools that improve healthcare equity. MATERIALS AND METHODS: We interviewed 25 BIPOC and/or LGBTQ+ people about their experiences of unfair treatment and discrimination when visiting healthcare providers. Through thematic analysis, we describe participants immediate reactions and longer-term consequences of those experiences. RESULTS: We identified 4 ways that participants reacted to discrimination in the moment: Fighting, Fleeing, Excusing, and Working Around Bias. Long-term consequences reflect 6 ways they coped: Delaying or Avoiding Care, Changing Healthcare Providers, Self-prescribing, Covering Behaviors, Experiencing Health Complications, and Mistrusting Healthcare Institutions. DISCUSSION: By describing how patients react to experiences of unfair treatment and discrimination, our findings enhance the understanding of health disparities as patients cope and struggle to speak out.To combat these problems, we identify 3 future directions for informatics interventions that improve provider behavior, support patient advocacy, and address power dynamics in healthcare. CONCLUSIONS: BIPOC and LGBTQ+ patients perspectives on navigating unfair treatment and discrimination in healthcare offers critical insight into their experiences and long-term consequences of those experiences. Understanding the circumstances and consequences of unfair treatment, discrimination, and the impact of bias through this patient-centered lens is crucial to inform informatics technologies that promote health equity.

Published
2022

8. Normal Corneal Thickness and Endothelial Cell Density in Rhesus Macaques (Macaca mulatta)

Author

Casanova, M Isabel, Young, Laura J, Park, Sangwan, Kim, Soohyun, Roszak, Karolina, Leonard, Brian C, Blandino, Andrew, Motta, Monica J, Yiu, Glenn, Li, Jennifer Y, Moshiri, Ala, and Thomasy, Sara M

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Eye Disease and Disorders of Vision, Adolescent, Adult, Aged, Animals, Body Weight, Child, Child, Preschool, Cornea, Corneal Dystrophies, Hereditary, Endothelial Cells, Female, Humans, Infant, Macaca mulatta, Male, Reproducibility of Results, Young Adult, cornea, corneal thickness, corneal endothelial cells, nonhuman primate, specular microscopy, Biomedical Engineering, Opthalmology and Optometry, Ophthalmology and optometry
Abstract

PurposeTo define the normal range of central corneal thickness (CCT) and corneal endothelial cell density (ECD) in rhesus macaques (Macaca mulatta) and the effects of age, body weight, sex, and intraocular pressure (IOP) on these parameters.MethodsOphthalmic examinations were performed on 144 rhesus macaques without anterior segment pathology. The CCT was measured via ultrasound pachymetry (USP) and specular microscopy, and the ECD was semiautomatically and manually counted using specular microscopy. Rebound tonometry was used to measure IOP. Linear regression and mixed-effects linear regression models were used to evaluate the effects of age, body weight, sex, and IOP on CCT and ECD.ResultsWe included 98 females and 46 males with an age range of 0.2 to 29.4 years. The mean CCT by USP and specular microscopy were 483 ± 39 and 463 ± 33 µm, respectively, and were statistically different (P < 0.001). The ECDs were 2717 ± 423 and 2747 ± 438 cells/mm2 by semiautomated and manual analysis, respectively. Corneal endothelial degeneration was identified in one aged rhesus macaque.ConclusionsThe mean USP and specular microscopy CCT values differed significantly, whereas the semiautomatic and manual ECD did not. The CCT was associated with the IOP and sex, whereas the ECD was associated with body weight and age (P < 0.05). As in humans, corneal disease in rhesus macaques is uncommon.Translational relevanceEstablishing reference values is fundamental to use rhesus macaques as a model for corneal disease or to identify toxicity in studies of ocular drugs or devices.

Published
2022

9. Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series

Author

Tassanakijpanich, Nattaporn, McKenzie, Forrest J, McLennan, Yingratana A, Makhoul, Elisabeth, Tassone, Flora, Jasoliya, Mittal J, Romney, Christopher, Petrasic, Ignacio Cortina, Napalinga, Kaye, Buchanan, Caroline B, Hagerman, Paul, Hagerman, Randi, and Casanova, Emily L

Subjects
Biological Sciences, Genetics, Brain Disorders, Rare Diseases, Intellectual and Developmental Disabilities (IDD), Fragile X Syndrome, Pediatric, Child, Preschool, Ehlers-Danlos Syndrome, Female, Fragile X Mental Retardation Protein, Heterozygote, Humans, Male, Phenotype, Trinucleotide Repeat Expansion, genetic predisposition to disease, genetics, medical, human genetics, gene expression, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract

BackgroundWhile an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 (FMR1) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55-200 repeats) of the FMR1 gene may be overlooked.ObjectiveTo report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype.MethodsWe collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS.ResultsFive cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity.ConclusionBoth hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.

Published
2022

10. A Window Into Mental Health: Developing and Pilot-Testing a Mental Health Promotion Intervention for Mexican Immigrants Through the Ventanilla de Salud Program

Author

Rodríguez, Delia Lilian Martínez, Vázquez, Tonatiuh González, Serrano, Margarita Márquez, de Groot, Mary, Fernandez, Alicia, and Casanova, Ines Gonzalez

Subjects
Health Services and Systems, Public Health, Health Sciences, Clinical Research, Mental Health, Mind and Body, Behavioral and Social Science, Prevention, Mental health, Good Health and Well Being, Adaptation, Psychological, Adult, Emigrants and Immigrants, Female, Health Promotion, Humans, Longitudinal Studies, Male, United States, Mexican immigrants in the United States, community based mental health, coping strategies, health promotion, mental health, protective factors, Public Health and Health Services, Health services and systems, Public health
Abstract

BackgroundMexican immigrants in the United States face mental health challenges, disparities, and limited access to healthcare; however, mental health promotion efforts specifically targeting this population have been insufficient. The objective of this study was to develop and test a mental health promotion intervention based on protective mental health factors and coping strategies for Mexican immigrants recruited through a free, consulate-based program in Atlanta.Material and methodsWorking with the Ventanilla de Salud program, we conducted a longitudinal study in three phases: formative research and design, pre-intervention assessment and post-implementation evaluation. The intervention was designed based on the health promotion model and interviews with stakeholders. Qualitative information was collected by semi-structured interviews with participants before and after the intervention. Quantitative outcomes were knowledge about protective factors and coping mechanisms, and psychosocial distress. Differences were assessed using the Wilcoxon non-parametrical test. Intent-to-treat analysis was conducted with all participants who signed the informed consent (carrying last observation forward), and a complete case analysis was conducted with those who attended at least 70% of the sessions and completed the post- implementation evaluation.ResultsTwenty-five participants were enrolled in the intervention. Mean age was 38 years, and the majority were women. Only nine participants attended at least 70% of the sessions and completed the final evaluation. Men, those who did not complete high school, and workers in service or construction jobs were more likely to drop out. Knowledge about protective factors [pre- vs. post-intervention median (inter-quartile range) = 111 (100, 120) vs. 115 (100, 124)] and coping mechanisms [96 (85, 104) vs. 99 (90, 110)], as well as psychosocial distress [3 (2, 3) vs. 2 (2, 3)] improved after the intervention in both intent-to treat and complete case analyses (p < 0.05). Qualitative results also support improvements in targeted protective factors.DiscussionThe intervention was successful in improving psychological distress among Mexican immigrants. These results support the implementation of evidence-based mental health promotion interventions among Mexican immigrants via free and familiar programs. A limitation was the high attrition; future studies should explore approaches to improve retention in this population.

Published
2022

11. Ocular morphologic traits in the American Cocker Spaniel may confer primary angle closure glaucoma susceptibility

Author

Park, Sangwan, Casanova, M Isabel, Bannasch, Danika L, Daley, Nicole L, Kim, Soohyun, Kuchtey, John, Gomes, Filipe Espinheira, Leonard, Brian C, Good, Kathryn L, Martins, Bianca da C, Murphy, Christopher J, and Thomasy, Sara M

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Neurodegenerative, Prevention, Aging, Clinical Research, Neurosciences, Eye Disease and Disorders of Vision, 2.1 Biological and endogenous factors, Aetiology, Eye, Dogs, Humans, Animals, Female, Glaucoma, Angle-Closure, Genome-Wide Association Study, Plant Breeding, Iris, Glaucoma, Open-Angle, Acute Disease, Intraocular Pressure
Abstract

Acute primary angle closure glaucoma is a potentially blinding ophthalmic emergency requiring prompt treatment to lower the elevated intraocular pressure in humans and dogs. The PACG in most of canine breeds is epidemiologically similar to humans with older and female patients overrepresented with the condition. The American Cocker Spaniel (ACS) is among the most common breeds observed with PACG development in dogs. This study initially sought to identify genetic risk factors to explain the high prevalence of PACG in ACSs by using a case-control breed-matched genome-wide association study. However, the GWAS failed to identify candidate loci associated with PACG in this breed. This study then assessed intrinsic ocular morphologic traits that may relate to PACG susceptibility in this breed. Normal ACSs without glaucoma have a crowded anterior ocular segment and narrow iridocorneal angle and ciliary cleft, which is consistent with anatomical risk factors identified in humans. The ACSs showed unique features consisting of posterior bowing of iris and longer iridolenticular contact, which mirrors reverse pupillary block and pigment dispersion syndrome in humans. The ACS could hold potential to serve as an animal model of naturally occurring PACG in humans.

Published
2022

12. Predicting Incident Heart Failure in Women With Machine Learning: The Women’s Health Initiative Cohort

Author

Tison, Geoffrey H, Avram, Robert, Nah, Gregory, Klein, Liviu, Howard, Barbara V, Allison, Matthew A, Casanova, Ramon, Blair, Rachael H, Breathett, Khadijah, Foraker, Randi E, Olgin, Jeffrey E, and Parikh, Nisha I

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Aging, Prevention, Cardiovascular, Heart Disease, Good Health and Well Being, Aged, Female, Follow-Up Studies, Forecasting, Heart Failure, Humans, Incidence, Machine Learning, Middle Aged, ROC Curve, Risk Assessment, Risk Factors, United States, Women's Health, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundHeart failure (HF) is a leading cause of cardiac morbidity among women, whose risk factors differ from those in men. We used machine-learning approaches to develop risk- prediction models for incident HF in a cohort of postmenopausal women from the Women's Health Initiative (WHI).MethodsWe used 2 machine-learning methods-Least Absolute Shrinkage and Selection Operator (LASSO) and Classification and Regression Trees (CART)-to perform variable selection on 1227 baseline WHI variables for the primary outcome of incident HF. These variables were then used to construct separate Cox proportional hazard models, and we compared these results, using receiver-operating characteristic (ROC) curve analysis, against a comparator model built using variables from the Atherosclerosis Risk in Communities (ARIC) HF prediction model. We analyzed 43,709 women who had 2222 incident HF events; median follow-up was 14.3 years.ResultsLASSO selected 10 predictors, and CART selected 11 predictors. The highest correlation between selected variables was 0.46. In addition to selecting well-established predictors such as age, myocardial infarction, and smoking, novel predictors included physical function, number of pregnancies, number of previous live births and age at menopause. In ROC analysis, the CART-derived model had the highest C-statistic of 0.83 (95% confidence interval [CI], 0.81-0.85), followed by LASSO 0.82 (95% CI, 0.81-0.84) and ARIC 0.73 (95% CI, 0.70-0.76).ConclusionsMachine-learning approaches can be used to develop HF risk-prediction models that can have better discrimination compared with an established HF risk model and may provide a basis for investigating novel HF predictors.

Published
2021

13. Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

Author

Asano, Takaki, Khourieh, Joëlle, Zhang, Peng, Rapaport, Franck, Spaan, András N, Li, Juan, Lei, Wei-Te, Pelham, Simon J, Hum, David, Chrabieh, Maya, Han, Ji Eun, Guérin, Antoine, Mackie, Joseph, Gupta, Sudhir, Saikia, Biman, Baghdadi, Jamila EI, Fadil, Ilham, Bousfiha, Aziz, Habib, Tanwir, Marr, Nico, Ganeshanandan, Luckshman, Peake, Jane, Droney, Luke, Williams, Andrew, Celmeli, Fatih, Hatipoglu, Nevin, Ozcelik, Tayfun, Picard, Capucine, Abel, Laurent, Tangye, Stuart G, Boisson-Dupuis, Stéphanie, Zhang, Qian, Puel, Anne, Béziat, Vivien, Casanova, Jean-Laurent, and Boisson, Bertrand

Subjects
Rare Diseases, Genetics, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Alleles, Alternative Splicing, Child, Child, Preschool, Codon, Nonsense, Evolution, Molecular, Family, Female, Frameshift Mutation, Genes, Dominant, Genetics, Population, HEK293 Cells, Humans, Infant, Infant, Newborn, Job Syndrome, Male, Middle Aged, Mutation, Pedigree, Protein Biosynthesis, RNA, Messenger, STAT3 Transcription Factor, Medical and Health Sciences, Immunology
Abstract

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.

Published
2021

14. Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Author

Bastard, Paul, Orlova, Elizaveta, Sozaeva, Leila, Lévy, Romain, James, Alyssa, Schmitt, Monica M, Ochoa, Sebastian, Kareva, Maria, Rodina, Yulia, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Neehus, Anna-Lena, Shaw, Elana, Migaud, Mélanie, Bizien, Lucy, Ekwall, Olov, Berg, Stefan, Beccuti, Guglielmo, Ghizzoni, Lucia, Thiriez, Gérard, Pavot, Arthur, Goujard, Cécile, Frémond, Marie-Louise, Carter, Edwin, Rothenbuhler, Anya, Linglart, Agnès, Mignot, Brigite, Comte, Aurélie, Cheikh, Nathalie, Hermine, Olivier, Breivik, Lars, Husebye, Eystein S, Humbert, Sébastien, Rohrlich, Pierre, Coaquette, Alain, Vuoto, Fanny, Faure, Karine, Mahlaoui, Nizar, Kotnik, Primož, Battelino, Tadej, Podkrajšek, Katarina Trebušak, Kisand, Kai, Ferré, Elise MN, DiMaggio, Thomas, Rosen, Lindsey B, Burbelo, Peter D, McIntyre, Martin, Kann, Nelli Y, Shcherbina, Anna, Pavlova, Maria, Kolodkina, Anna, Holland, Steven M, Zhang, Shen-Ying, Crow, Yanick J, Notarangelo, Luigi D, Su, Helen C, Abel, Laurent, Anderson, Mark S, Jouanguy, Emmanuelle, Neven, Bénédicte, Puel, Anne, Casanova, Jean-Laurent, and Lionakis, Michail S

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Infectious Diseases, Rare Diseases, Pneumonia, Pneumonia & Influenza, Autoimmune Disease, Clinical Research, Lung, Adolescent, Adult, Autoantibodies, COVID-19, Child, Female, Humans, Interferon Type I, Male, Middle Aged, Polyendocrinopathies, Autoimmune, SARS-CoV-2, Young Adult, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

Published
2021

15. Broken down by bias: Healthcare biases experienced by BIPOC and LGBTQ+ patients.

Author

Casanova-Perez, Reggie, Apodaca, Calvin, Bascom, Emily, Mohanraj, Deepthi, Lane, Cezanne, Vidyarthi, Drishti, Beneteau, Erin, Sabin, Janice, Pratt, Wanda, Weibel, Nadir, and Hartzler, Andrea

Subjects
Bias, Female, Health Promotion, Healthcare Disparities, Humans, Sexual Behavior, Sexual and Gender Minorities
Abstract

Bias toward historically marginalized patients affects patient-provider interactions and can lead to lower quality of care and poor health outcomes for patients who are Black, Indigenous, People of Color (BIPOC) and Lesbian, Gay, Bisexual, Transgender and Gender Diverse (LGBTQ+). We gathered experiences with biased healthcare interactions and suggested solutions from 25 BIPOC and LGBTQ+ people. Through qualitative thematic analysis of interviews, we identified ten themes. Eight themes reflect the experience of bias: Transactional Care, Power Inequity, Communication Casualties, Bias-Embedded Medicine, System-level problems, Bigotry in Disguise, Fight or Flight, and The Aftermath. The remaining two themes reflect strategies for improving those experiences: Solutions and Good Experiences. Characterizing these themes and their interconnections is crucial to design effective informatics solutions that can address biases operating in clinical interactions with BIPOC and LGBTQ+ patients, improve the quality of patient-provider interactions, and ultimately promote health equity.

Published
2021

16. Evolution of ocular defects in infant macaques following in utero zika virus infection

Author

Yiu, Glenn, Thomasy, Sara M, Casanova, M Isabel, Rusakevich, Alexander M, Keesler, Rebekah I, Watanabe, Jennifer, Usachenko, Jodie, Singapuri, Anil, Ball, Erin E, Bliss-Moreau, Eliza, Guo, Wendi, Webster, Helen, Singh, Tulika, Permar, Sallie R, Ardeshir, Amir, Coffey, Lark L, and Van Rompay, Koen KA

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Rare Diseases, Infectious Diseases, Pregnancy, Congenital Structural Anomalies, Perinatal Period - Conditions Originating in Perinatal Period, Eye Disease and Disorders of Vision, Neurosciences, Pediatric, Vector-Borne Diseases, Biodefense, Women's Health, Emerging Infectious Diseases, 2.1 Biological and endogenous factors, Reproductive health and childbirth, Eye, Good Health and Well Being, Animals, Blood-Retinal Barrier, Female, Macaca, Macaca mulatta, Pregnancy Complications, Infectious, Prenatal Exposure Delayed Effects, Retina, Retinal Degeneration, Retinal Ganglion Cells, Virus Replication, Zika Virus, Zika Virus Infection, Immunology, Neurodevelopment, Ophthalmology, Retinopathy, Biomedical and clinical sciences, Health sciences
Abstract

Congenital Zika syndrome (CZS) is associated with microcephaly and various neurological, musculoskeletal, and ocular abnormalities, but the long-term pathogenesis and postnatal progression of ocular defects in infants are not well characterized. Rhesus macaques are superior to rodents as models of CZS because they are natural hosts of the virus and share similar immune and ocular characteristics, including blood-retinal barrier characteristics and the unique presence of a macula. Using a previously described model of CZS, we infected pregnant rhesus macaques with Zika virus (ZIKV) during the late first trimester and characterized postnatal ocular development and evolution of ocular defects in 2 infant macaques over 2 years. We found that one of them exhibited colobomatous chorioretinal atrophic lesions with macular and vascular dragging as well as retinal thinning caused by loss of retinal ganglion neuron and photoreceptor layers. Despite these congenital ocular malformations, axial elongation and retinal development in these infants progressed at normal rates compared with healthy animals. The ZIKV-exposed infants displayed a rapid loss of ZIKV-specific antibodies, suggesting the absence of viral replication after birth, and did not show any behavioral or neurological defects postnatally. Our findings suggest that ZIKV infection during early pregnancy can impact fetal retinal development and cause congenital ocular anomalies but does not appear to affect postnatal ocular growth.

Published
2020

17. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

Author

Béziat, Vivien, Tavernier, Simon J, Chen, Yin-Huai, Ma, Cindy S, Materna, Marie, Laurence, Arian, Staal, Jens, Aschenbrenner, Dominik, Roels, Lisa, Worley, Lisa, Claes, Kathleen, Gartner, Lisa, Kohn, Lisa A, De Bruyne, Marieke, Schmitz-Abe, Klaus, Charbonnier, Louis-Marie, Keles, Sevgi, Nammour, Justine, Vladikine, Natasha, Maglorius Renkilaraj, Majistor Raj Luxman, Seeleuthner, Yoann, Migaud, Mélanie, Rosain, Jérémie, Jeljeli, Mohamed, Boisson, Bertrand, Van Braeckel, Eva, Rosenfeld, Jill A, Dai, Hongzheng, Burrage, Lindsay C, Murdock, David R, Lambrecht, Bart N, Avettand-Fenoel, Véronique, Vogel, Tiphanie P, Undiagnosed Diseases Network, Esther, Charles R, Haskologlu, Sule, Dogu, Figen, Ciznar, Peter, Boutboul, David, Ouachée-Chardin, Marie, Amourette, Jean, Lebras, Marie-Noëlle, Gauvain, Clément, Tcherakian, Colas, Ikinciogullari, Aydan, Beyaert, Rudi, Abel, Laurent, Milner, Joshua D, Grimbacher, Bodo, Couderc, Louis-Jean, Butte, Manish J, Freeman, Alexandra F, Catherinot, Émilie, Fieschi, Claire, Chatila, Talal A, Tangye, Stuart G, Uhlig, Holm H, Haerynck, Filomeen, Casanova, Jean-Laurent, and Puel, Anne

Subjects
Undiagnosed Diseases Network, Th2 Cells, Cells, Cultured, Cell Membrane, Fibroblasts, Humans, C-Reactive Protein, Cytokines, Pedigree, Genetics, Population, Up-Regulation, Kinetics, Genes, Dominant, Phenotype, Mutation, Alleles, Models, Biological, Adolescent, Middle Aged, Child, Female, Male, Cytokine Receptor gp130, Young Adult, HEK293 Cells, Job Syndrome, Loss of Function Mutation, Cells, Cultured, Genetics, Population, Genes, Dominant, Models, Biological, Medical and Health Sciences, Immunology
Abstract

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Published
2020

18. Factors Associated With Large Improvements in Health-Related Quality of Life in Patients With Atrial Fibrillation

Author

Steinberg, Benjamin A, Holmes, DaJuanicia N, Pieper, Karen, Allen, Larry A, Chan, Paul S, Ezekowitz, Michael D, Freeman, James V, Fonarow, Gregg C, Gersh, Bernard J, Hylek, Elaine M, Kowey, Peter R, Mahaffey, Kenneth W, Naccarelli, Gerald, Reiffel, James, Singer, Daniel E, Peterson, Eric D, Piccini, Jonathan P, Mendelson, R, Nahhas, A, Neutel, J, Padanilam, B, Pan, D, Poock, J, Raffetto, J, Greengold, R, Roan, P, Saba, F, Sackett, M, Schneider, R, Seymour, Z, Shanes, J, Shoemaker, J, Simms, V, Smiley, N, Smith, D, Snipes, C, Sotolongo, R, Staniloae, C, Stoltz, S, Suresh, DP, Tak, T, Tannenbaum, A, Turk, S, Vora, K, Randhawa, P, Zebrack, J, Silva, E, Riley, E, Weinstein, D, Vasiliauskas, T, Goldbarg, S, Hayward, D, Yarlagadda, C, Laurion, D, Osunkoya, A, Burns, R, Castor, T, Spiller, D, Luttman, C, Anton, S, McGarvey, J, Guthrie, R, Deriso, G, Flood, R, Fleischer, L, Fierstein, JS, Aggarwal, R, Jacobs, G, Adjei, N, Akyea-Djamson, A, Alfieri, A, Bacon, J, Bedwell, N, Berger, P, Berry, J, Bhagwat, R, Bloom, S, Boccalandro, F, Capo, J, Kapadia, S, Casanova, R, Morriss III, JE, Christensen, T, Elsen, J, Farsad, R, Fox, D, Frandsen, B, Gelernt, M, Gill, S, Grubb, S, Hall, C, Harris, H, Hotchkiss, D, Ip, J, Jaffrani, N, Jones, A, Kazmierski, J, Waxman, F, Kneller, GL, and Labroo, A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Heart Disease, Substance Misuse, Genetics, Health Services, Cardiovascular, Clinical Research, Good Health and Well Being, Aged, Aged, 80 and over, Anti-Arrhythmia Agents, Atrial Fibrillation, Catheter Ablation, Comorbidity, Electric Countershock, Female, Health Status, Heart Rate, Humans, Male, Outpatients, Quality of Life, Recovery of Function, Registries, Risk Factors, Time Factors, Treatment Outcome, United States, ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) Investigators and Patients, atrial fibrillation, cardiac resynchronization therapy, health status, patient-reported outcomes, quality of life, Cardiorespiratory Medicine and Haematology, Medical Physiology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences, Medical physiology
Abstract

BackgroundAtrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described.MethodsWe assessed factors associated with a 1-year increase in the Atrial Fibrillation Effect on Quality-of-Life score of 1 SD (≥18 points; 3× clinically important difference), among outpatients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I registry.ResultsOverall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 versus 74, P=0.3), equally likely to be female (44% versus 48%, P=0.3), but more likely to have newly diagnosed AF at baseline (18% versus 8%; P=0.0004), prior antiarrhythmic drug use (52% versus 40%, P=0.005), baseline antiarrhythmic drug use (34.8% versus 26.8%, P=0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% versus 2.0%, P=0.003; cardioversion: 12.2% versus 5.9%, P=0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR, 2.41; P=0.01) and increased baseline diastolic blood pressure (adjusted OR, 1.23 per 10-point increase and >65 mm Hg; P=0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/transient ischemic attack, chronic obstructive pulmonary disease, and peripheral arterial disease were less likely to improve (P

Published
2020

19. Low Dose Carbon Monoxide Exposure in Idiopathic Pulmonary Fibrosis Produces a CO Signature Comprised of Oxidative Phosphorylation Genes.

Author

Casanova, Nancy, Zhou, Tong, Gonzalez-Garay, Manuel, Rosas, Ivan, Goldberg, Hilary, Ryter, Stefan, Collard, Harold, El-Chemaly, Souheil, Flaherty, Kevin, Hunninghake, Gary, Lasky, Joseph, Lederer, David, Machado, Roberto, Martinez, Fernando, Noth, Imre, Raghu, Ganesh, Choi, Augustine, and Garcia, Joe

Subjects
Administration, Inhalation, Aged, Carbon Monoxide, Case-Control Studies, Dose-Response Relationship, Drug, Female, Gene Expression Profiling, Gene Expression Regulation, Genetic Markers, Humans, Idiopathic Pulmonary Fibrosis, Leukocytes, Mononuclear, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Oxidative Phosphorylation, Precision Medicine, Transcriptome, Treatment Outcome, Up-Regulation
Abstract

Compelling preclinical studies indicate that low-dose carbon monoxide (CO) abrogates experimental lung fibrosis. We recently reported the results of a multicenter, double-blinded, clinical trial of inhaled CO in patients with idiopathic pulmonary fibrosis (IPF). Identifying no significantly changes in metalloproteinase-7 (MMP7) serum concentration, or secondary endpoints of physiologic measurements, hospitalization, death, or patient-reported outcomes. In the present study, we evaluated the effect of low dose CO exposure (100-200 ppm) for 12 weeks on genome-wide gene expression in peripheral blood mononuclear cells (PBMC) derived from these IPF study subjects. We conducted transcriptome profiling on 38 IPF subjects with time points available at 0, 12, and 24 weeks. Total RNA isolated from PBMCs was hybridized onto the Affymetrix Human Gene 2.0 ST Array. We identified 621 genes significantly upregulated in the 24-week CO exposed group compared with the 12-week. Pathway analysis demonstrated association with Oxidative Phosphorylation (adjusted P

Published
2019

20. An essential role for the Zn2+ transporter ZIP7 in B cell development

Author

Anzilotti, Consuelo, Swan, David J, Boisson, Bertrand, Deobagkar-Lele, Mukta, Oliveira, Catarina, Chabosseau, Pauline, Engelhardt, Karin R, Xu, Xijin, Chen, Rui, Alvarez, Luis, Berlinguer-Palmini, Rolando, Bull, Katherine R, Cawthorne, Eleanor, Cribbs, Adam P, Crockford, Tanya L, Dang, Tarana Singh, Fearn, Amy, Fenech, Emma J, de Jong, Sarah J, Lagerholm, B Christoffer, Ma, Cindy S, Sims, David, van den Berg, Bert, Xu, Yaobo, Cant, Andrew J, Kleiner, Gary, Leahy, T Ronan, de la Morena, M Teresa, Puck, Jennifer M, Shapiro, Ralph S, van der Burg, Mirjam, Chapman, J Ross, Christianson, John C, Davies, Benjamin, McGrath, John A, Przyborski, Stefan, Santibanez Koref, Mauro, Tangye, Stuart G, Werner, Andreas, Rutter, Guy A, Padilla-Parra, Sergi, Casanova, Jean-Laurent, Cornall, Richard J, Conley, Mary Ellen, and Hambleton, Sophie

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Prevention, Genetics, Brain Disorders, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Agammaglobulinemia, Animals, B-Lymphocytes, Cation Transport Proteins, Child, Preschool, Cytosol, Disease Models, Animal, Endoplasmic Reticulum, Female, Gene Expression Profiling, Humans, Infant, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Pedigree, Zinc, Immunology, Biochemistry and cell biology
Abstract

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

Published
2019

21. Patterns of FIRST recurrence of stage IIIC1 endometrial cancer with no PARAAORTIC nodal assessment.

Author

Aloisi, Alessia, Casanova, João, Tseng, Jill, Seader, Kristina, Nguyen, Nancy, Alektiar, Kaled, Makker, Vicky, Chiang, Sarah, Soslow, Robert, Leitao, Mario, and Abu-Rustum, Nadeem

Subjects
Endometrial cancer, ITC, Isolated tumor cells, Recurrence, Stage IIIC1, Adult, Aged, Aged, 80 and over, Endometrial Neoplasms, Female, Humans, Lymph Nodes, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Retrospective Studies
Abstract

OBJECTIVE: To assess the rates and distribution of first recurrence in patients with FIGO stage IIIC1 endometrial cancer (EC) who did not undergo paraaortic dissection at surgical staging. METHODS: We retrospectively selected all (n = 207) stage IIIC1 patients treated at a single institution from 5/1993-1/2017. Sites of first recurrence were identified, disease-free (DFS) and overall survival (OS) calculated, multivariate logistic regression performed to identify factors associated with recurrence. RESULTS: Three-year DFS and OS were 66.5% and 85.7%, respectively. The most common histology was endometroid (64.2%). Three-year DFS was 81% (SE±3.8%) endometrioid vs. 39.5% (SE±6.6%) non-endometrioid (P

Published
2018

22. Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons

Author

Bolze, Alexandre, Boisson, Bertrand, Bosch, Barbara, Antipenko, Alexander, Bouaziz, Matthieu, Sackstein, Paul, Chaker-Margot, Malik, Barlogis, Vincent, Briggs, Tracy, Colino, Elena, Elmore, Aurora C, Fischer, Alain, Genel, Ferah, Hewlett, Angela, Jedidi, Maher, Kelecic, Jadranka, Krüger, Renate, Ku, Cheng-Lung, Kumararatne, Dinakantha, Lefevre-Utile, Alain, Loughlin, Sam, Mahlaoui, Nizar, Markus, Susanne, Garcia, Juan-Miguel, Nizon, Mathilde, Oleastro, Matias, Pac, Malgorzata, Picard, Capucine, Pollard, Andrew J, Rodriguez-Gallego, Carlos, Thomas, Caroline, Von Bernuth, Horst, Worth, Austen, Meyts, Isabelle, Risolino, Maurizio, Selleri, Licia, Puel, Anne, Klinge, Sebastian, Abel, Laurent, and Casanova, Jean-Laurent

Subjects
Clinical Research, Human Genome, Pediatric, Genetics, 2.1 Biological and endogenous factors, Aetiology, 5' Untranslated Regions, Exons, Female, Founder Effect, Heterozygote, Humans, Immunologic Deficiency Syndromes, Male, Mutation, Penetrance, Primary Immunodeficiency Diseases, Protein Biosynthesis, RNA Splicing, Receptors, Laminin, Ribosomal Proteins, Spleen, isolated congenital asplenia, spleen, incomplete penetrance, ribosomopathy, RPSA
Abstract

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5'-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5'-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.

Published
2018

23. Trajectories of Relative Performance with 2 Measures of Global Cognitive Function

Author

Espeland, Mark A, Chen, Jiu‐Chiuan, Weitlauf, Julie, Hayden, Kathleen M, Rapp, Stephen R, Resnick, Susan M, Garcia, Lorena, Cannell, Brad, Baker, Laura D, Sachs, Bonnie C, Tindle, Hilary A, Wallace, Robert, Casanova, Ramon, and Group, for the Women's Health Initiative Memory Study Magnetic Resonance Imaging Study

Subjects
Health Services and Systems, Health Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Dementia, Alzheimer's Disease, Brain Disorders, Aging, Behavioral and Social Science, Prevention, Clinical Research, Neurodegenerative, Neurosciences, Good Health and Well Being, Aged, Aged, 80 and over, Cognition, Cohort Studies, Female, Follow-Up Studies, Geriatric Assessment, Humans, Longitudinal Studies, Mental Status and Dementia Tests, Postmenopause, Reproducibility of Results, Time Factors, global cognitive function, longitudinal trajectories, assessment modalities, risk factors, Women's Health Initiative Memory Study Magnetic Resonance Imaging Study Group, Medical and Health Sciences, Geriatrics, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

ObjectivesTo examine whether trajectories of global cognitive function over time in studies that change assessment protocols may be modeled based on an individual's performance relative to others in the study cohort.DesignExtended follow-up of a cohort originally enrolled in a clinical trial of postmenopausal hormone therapy.SettingThe Women's Health Initiative Memory Study switched from an in-person interview with the Modified Mini-Mental State Examination to a telephone-based interview with the modified Telephone Interview for Cognitive Status to assess global cognitive function over long-term follow-up.ParticipantsWomen aged 75 to 92 (N=2,561).MeasurementsAnnual cognitive assessments from participants, ranked according to age-, race- and ethnicity-adjusted performance levels, were used to identify distinct trajectories. Participants assigned to the resulting trajectories were compared for selected risk factor profiles.ResultsOur approach grouped participants into five trajectories according to relative cognitive performance over time. These groups differed significantly according to 3 known risk factors for cognitive decline-education level, apolipoprotein E-ϵ4 genotype, and type 2 diabetes mellitus-and a biomarker based on brain structure that has been linked to cognitive decline and Alzheimer's disease. Participants with consistently low relative levels of cognitive function over time and those whose relative performance over time declined to these levels tended to have poorer risk factor profiles.ConclusionLongitudinal measures of an individual's relative performance on different assessment protocols for global cognitive function can be used to identify trajectories of change over time that appear to have internal validity with respect to known risk factors.

Published
2018

24. Metabolic network failures in Alzheimer's disease: A biochemical road map

Author

Toledo, Jon B, Arnold, Matthias, Kastenmüller, Gabi, Chang, Rui, Baillie, Rebecca A, Han, Xianlin, Thambisetty, Madhav, Tenenbaum, Jessica D, Suhre, Karsten, Thompson, J Will, St. John‐Williams, Lisa, MahmoudianDehkordi, Siamak, Rotroff, Daniel M, Jack, John R, Motsinger‐Reif, Alison, Risacher, Shannon L, Blach, Colette, Lucas, Joseph E, Massaro, Tyler, Louie, Gregory, Zhu, Hongjie, Dallmann, Guido, Klavins, Kristaps, Koal, Therese, Kim, Sungeun, Nho, Kwangsik, Shen, Li, Casanova, Ramon, Varma, Sudhir, Legido‐Quigley, Cristina, Moseley, M Arthur, Zhu, Kuixi, Henrion, Marc YR, van der Lee, Sven J, Harms, Amy C, Demirkan, Ayse, Hankemeier, Thomas, van Duijn, Cornelia M, Trojanowski, John Q, Shaw, Leslie M, Saykin, Andrew J, Weiner, Michael W, Doraiswamy, P Murali, and Kaddurah‐Daouk, Rima

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Clinical Research, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Alzheimer's Disease, Acquired Cognitive Impairment, Aging, Dementia, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Amino Acids, Amyloid beta-Peptides, Aniline Compounds, Cognitive Dysfunction, Cohort Studies, Cross-Sectional Studies, Fasting, Female, Humans, Male, Metabolic Diseases, Metabolic Networks and Pathways, Metabolomics, Peptide Fragments, Phosphatidylcholines, Sphingomyelins, Thiazoles, tau Proteins, Metabonomics, Pharmacometabolomics, Pharmacometabonomics, Biomarkers, Serum, Metabolism, Systems biology, Biochemical networks, Precision medicine, Alzheimer's disease, Branched-chain amino acids, Phospholipids, Acylcarnitines, Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium, Clinical Sciences, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionThe Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.MethodsFasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.ResultsMultivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1-42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease.DiscussionMetabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.

Published
2017

25. Drop set versus traditional strength training protocols equated in volume on muscle thickness in women.

Author

Vilaça-Alves, José, Paulo Brito, João, Machado, Beatriz, Canário-Lemos, Rui, Moreira, Tiago, Matos, Filipe, Peixoto, Rafael, Monteiro, Gabriéla, Lucas Chaves, Gabriela, Garrido, Nuno, Casanova, Filipe, Costa, Pablo B., and Machado Reis, Victor

Subjects
ADIPOSE tissues, FLEXOR muscles, STRENGTH training, YOUNG women, EXPERIMENTAL groups, RESISTANCE training
Abstract

Copyright of Retos: Nuevas Perspectivas de Educación Física, Deporte y Recreación is the property of Federacion Espanola de Asociaciones de Docentes de Educacion Fisica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2024
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26. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Author

Lévy, Romain, Okada, Satoshi, Béziat, Vivien, Moriya, Kunihiko, Liu, Caini, Chai, Louis Yi Ann, Migaud, Mélanie, Hauck, Fabian, Al Ali, Amein, Cyrus, Cyril, Vatte, Chittibabu, Patiroglu, Turkan, Unal, Ekrem, Ferneiny, Marie, Hyakuna, Nobuyuki, Nepesov, Serdar, Oleastro, Matias, Ikinciogullari, Aydan, Dogu, Figen, Asano, Takaki, Ohara, Osamu, Yun, Ling, Della Mina, Erika, Bronnimann, Didier, Itan, Yuval, Gothe, Florian, Bustamante, Jacinta, Boisson-Dupuis, Stéphanie, Tahuil, Natalia, Aytekin, Caner, Salhi, Aicha, Al Muhsen, Saleh, Kobayashi, Masao, Toubiana, Julie, Abel, Laurent, Li, Xiaoxia, Camcioglu, Yildiz, Celmeli, Fatih, Klein, Christoph, AlKhater, Suzan A, Casanova, Jean-Laurent, and Puel, Anne

Subjects
Pediatric, Genetics, Clinical Research, Infectious Diseases, Rare Diseases, Emerging Infectious Diseases, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Alleles, Bacterial Infections, Candida, Candidiasis, Cell Membrane, Child, Child, Preschool, Family Health, Female, Fibroblasts, Genes, Recessive, Genome-Wide Association Study, HEK293 Cells, Homozygote, Humans, Immunophenotyping, Infant, Infant, Newborn, Interleukin-17, Male, Mutation, Mycoses, Open Reading Frames, Pedigree, Receptors, Interleukin-17, Skin, T-Lymphocytes, genetics, immunodeficiency, candidiasis
Abstract

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

Published
2016

27. Incomplete Protection against Dengue Virus Type 2 Re-infection in Peru.

Author

Forshey, Brett M, Reiner, Robert C, Olkowski, Sandra, Morrison, Amy C, Espinoza, Angelica, Long, Kanya C, Vilcarromero, Stalin, Casanova, Wilma, Wearing, Helen J, Halsey, Eric S, Kochel, Tadeusz J, Scott, Thomas W, and Stoddard, Steven T

Subjects
Humans, Dengue Virus, Dengue, Recurrence, Antibodies, Viral, Prevalence, Longitudinal Studies, Prospective Studies, Disease Outbreaks, Age Distribution, Adolescent, Adult, Aged, Middle Aged, Child, Child, Preschool, Peru, Female, Male, Young Adult, Antibodies, Neutralizing, Antibodies, Viral, Preschool, Neutralizing, Tropical Medicine, Biological Sciences, Medical and Health Sciences
Abstract

BackgroundNearly half of the world's population is at risk for dengue, yet no licensed vaccine or anti-viral drug is currently available. Dengue is caused by any of four dengue virus serotypes (DENV-1 through DENV-4), and infection by a DENV serotype is assumed to provide life-long protection against re-infection by that serotype. We investigated the validity of this fundamental assumption during a large dengue epidemic caused by DENV-2 in Iquitos, Peru, in 2010-2011, 15 years after the first outbreak of DENV-2 in the region.Methodology/principal findingsWe estimated the age-dependent prevalence of serotype-specific DENV antibodies from longitudinal cohort studies conducted between 1993 and 2010. During the 2010-2011 epidemic, active dengue cases were identified through active community- and clinic-based febrile surveillance studies, and acute inapparent DENV infections were identified through contact tracing studies. Based on the age-specific prevalence of DENV-2 neutralizing antibodies, the age distribution of DENV-2 cases was markedly older than expected. Homologous protection was estimated at 35.1% (95% confidence interval: 0%-65.2%). At the individual level, pre-existing DENV-2 antibodies were associated with an incomplete reduction in the frequency of symptoms. Among dengue cases, 43% (26/66) exhibited elevated DENV-2 neutralizing antibody titers for years prior to infection, compared with 76% (13/17) of inapparent infections (age-adjusted odds ratio: 4.2; 95% confidence interval: 1.1-17.7).Conclusions/significanceOur data indicate that protection from homologous DENV re-infection may be incomplete in some circumstances, which provides context for the limited vaccine efficacy against DENV-2 in recent trials. Further studies are warranted to confirm this phenomenon and to evaluate the potential role of incomplete homologous protection in DENV transmission dynamics.

Published
2016

28. Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes

Author

Espeland, Mark A, Brinton, Roberta Diaz, Manson, JoAnn E, Yaffe, Kristine, Hugenschmidt, Christina, Vaughan, Leslie, Craft, Suzanne, Edwards, Beatrice J, Casanova, Ramon, Masaki, Kamal, and Resnick, Susan M

Subjects
Neurosciences, Diabetes, Clinical Trials and Supportive Activities, Estrogen, Aging, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Metabolic and endocrine, Aged, Diabetes Mellitus, Type 2, Estrogen Replacement Therapy, Estrogens, Conjugated (USP), Female, Follow-Up Studies, Gray Matter, Humans, Postmenopause, Randomized Controlled Trials as Topic, WHIMS-MRI2 Study Group, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo examine whether the effect of postmenopausal hormone therapy (HT) on brain volumes in women aged 65-79 years differs depending on type 2 diabetes status during postintervention follow-up of a randomized controlled clinical trial.MethodsThe Women's Health Initiative randomized clinical trials assigned women to HT (0.625 mg/day conjugated equine estrogens with or without 2.5 mg/day medroxyprogesterone acetate) or placebo for an average of 5.6 years. A total of 1,402 trial participants underwent brain MRI 2.4 years after the trials; these were repeated in 699 women 4.7 years later. General linear models were used to assess the interaction between diabetes status and HT assignment on brain volumes.ResultsWomen with diabetes at baseline or during follow-up who had been assigned to HT compared to placebo had mean decrement in total brain volume of -18.6 mL (95% confidence interval [CI] -29.6, -7.6). For women without diabetes, this mean decrement was -0.4 (95% CI -3.8, 3.0) (interaction p=0.002). This interaction was evident for total gray matter (p

Published
2015

29. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction

Author

Akizu, Naiara, Cantagrel, Vincent, Zaki, Maha S, Al-Gazali, Lihadh, Wang, Xin, Rosti, Rasim Ozgur, Dikoglu, Esra, Gelot, Antoinette Bernabe, Rosti, Basak, Vaux, Keith K, Scott, Eric M, Silhavy, Jennifer L, Schroth, Jana, Copeland, Brett, Schaffer, Ashleigh E, Gordts, Philip LSM, Esko, Jeffrey D, Buschman, Matthew D, Field, Seth J, Napolitano, Gennaro, Abdel-Salam, Ghada M, Ozgul, R Koksal, Sagıroglu, Mahmut Samil, Azam, Matloob, Ismail, Samira, Aglan, Mona, Selim, Laila, Mahmoud, Iman G, Abdel-Hadi, Sawsan, Badawy, Amera El, Sadek, Abdelrahim A, Mojahedi, Faezeh, Kayserili, Hulya, Masri, Amira, Bastaki, Laila, Temtamy, Samia, Müller, Ulrich, Desguerre, Isabelle, Casanova, Jean-Laurent, Dursun, Ali, Gunel, Murat, Gabriel, Stacey B, de Lonlay, Pascale, and Gleeson, Joseph G

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Brain Disorders, Clinical Research, Animals, Atrophy, Autophagy, Cerebellar Diseases, Cerebellum, Child, Preschool, Female, Gene Frequency, Humans, Infant, Lod Score, Lysosomal Storage Diseases, Lysosomes, Male, Mutation, Phagosomes, Sorting Nexins, Spinocerebellar Ataxias, Syndrome, Zebrafish, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology, Genetics
Abstract

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

Published
2015

30. Influence of type 2 diabetes on brain volumes and changes in brain volumes: results from the Womens Health Initiative Magnetic Resonance Imaging studies.

Author

Espeland, Mark, Bryan, R, Goveas, Joseph, Robinson, Jennifer, Siddiqui, Mustafa, Liu, Simin, Hogan, Patricia, Casanova, Ramon, Coker, Laura, Masaki, Kamal, Rossom, Rebecca, Resnick, Susan, and Yaffe, Kristine

Subjects
Aged, Aged, 80 and over, Brain, Cognition, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Humans, Womens Health
Abstract

OBJECTIVE: To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function. RESEARCH DESIGN AND METHODS: Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72-89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined. RESULTS: The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits. CONCLUSIONS: Diabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function.

Published
2013

31. Influence of Type 2 Diabetes on Brain Volumes and Changes in Brain Volumes Results from the Women’s Health Initiative Magnetic Resonance Imaging Studies

Author

Espeland, Mark A, Bryan, R Nick, Goveas, Joseph S, Robinson, Jennifer G, Siddiqui, Mustafa S, Liu, Simin, Hogan, Patricia E, Casanova, Ramon, Coker, Laura H, Yaffe, Kristine, Masaki, Kamal, Rossom, Rebecca, and Resnick, Susan M

Subjects
Biomedical and Clinical Sciences, Health Sciences, Biomedical Imaging, Neurosciences, Behavioral and Social Science, Brain Disorders, Diabetes, 2.3 Psychological, social and economic factors, Aetiology, Metabolic and endocrine, Aged, Aged, 80 and over, Brain, Cognition, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Humans, Women's Health, WHIMS-MRI Study Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveTo study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function.Research design and methodsRegional brain volumes and ischemic lesion volumes in 1,366 women, aged 72-89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined.ResultsThe 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits.ConclusionsDiabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function.

Published
2013

32. Classification of structural MRI images in Alzheimer's disease from the perspective of ill-posed problems.

Author

Casanova, Ramon, Hsu, Fang-Chi, Espeland, Mark A, and Alzheimer's Disease Neuroimaging Initiative

Subjects
Alzheimer's Disease Neuroimaging Initiative, Humans, Alzheimer Disease, Magnetic Resonance Imaging, Linear Models, Logistic Models, Algorithms, Principal Component Analysis, Artificial Intelligence, Databases, Factual, Aged, Aged, 80 and over, Female, Male, Neuroimaging, Support Vector Machine, Databases, Factual, and over, General Science & Technology
Abstract

BackgroundMachine learning neuroimaging researchers have often relied on regularization techniques when classifying MRI images. Although these were originally introduced to deal with "ill-posed" problems it is rare to find studies that evaluate the ill-posedness of MRI image classification problems. In addition, to avoid the effects of the "curse of dimensionality" very often dimension reduction is applied to the data.MethodologyBaseline structural MRI data from cognitively normal and Alzheimer's disease (AD) patients from the AD Neuroimaging Initiative database were used in this study. We evaluated here the ill-posedness of this classification problem across different dimensions and sample sizes and its relationship to the performance of regularized logistic regression (RLR), linear support vector machine (SVM) and linear regression classifier (LRC). In addition, these methods were compared with their principal components space counterparts.Principal findingsIn voxel space the prediction performance of all methods increased as sample sizes increased. They were not only relatively robust to the increase of dimension, but they often showed improvements in accuracy. We linked this behavior to improvements in conditioning of the linear kernels matrices. In general the RLR and SVM performed similarly. Surprisingly, the LRC was often very competitive when the linear kernel matrices were best conditioned. Finally, when comparing these methods in voxel and principal component spaces, we did not find large differences in prediction performance.Conclusions and significanceWe analyzed the problem of classifying AD MRI images from the perspective of linear ill-posed problems. We demonstrate empirically the impact of the linear kernel matrix conditioning on different classifiers' performance. This dependence is characterized across sample sizes and dimensions. In this context we also show that increased dimensionality does not necessarily degrade performance of machine learning methods. In general, this depends on the nature of the problem and the type of machine learning method.

Published
2012

33. Clinico-epidemiological profile of patients at children’s psychosocial care centers in São Bernardo do Campo: a cross-sectional study

Author

Maialu Pedreira Messias, Etienne de Miranda e Silva, Mariele Hertha de Andrade, Isabela Cristina Casanova Cavallo, Lucas Pequeno Galvão, Cintia de Azevedo Marques Périco, Julio Torales, Antonio Ventriglio, João Mauricio Castaldelli-Maia, and Anderson Sousa Martins-da-Silva

Subjects
Male, Adolescent, Mental hygiene services, Autism Spectrum Disorder, Epidemiology, Precision medicine, General Medicine, Psychiatric Rehabilitation, Cross-Sectional Studies, Mental health services, Attention Deficit Disorder with Hyperactivity, Humans, Female, Health profile, Teen, Child, Children, Brazil
Abstract

BACKGROUDS: Child and Adolescent Psychosocial Care Centers (Centros de Atenção Psicossocial, CAPSI) are dedicated centers for persistent psychiatric disorders, which provide an individualized therapeutic approach based on extra-hospital services. OBJECTIVES: We aimed to describe the clinico-epidemiological profiles of the patients seeking interventions at the CAPSIs. DESIGN AND SETTING: A cross-sectional study was conducted in two CAPSI in São Bernardo do Campo, SP, Brazil. One CAPSI is dedicated to the treatment of alcohol- and drug-related disorders, and the other to the treatment of other mental disorders. METHODS: In July 2017, we reviewed all active medical records of these two CAPSI, and collected the patients information including sex, race, education, type of referral, initial complaints, psychiatric diagnoses, and medication utilization. RESULTS: Of the 233 patients, 69.5% were male and 42.5% lived with their immediate family. Most of the patients were referred from other health services. Complaints on admission included agitation and aggressive behavior (30.9%). Autism spectrum disorder (ASD) was the most prevalent diagnosis (46.8%), followed by depressive disorder (13.8%). Of the patients, 81.5% were on regular medical follow-up and 70.3% were on a single medication only. CONCLUSION: Aggression complaints are the most prevalent in CAPSI, and diagnoses of ASD and psychotic disorders are more common. This situation differs from most CAPSI that present school complaints as the most prevalent, in which diagnoses of attention-deficit/hyperactivity disorder and conduct disorders are likely to be more frequent. The epidemiological profile of each CAPSI should guide the implementation of human and structural resources targeting the most prevalent complaints and diagnoses.

Published
2022

34. Satisfaction with and Use of Inhalation Devices in Patients with Bronchial Asthma

Author

Luis Fernando Valladales-Restrepo, Juan Camilo Saavedra-Navia, Carlos Andrés Montezuma-Casanova, Valentina Montañez-Díaz, Jairo Andrés González-Ospina, Laura Manuela Caballero-Martínez, Andrés Gaviria-Mendoza, Manuel Enrique Machado-Duque, and Jorge Enrique Machado-Alba

Subjects
Male, Pulmonary and Respiratory Medicine, Nebulizers and Vaporizers, Pharmaceutical Science, Personal Satisfaction, Middle Aged, Asthma, Bronchodilator Agents, Cross-Sectional Studies, Patient Satisfaction, Administration, Inhalation, Quality of Life, Humans, Female, Pharmacology (medical), Metered Dose Inhalers
Published
2022

35. Reservoir Pressure Integral Is Independently Associated With the Reduction in Renal Function in Older Adults

Author

Kunihiko Aizawa, Alun D. Hughes, Francesco Casanova, Phillip E. Gates, David M. Mawson, Kim M. Gooding, Mark Gilchrist, Isabel Goncalves, Jan Nilsson, Faisel Khan, Helen M. Colhoun, Carlo Palombo, Kim H. Parker, and Angela C Shore

Subjects
Hypertension, Radial Artery, Internal Medicine, Humans, Blood Pressure, Female, Kidney, Aged, Glomerular Filtration Rate
Abstract

Background: Arterial hemodynamic parameters derived from reservoir-excess pressure analysis exhibit prognostic utility. Reservoir-excess pressure analysis may provide useful information about an influence of altered hemodynamics on target organ such as the kidneys. We determined whether the parameters derived from the reservoir-excess pressure analysis were associated with the reduction in estimated glomerular filtration rate in 542 older adults (69.4±7.9 years, 194 females) at baseline and after 3 years. Methods: Reservoir-excess pressure parameters, including reservoir pressure integral, excess pressure integral, systolic, and diastolic rate constants, were obtained by radial artery tonometry. Results: After 3 years, and in a group of 94 individuals (72.4±7.6 years, 26 females), there was an estimated glomerular filtration rate reduction of >5% per year (median reduction of 20.5% over 3 years). A multivariable logistic regression analysis revealed that higher baseline reservoir pressure integral was independently associated with a smaller reduction in estimated glomerular filtration rate after accounting for conventional cardiovascular risk factors and study centers (odds ratio: 0.660 [95% CIs, 0.494–0.883]; P =0.005). The association remained unchanged after further adjustments for potential confounders and baseline renal function (odds ratio: 0.528 [95% CIs, 0.351–0.794]; P =0.002). No other reservoir-excess pressure parameters exhibited associations with the reduction in renal function. Conclusions: This study demonstrates that baseline reservoir pressure integral was associated with the decline in renal function in older adults at 3-year follow-up, independently of conventional cardiovascular risk factors. This suggests that reservoir pressure integral may play a role in the functional decline of the kidneys.

Published
2022

36. The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021

Author

Carmen Tur, Anne-Laure Dubessy, Susana Otero-Romero, Maria Pia Amato, Tobias Derfuss, Franziska Di Pauli, Ellen Iacobaeus, Marcin Mycko, Hesham Abboud, Anat Achiron, Angelo Bellinvia, Alexey Boyko, Jean-Laurent Casanova, David Clifford, Ruth Dobson, Mauricio F Farez, Massimo Filippi, Kathryn C Fitzgerald, Mattia Fonderico, Riadh Gouider, Yael Hacohen, Kerstin Hellwig, Bernhard Hemmer, Ludwig Kappos, Filipa Ladeira, Christine Lebrun-Frénay, Céline Louapre, Melinda Magyari, Matthias Mehling, Celia Oreja-Guevara, Lekha Pandit, Caroline Papeix, Fredrik Piehl, Emilio Portaccio, Isabel Ruiz-Camps, Krzysztof Selmaj, Steve Simpson-Yap, Aksel Siva, Per Soelberg Sorensen, Maria Pia Sormani, Maria Trojano, Adi Vaknin-Dembinsky, Sandra Vukusic, Brian Weinshenker, Heinz Wiendl, Alexander Winkelmann, María Isabel Zuluaga Rodas, Mar Tintoré, Bruno Stankoff, Tur, Carmen, Dubessy, Anne-Laure, Otero-Romero, Susana, Amato, Maria Pia, Derfuss, Tobia, Di Pauli, Franziska, Iacobaeus, Ellen, Mycko, Marcin, Abboud, Hesham, Achiron, Anat, Bellinvia, Angelo, Boyko, Alexey, Casanova, Jean-Laurent, Clifford, David, Dobson, Ruth, Farez, Mauricio F, Filippi, Massimo, Fitzgerald, Kathryn C, Fonderico, Mattia, Gouider, Riadh, Hacohen, Yael, Hellwig, Kerstin, Hemmer, Bernhard, Kappos, Ludwig, Ladeira, Filipa, Lebrun-Frénay, Christine, Louapre, Céline, Magyari, Melinda, Mehling, Matthia, Oreja-Guevara, Celia, Pandit, Lekha, Papeix, Caroline, Piehl, Fredrik, Portaccio, Emilio, Ruiz-Camps, Isabel, Selmaj, Krzysztof, Simpson-Yap, Steve, Siva, Aksel, Sorensen, Per Soelberg, Sormani, Maria Pia, Trojano, Maria, Vaknin-Dembinsky, Adi, Vukusic, Sandra, Weinshenker, Brian, Wiendl, Heinz, Winkelmann, Alexander, Zuluaga Rodas, María Isabel, Tintoré, Mar, and Stankoff, Bruno

Subjects
SARS-CoV-2, Neuromyelitis Optica, neuromyelitis optica spectrum disorder, COVID-19, DMT-associated infections, Multiple sclerosis, coronavirus disease 2019, disease-modifying treatment, progressive multifocal leukoencephalopathy, risk mitigation strategies, ddc, Neurology, Pregnancy, Original Research Papers, Humans, Female, Neurology (clinical), Child, Pandemics
Abstract

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

Published
2022

37. Maybe they had a bad day: how LGBTQ and BIPOC patients react to bias in healthcare and struggle to speak out

Author

Calvin Apodaca, Reggie Casanova-Perez, Emily Bascom, Deepthi Mohanraj, Cezanne Lane, Drishti Vidyarthi, Erin Beneteau, Janice Sabin, Wanda Pratt, Nadir Weibel, and Andrea L Hartzler

Subjects
Male, Sexual and Gender Minorities, Sexual Behavior, Humans, Gender Identity, Female, Health Informatics, Health Promotion, Healthcare Disparities
Abstract

Objective People who experience marginalization, including Black, Indigenous, People of Color (BIPOC) and Lesbian, Gay, Bisexual, Transgender, Queer, Plus (ie, all other marginalized genders and sexual orientations) people (LGBTQ+) experience discrimination during healthcare interactions, which negatively impacts patient–provider communication and care. Yet, scarce research examines the lived experience of unfair treatment among patients from marginalized groups to guide patient-centered tools that improve healthcare equity. Materials and Methods We interviewed 25 BIPOC and/or LGBTQ+ people about their experiences of unfair treatment and discrimination when visiting healthcare providers. Through thematic analysis, we describe participants’ immediate reactions and longer-term consequences of those experiences. Results We identified 4 ways that participants reacted to discrimination in the moment: Fighting, Fleeing, Excusing, and Working Around Bias. Long-term consequences reflect 6 ways they coped: Delaying or Avoiding Care, Changing Healthcare Providers, Self-prescribing, Covering Behaviors, Experiencing Health Complications, and Mistrusting Healthcare Institutions. Discussion By describing how patients react to experiences of unfair treatment and discrimination, our findings enhance the understanding of health disparities as patients cope and struggle to speak out. To combat these problems, we identify 3 future directions for informatics interventions that improve provider behavior, support patient advocacy, and address power dynamics in healthcare. Conclusions BIPOC and LGBTQ+ patients’ perspectives on navigating unfair treatment and discrimination in healthcare offers critical insight into their experiences and long-term consequences of those experiences. Understanding the circumstances and consequences of unfair treatment, discrimination, and the impact of bias through this patient-centered lens is crucial to inform informatics technologies that promote health equity.

Published
2022

38. Differences in Health Care Access, Utilization, and Experiences Among LGBTQ+ Subgroups in the Southern United States

Author

Natalie R. Holt, Elizabeth D. Eldridge-Smith, James A. Griffin, Lara M. Stepleman, Christopher F. Drescher, and Tracy Casanova

Subjects
Sexual and Gender Minorities, Public Health, Environmental and Occupational Health, Humans, Homosexuality, Female, Bisexuality, Female, Transgender Persons, United States, Health Services Accessibility
Abstract

Lesbian, gay, bisexual, transgender, queer, and other sexual and gender minority (LGBTQ+) individuals experience health inequities and barriers to accessing appropriate, affirming care. Little is known about differing health care experiences within the LGBTQ+ population, particularly among individuals living in underserved areas. This study explored health care experiences and utilization among LGBTQ+ subgroups: lesbian and gay cisgender individuals (n = 258), bisexual+ cisgender individuals (n = 71), and transgender and gender-diverse individuals (n = 80). Participants were recruited from a geographic region in South Carolina and Georgia and completed an online survey regarding negative health care experiences, barriers to care, and utilization of different health care venues and services. Results revealed significant differences between LGBTQ+ subgroups, with transgender and gender-diverse participants reporting more discriminatory experiences and greater barriers to care. Bisexual+ cisgender individuals also experienced some disparities compared with lesbian and gay cisgender individuals. Most participants endorsed a need for more competent providers. Findings and recommendations are considered within the context of the Southeastern United States for addressing access and utilization disparities among LGBTQ+ communities.

Published
2022

39. [Translated article] Contact Allergy in Patients With Rosacea

Author

J, Magdaleno-Tapial, C, López-Martí, M, García-Legaz-Martínez, A, Martínez-Domenech, F, Partarrieu-Mejías, A, Casanova-Esquembre, J, Lorca-Spröhnle, C, Labrandero-Hoyos, R, Peñuelas-Leal, C, Sierra-Talamantes, A, Pérez-Ferriols, and V, Zaragoza-Ninet

Subjects
Adult, Male, Dermatitis, Allergic Contact, Rosacea, Humans, Female, Cosmetics, General Medicine, Allergens, Patch Tests, Glucocorticoids, Retrospective Studies
Abstract

Rosacea is a chronic acneiform skin disorder in which impaired skin barrier function can lead to sensitization to allergens. We aimed to analyze contact allergies in our patients with rosacea.Retrospective cohort study of all patients who underwent patch testing in our skin allergy clinic between May 1991 and May 2019.A total of 200 patients with rosacea were referred to our clinic for patch testing during the study period; they represented 2.1% of all patch tested patients in the period. Eighty-one percent were women (mean age, 44.7years). At least 1 positive patch test was recorded for 46.5%; 15% were of current relevance. The most frequent positive reaction was to nickel (26%), followed by cobalt chloride (6.5%), isothiazolinones (6%), p-phenylenediamine (5.5%), fragrance mix II (5%), and thimerosal (3.5%). The most common currently relevant patch test reactions were to isothiazolinones in 10 of the 200 patients (5%); to phenylenediamine, fragrance mix II, and toluensulfonamide formaldehyde resin in 4 patients (2%) each; and to tixocortol and fragrance mix I in 2 patients (1%) each. The allergen groups most often implicated were metals (of current relevance in 12.6%) and drugs (of current relevance in 25.8%). Preservatives and fragrances were the next most common allergen groups, and 70.8% and 43.7% of the positive reactions in these groups, respectively, were of current relevance. Cosmetics were the most frequent source of sensitization, followed by topical medications-notably corticosteroids and antifungal agents.We emphasize the high prevalence of allergic contact dermatitis in patients with rosacea, a finding which supports patch testing, especially if eruptions worsen when these patients use cosmetics and topical medications.

Published
2022

40. Development of effective messages to promote maternal immunization in Kenya

Author

Paula M, Frew, Ines, Gonzalez-Casanova, Nancy A, Otieno, Fauzia A, Malik, Vincent L, Fenimore, Dominique, Owino, Maxwell O, Adero, Raphael O, Atito, Godfrey, Bigogod, Sandra S, Chaves, Jennifer R, Verani, Marc, Alain Widdowson, and Saad B, Omer

Subjects
Male, Health Knowledge, Attitudes, Practice, General Veterinary, General Immunology and Microbiology, Vaccination, Public Health, Environmental and Occupational Health, Reproducibility of Results, Patient Acceptance of Health Care, Kenya, Infectious Diseases, Pregnancy, Influenza, Human, Humans, Molecular Medicine, Female, Immunization
Abstract

This study evaluated messages and communication approaches for maternal immunization uptake in Kenya. We identified persuasive communication aspects that would inform maternal immunization attitudes, intent, and vaccine uptake.We conducted a two-phased mixed methods study with pregnant women and their male partners in three regions of Kenya. Discussions were conducted in English and Swahili languages by trained focus group moderators. Baseline measures included a survey and discussions about potential messages and accompanying visuals. Follow-up focus groups with the same participants included a survey about previously discussed messages, visuals, and communication impressions. The second round of focus groups focused on message preferences developed from the first round, along with rank order discussion for final message selection. Following transcription of focus group discussions, we conducted analyses using NVivo software. Quantitative data analyses included frequencies, factor analyses, reliability assessment, regression modeling, and comparative assessment of rank order.The sample (N = 118) included pregnant women (n = 91) and their partners (n = 27) from diverse Kenyan regions (Bondo/Lwak/Siaya, Mombasa, and Nairobi). A four-factor solution resulted from factor analyses that included subscales "positive ad attitudes" (n = 5 items, α = 0.82), "negative ad attitudes" (n = 4 items, α = 0.75), "ad indifference" (n = 2 items, α = 0.52), and "ad motivation" (n = 4 items, α = 0.71). Overall, the positive ad attitudes factor (β = 0.61, p = 0.03) was the only significant component in the overall model examining message selections (χThe results indicated that positive attitudes were shaped by incorporating highly relatable factors in messages. Implications for subsequent campaigns and research directions are discussed.

Published
2022

41. Chronic Granulomatous Disease-Like Presentation of a Child with Autosomal Recessive PKCδ Deficiency

Author

Anna-Lena Neehus, Karen Tuano, Tom Le Voyer, Sarada L. Nandiwada, Kruthi Murthy, Anne Puel, Jean-Laurent Casanova, Javier Chinen, and Jacinta Bustamante

Subjects
Child, Preschool, Immunology, Humans, NADPH Oxidases, Immunology and Allergy, Female, RNA Splice Sites, Child, Granulomatous Disease, Chronic, Reactive Oxygen Species, Respiratory Burst
Abstract

Background Autosomal recessive (AR) PKCδ deficiency is a rare inborn error of immunity (IEI) characterized by autoimmunity and susceptibility to bacterial, fungal, and viral infections. PKCδ is involved in the intracellular production of reactive oxidative species (ROS). Material and Methods We studied a 5-year old girl presenting with a history of Burkholderia cepacia infection. She had no history of autoimmunity, lymphocyte counts were normal, and no auto-antibodies were detected in her plasma. We performed a targeted panel analysis of 407 immunity-related genes and immunological investigations of the underlying genetic condition in this patient. Results Consistent with a history suggestive of chronic granulomatous disease (CGD), oxidative burst impairment was observed in the patient’s circulating phagocytes in a dihydrorhodamine 123 (DHR) assay. However, targeted genetic panel analysis identified no candidate variants of known CGD-causing genes. Two heterozygous candidate variants were detected in PRKCD: c.285C > A (p.C95*) and c.376G > T (p.D126Y). The missense variant was also predicted to cause abnormal splicing, as it is located at the splice donor site of exon 5. TOPO-TA cloning confirmed that exon 5 was completely skipped, resulting in a truncated protein. No PKCδ protein was detected in the patient’s neutrophils and monocyte-derived macrophages. The monocyte-derived macrophages of the patient produced abnormally low levels of ROS, as shown in an Amplex Red assay. Conclusion PKCδ deficiency should be considered in young patients with CGD-like clinical manifestations and abnormal DHR assay results, even in the absence of clinical and biological manifestations of autoimmunity.

Published
2022

42. Combined PET-CT and MRI for response evaluation in patients with squamous cell anal carcinoma treated with curative-intent chemoradiotherapy

Author

Pratik Adusumilli, Noha Elsayed, Stelios Theophanous, Robert Samuel, Rachel Cooper, Nathalie Casanova, Damien J. Tolan, Alexandra Gilbert, and Andrew F. Scarsbrook

Subjects
Male, Epithelial Cells, Chemoradiotherapy, General Medicine, Anus Neoplasms, Magnetic Resonance Imaging, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography, Positron-Emission Tomography, Carcinoma, Squamous Cell, Humans, Female, Radiology, Nuclear Medicine and imaging, Radiopharmaceuticals, Retrospective Studies
Abstract

Objectives To assess the effectiveness of fluorine-18 fluorodeoxyglucose (FDG) positron-emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI) for response assessment post curative-intent chemoradiotherapy (CRT) in anal squamous cell carcinoma (ASCC). Methods Consecutive ASCC patients treated with curative-intent CRT at a single centre between January 2018 and April 2020 were retrospectively identified. Clinical meta-data including progression-free survival (PFS) and overall survival (OS) outcomes were collated. Three radiologists evaluated PET-CT and MRI using qualitative response assessment criteria and agreed in consensus. Two-proportion z test was used to compare diagnostic performance metrics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy). Kaplan-Meier analysis (Mantel-Cox log-rank) was performed. Results MRI (accuracy 76%, PPV 44.8%, NPV 95.7%) and PET-CT (accuracy 69.3%, PPV 36.7%, NPV 91.1%) performance metrics were similar; when combined, there were statistically significant improvements (accuracy 94.7%, PPV 78.9%, NPV 100%). Kaplan-Meier analysis demonstrated significant differences in PFS between responders and non-responders at PET-CT (p = 0.007), MRI (p = 0.005), and consensus evaluation (p < 0.001). Cox regression analysis of PFS demonstrated a lower hazard ratio (HR) and narrower 95% confidence intervals for consensus findings (HR = 0.093, p < 0.001). Seventy-five patients, of which 52 (69.3%) were females, with median follow-up of 17.8 months (range 5–32.6) were included. Fifteen of the 75 (20%) had persistent anorectal and/or nodal disease after CRT. Three patients died, median time to death 6.2 months (range 5–18.3). Conclusion Combined PET-CT and MRI response assessment post-CRT better predicts subsequent outcome than either modality alone. This could have valuable clinical benefits by guiding personalised risk-adapted patient follow-up. Key Points • MRI and PET-CT performance metrics for assessing response following chemoradiotherapy (CRT) in patients with anal squamous cell carcinoma (ASCC) were similar. • Combined MRI and PET-CT treatment response assessment 3 months after CRT in patients with ASCC was demonstrated to be superior to either modality alone. • A combined MRI and PET-CT assessment 3 months after CRT in patients with ASCC has the potential to improve accuracy and guide optimal patient management with a greater ability to predict outcome than either modality alone

Published
2022

43. The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies

Author

Manry, Jérémy, Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Michailidis, Eleftherios, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martínez, Alba, Yang, Rui, Haljasmägi, Liis, Migaud, Mélanie, Särekannu, Karita, Maslovskaja, Julia, de Prost, Nicolas, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesús, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garçon, Pierre, Rivière, Jacques, Lagier, Jean-Christophe, Gentile, Stéphanie, Rosen, Lindsey, Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Louis, Sene, Damien, Stepanian, Alain, Mégarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James, Franco, José Luis, Anaya, Juan-Manuel, Solé-Violán, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia, Zhang, Yu, Snow, Andrew, Holland, Steven, Biggs, Catherine, Moncada-Vélez, Marcela, Arias, Andrés Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Anglicheau, Dany, Planas, Anna, Haerynck, Filomeen, Duvlis, Sotirija, Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed, El Bakkouri, Jalila, Ramirez-Santana, Carolina, Paul, Stéphane, Pan-Hammarström, Qiang, Hammarström, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine, Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila, Dominguez-Garrido, Elena, Vidigal, Mateus, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart, Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Lluis, Klocperk, Adam, Kann, Nelli, Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angélique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel, Arrestier, Romain, Boudhabhay, Idris, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam, Kennelly, Sean, Bourke, Nollaig, Halwani, Rabih, Sharif-Askari, Fatemeh Saheb, Dorgham, Karim, Sallette, Jérôme, Sedkaoui, Souad Mehlal, Alkhater, Suzan, Rigo-Bonnin, Raúl, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald, Erikstrup, Christian, Condino-Neto, Antonio, Prando, Carolina, Bondarenko, Anastasiia, Spaan, András, Gilardin, Laurent, Fellay, Jacques, Lyonnet, Stanislas, Bilguvar, Kaya, Lifton, Richard, Mane, Shrikant, Anderson, Mark, Boisson, Bertrand, Béziat, Vivien, Zhang, Shen-Ying, Andreakos, Evangelos, Hermine, Olivier, Pujol, Aurora, Peterson, Pärt, Mogensen, Trine, Rowen, Lee, Mond, James, Debette, Stéphanie, de Lamballerie, Xavier, Burdet, Charles, Bouadma, Lila, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter, Piemonti, Lorenzo, Rodríguez-Gallego, Carlos, Notarangelo, Luigi, Su, Helen, Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles, Tiberghien, Pierre, Zhang, Qian, Casanova, Jean-Laurent, Abel, Laurent, Cobat, Aurélie, Zhang, Peng, Seeleuthner, Yoann, Talouarn, Estelle, Marchal, Astrid, Matuozzo, Daniela, de la Chapelle, Aliénor, Chen, Jie, Chrabieh, Maya, Liu, Dana, Nemirowskaya, Yelena, Cruz, Inés Marín, Materna, Marie, Pelet, Sophie, Thibault, Chloé, Liu, Zhiyong, Abad, Jorge, Accordino, Giulia, Achille, Cristian, Aguilera-Albesa, Sergio, Aguiló-Cucurull, Aina, Özkan, Esra Akyüz, Darazam, Ilad Alavi, Albisures, Jonathan Antonio Roblero, Aldave, Juan, Ramos, Miquel Alfonso, Khan, Taj Ali, Aliberti, Anna, Nadji, Seyed Alireza, Alkan, Gulsum, Allardet-Servent, Jerome, Allende, Luis, Alonso-Arias, Rebeca, Alshahrani, Mohammed, Alsina, Laia, Alyanakian, Marie-Alexandra, Borrero, Blanca Amador, Amoura, Zahir, Antolí, Arnau, Aubart, Mélodie, Auguet, Teresa, Avramenko, Iryna, Aytekin, Gökhan, Azot, Axelle, Bahram, Seiamak, Bajolle, Fanny, Baldanti, Fausto, Baldolli, Aurélie, Ballester, Maite, Feldman, Hagit Baris, Barrou, Benoit, Barzaghi, Federica, Basso, Sabrina, Bayhan, Gulsum Iclal, Bezrodnik, Liliana, Bilbao, Agurtzane, Blanchard-Rohner, Geraldine, Blanco, Ignacio, Blandinières, Adeline, Blázquez-Gamero, Daniel, Bleibtreu, Alexandre, Bloomfield, Marketa, Bolivar-Prados, Mireia, Borghesi, Alessandro, Borie, Raphael, Botdhlo-Nevers, Elisabeth, Bousquet, Aurore, Boutolleau, David, Bouvattier, Claire, Bravais, Juliette, Briones, M. Luisa, Brunner, Marie-Eve, Bruno, Raffaele, Bueno, Maria Rita P., Bukhari, Huda, Bustamante, Jacinta, Agra, Juan José Cáceres, Capra, Ruggero, Carapito, Raphael, Carrabba, Maria, Casasnovas, Carlos, Caseris, Marion, Cassaniti, Irene, Castelle, Martin, Castelli, Francesco, de Vera, Martín Castillo, Castro, Mateus, Catherinot, Emilie, Celik, Jale Bengi, Ceschi, Alessandro, Chalumeau, Martin, Charbit, Bruno, Cheng, Matthew, Clavé, Pere, Clotet, Bonaventura, Codina, Anna, Cohen, Yves, Comarmond, Cloé, Combes, Alain, Comoli, Patrizia, Corsico, Angelo, Coşkuner, Taner, Cvetkovski, Aleksandar, Cyrus, Cyril, Danion, François, Darley, David Ross, Das, Vincent, Dauby, Nicolas, Dauger, Stéphane, de Munter, Paul, de Pontual, Loic, Dehban, Amin, Delplancq, Geoffroy, Demoule, Alexandre, Desguerre, Isabelle, Di Sabatino, Antonio, Diehl, Jean-Luc, Dobbelaere, Stephanie, Domínguez-Garrido, Elena, Dubost, Clément, Ekwall, Olov, Bozdemir, Şefika Elmas, Elnagdy, Marwa, Emiroglu, Melike, Endo, Akifumi, Erdeniz, Emine Hafize, Aytekin, Selma Erol, Lasa, Maria Pilar Etxart, Euvrard, Romain, Fabio, Giovanna, Faivre, Laurence, Falck, Antonin, Fartoukh, Muriel, Faure, Morgane, Arquero, Miguel Fernandez, Ferrer, Ricard, Ferreres, Jose, Flores, Carlos, Francois, Bruno, Fumadó, Victoria, Fung, Kitty, Fusco, Francesca, Gagro, Alenka, Solis, Blanca Garcia, Gaussem, Pascale, Gayretli, Zeynep, Gil-Herrera, Juana, Gatineau, Audrey Giraud, Girona-Alarcón, Mònica, Godínez, Karen Alejandra Cifuentes, Goffard, Jean-Christophe, Gonzales, Nacho, Gonzalez-Granado, Luis, González-Montelongo, Rafaela, Guerder, Antoine, Gülhan, Belgin, Gumucio, Victor Daniel, Hanitsch, Leif Gunnar, Gunst, Jan, Gut, Marta, Hadjadj, Jérôme, Hancerli, Selda, Hariyan, Tetyana, Hatipoglu, Nevin, Heppekcan, Deniz, Hernandez-Brito, Elisa, Ho, Po-Ki, Holanda-Peña, María Soledad, Horcajada, Juan, Hraiech, Sami, Humbert, Linda, Hung, Ivan, Iglesias, Alejandro, Íñigo-Campos, Antonio, Jamme, Matthieu, Arranz, María Jesús, Jimeno, Marie-Thérèse, Jordan, Iolanda, Kanık-Yüksek, Saliha, Kara, Yalcin Burak, Karahan, Aydın, Karbuz, Adem, Yasar, Kadriye Kart, Kasapcopur, Ozgur, Kashimada, Kenichi, Demirkol, Yasemin Kendir, Kido, Yasutoshi, Kizil, Can, Kılıç, Ahmet Osman, Daganou, Maria, Koukaki, Evangelia, Koutsoukou, Antonia, Rapti, Vasiliki, Syrigos, Konstantinos, Król, Zbigniew, Ksouri, Hatem, Kuentz, Paul, Kwan, Arthur, Kwan, Yat Wah M., Kwok, Janette, Lam, David, Conti, Francesca, Pession, Andrea, Lampropoulou, Vicky, Lanternier, Fanny, Bourgeois, Fleur Le, Leo, Yee-Sin, Lopez, Rafael Leon, Levin, Michael, Levy, Michael, Lévy, Romain, Li, Zhi, Lilleri, Daniele, Lima, Edson Jose Adrian Bolanos, Linglart, Agnes, López-Collazo, Eduardo, Lorenzo-Salazar, José, Louapre, Céline, Lubetzki, Catherine, Lung, Kwok-Cheung, Lye, David, Magnone, Cinthia, Mansouri, Davood, Marchioni, Enrico, Marioli, Carola, Marjani, Majid, Marques, Laura, Pereira, Jesus Marquez, Martín-Nalda, Andrea, Pueyo, David Martínez, Marzana, Iciar, Mata-Martínez, Carmen, Mathian, Alexis, Matos, Larissa Rb, Matthews, Gail, Mayaux, Julien, Mclaughlin-Garcia, Raquel, Meersseman, Philippe, Mège, Jean-Louis, Mekontso-Dessap, Armand, Melki, Isabelle, Meloni, Federica, Meritet, Jean-François, Merlani, Paolo, Akcan, Özge Metin, Mezidi, Mehdi, Migeotte, Isabelle, Millereux, Maude, Million, Matthieu, Mirault, Tristan, Mircher, Clotilde, Mirsaeidi, Mehdi, Mizoguchi, Yoko, Modi, Bhavi, Mojoli, Francesco, Moncomble, Elsa, Melián, Abián Montesdeoca, Martinez, Antonio Morales, Morange, Pierre-Emmanuel, Mordacq, Clémence, Morelle, Guillaume, Mouly, Stéphane, Muñoz-Barrera, Adrián, Nafati, Cyril, Nagashima, Shintaro, Nakagama, Yu, Neven, Bénédicte, Neves, João Farela, Ng, Lisa, Ng, Yuk-Yung, Nielly, Hubert, Medina, Yeray Novoa, Cuadros, Esmeralda Nuñez, Ocejo-Vinyals, J. Gonzalo, Okamoto, Keisuke, Oualha, Mehdi, Ouedrani, Amani, Özçelik, Tayfun, Ozkaya-Parlakay, Aslinur, Pagani, Michele, Papadaki, Maria, Parizot, Christophe, Parola, Philippe, Pascreau, Tiffany, Paz-Artal, Estela, Pedraza-Sánchez, Sigifredo, Gálvez-Romero, José Luis, Pellecer, Nancy Carolina González, Pellegrini, Silvia, Diego, Rebeca Pérez De, Pérez-Fernández, Xosé Luis, Philippe, Aurélien, Picod, Adrien, de Chambrun, Marc Pineton, Piralla, Antonio, Planas-Serra, Laura, Ploin, Dominique, Poncelet, Géraldine, Poulakou, Garyphallia, Pouletty, Marie, Pourshahnazari, Persia, Qiu-Chen, Jia Li, Quentric, Paul, Rambaud, Thomas, Raoult, Violette, Rebillat, Anne-Sophie, Redin, Claire, Resmini, Léa, Ricart, Pilar, Richard, Jean-Christophe, Rivet, Nadia, Rocamora-Blanch, Gemma, Rodero, Mathieu, Rodrigo, Carlos, Rodriguez, Luis Antonio, Rodriguez-Gallego, Carlos, Rodriguez-Palmero, Agustí, Romero, Carolina Soledad, Rothenbuhler, Anya, Roux, Damien, Rovina, Nikoletta, Rozenberg, Flore, Ruch, Yvon, Ruiz, Montse, Prado, Maria Yolanda Ruiz Del, Ruiz-Rodriguez, Juan Carlos, Sabater-Riera, Joan, Saks, Kai, Salagianni, Maria, Sanchez, Oliver, Sánchez-Montalvá, Adrián, Sánchez-Ramón, Silvia, Schidlowski, Laire, Schluter, Agatha, Schmidt, Julien, Schmidt, Matthieu, Schuetz, Catharina, Schweitzer, Cyril, Scolari, Francesco, Sediva, Anna, Seijo, Luis, Seminario, Analia Gisela, Seng, Piseth, Senoglu, Sevtap, Seppänen, Mikko, Llovich, Alex Serra, Shahrooei, Mohammad, Siguret, Virginie, Siouti, Eleni, Smadja, David, Smith, Nikaia, Sobh, Ali, Soler, Catherine, Soler-Palacín, Pere, Sözeri, Betül, Stella, Giulia Maria, Stepanovskiy, Yuriy, Stoclin, Annabelle, Taccone, Fabio, Taupin, Jean-Luc, Tavernier, Simon, Terrier, Benjamin, Thiery, Guillaume, Thorball, Christian, Thorn, Karolina, Thumerelle, Caroline, Tipu, Imran, Tolstrup, Martin, Tomasoni, Gabriele, Toubiana, Julie, Alvarez, Josep Trenado, Tsang, Owen, Tserel, Liina, Tso, Eugene, Tucci, Alessandra, Öz, Şadiye Kübra Tüter, Ursini, Matilde Valeria, Utsumi, Takanori, Uzunhan, Yurdagul, Vabres, Pierre, Valencia-Ramos, Juan, van den Rym, Ana Maria, Vandernoot, Isabelle, Velez-Santamaria, Valentina, Veliz, Silvia Patricia Zuniga, Viel, Sébastien, Villain, Cédric, Vilaire-Meunier, Marie, Villar-García, Judit, Vincent, Audrey, Vogt, Guillaume, Voiriot, Guillaume, Volokha, Alla, Vuotto, Fanny, Wauters, Els, Wu, Alan, Wu, Tak-Chiu, Yahşi, Aysun, Yesilbas, Osman, Yildiz, Mehmet, Young, Barnaby, Yükselmiş, Ufuk, Ghirardello, Stefano, Zuccaro, Valentina, Andrés, Ana De, van Praet, Jens, Lambrecht, Bart, van Braeckel, Eva, Bosteels, Cédric, Hoste, Levi, Hoste, Eric, Bauters, Fré, Clercq, Jozefien De, Heijmans, Cathérine, Slabbynck, Hans, Naesens, Leslie, Florkin, Benoit, Boulanger, Cécile, Vanderlinden, Dimitri, Foti, Giuseppe, Bellani, Giacomo, Citerio, Giuseppe, Contro, Ernesto, Pesci, Alberto, Valsecchi, Maria Grazia, Cazzaniga, Marina, Danielson, Jeffrey, Dobbs, Kerry, Kashyap, Anuj, Ding, Li, Dalgard, Clifton, Sottini, Alessandra, Quaresima, Virginia, Quiros-Roldan, Eugenia, Rossi, Camillo, Bettini, Laura Rachele, D’angio, Mariella, Beretta, Ilaria, Montagna, Daniela, Licari, Amelia, Marseglia, Gian Luigi, Batten, Isabella, Reddy, Conor, Mcelheron, Matt, Noonan, Claire, Connolly, Emma, Fallon, Aoife, Storgaard, Merete, Jørgensen, Sofie, Pedersen, Ole Birger, Sørensen, Erik, Mikkelsen, Susan, Dinh, Khoa Manh, Larsen, Margit Anita Hørup, Paulsen, Isabella Worlewenut, von Stemann, Jakob Hjorth, Hansen, Morten Bagge, Ostrowski, Sisse Rye, Townsend, Liam, Ni Cheallaigh, Cliona, Bergin, Colm, Martin-Loeches, Ignacio, Dunne, Jean, Conlon, Niall, O’farrelly, Cliona, Allavena, Clotilde, Andrejak, Claire, Angoulvant, François, Azoulay, Cecile, Bachelet, Delphine, Bartoli, Marie, Basmaci, Romain, Behillill, Sylvie, Beluze, Marine, Benech, Nicolas, Benkerrou, Dehbia, Bhavsar, Krishna, Bitker, Laurent, Bouscambert-Duchamp, Maude, Paz, Pauline Caraux, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chirouze, Catherine, Coelho, Alexandra, Cordel, Hugues, Couffignal, Camille, Couffin-Cadiergues, Sandrine, D’ortenzio, Eric, de Montmollin, Etienne, Debard, Alexa, Debray, Marie-Pierre, Deplanque, Dominique, Descamps, Diane, Desvallée, Mathilde, Diallo, Alpha, Diouf, Alphonsine, Dorival, Céline, Dubos, François, Duval, Xavier, Eloy, Philippine, Enouf, Vincent, Epaulard, Olivier, Esperou, Hélène, Esposito-Farase, Marina, Etienne, Manuel, Garot, Denis, Gault, Nathalie, Gaymard, Alexandre, Ghosn, Jade, Gigante, Tristan, Gilg, Morgane, Goehringer, François, Guedj, Jérémie, Hoctin, Alexandre, Hoffmann, Isabelle, Houas, Ikram, Hulot, Jean-Sébastien, Jaafoura, Salma, Kafif, Ouifiya, Kaguelidou, Florentia, Kali, Sabrina, Kerroumi, Younes, Khalil, Antoine, Khan, Coralie, Kimmoun, Antoine, Laine, Fabrice, Laouénan, Cédric, Laribi, Samira, Le, Minh, Le Bris, Cyril, Le Gac, Sylvie, Le Hingrat, Quentin, Le Mestre, Soizic, Le Nagard, Hervé, Lemaignen, Adrien, Lemee, Véronique, Lescure, François-Xavier, Letrou, Sophie, Levy, Yves, Lina, Bruno, Lingas, Guillaume, Lucet, Jean Christophe, Machado, Moïse, Malvy, Denis, Mambert, Marina, Manuel, Aldric, Mentré, France, Meziane, Amina, Mouquet, Hugo, Mullaert, Jimmy, Neant, Nadège, Nguyen, Duc, Noret, Marion, Papadopoulos, Aurélie, Paul, Christelle, Peiffer-Smadja, Nathan, Peigne, Vincent, Petrov-Sanchez, Ventzislava, Peytavin, Gilles, Pham, Huong, Picone, Olivier, Piquard, Valentine, Puéchal, Oriane, Rosa-Calatrava, Manuel, Rossignol, Bénédicte, Rossignol, Patrick, Roy, Carine, Schneider, Marion, Su, Richa, Tardivon, Coralie, Tellier, Marie-Capucine, Téoulé, François, Terrier, Olivier, Timsit, Jean-François, Tual, Christelle, Tubiana, Sarah, van der Werf, Sylvie, Vanel, Noémie, Veislinger, Aurélie, Visseaux, Benoit, Wiedemann, Aurélie, Yazdanpanah, Yazdan, Annereau, Jean-Philippe, Briseño-Roa, Luis, Gribouval, Olivier, Jaïs, Jean-Philippe, Pelet, Anna, Alcover, Andres, Aschard, Hugues, Bousso, Philippe, Brodin, Petter, Bruhns, Pierre, Cerf-Bensussan, Nadine, Cumano, Ana, D’enfert, Christophe, Deriano, Ludovic, Dillies, Marie-Agnès, Di Santo, James, Dromer, Françoise, Eberl, Gérard, Enninga, Jost, Gomperts-Boneca, Ivo, Hasan, Milena, Hedestam, Gunilla Karlsson, Hercberg, Serge, Ingersoll, Molly, Lantz, Olivier, Kenny, Rose Anne, Ménager, Mickaël, Michel, Frédérique, Patin, Etienne, Pellegrini, Sandra, Rausell, Antonio, Rieux-Laucat, Frédéric, Rogge, Lars, Fontes, Magnus, Sakuntabhai, Anavaj, Schwartz, Olivier, Schwikowski, Benno, Shorte, Spencer, Tangy, Frédéric, Toubert, Antoine, Touvier, Mathilde, Ungeheuer, Marie-Noëlle, Zimmer, Christophe, Albert, Matthew, Alavoine, Loubna, Behillil, Sylvie, Charpentier, Charlotte, Dechanet, Aline, Ecobichon, Jean-Luc, Frezouls, Wahiba, Houhou, Nadhira, Lehacaut, Jonathan, Lucet, Jean-Christophe, Manchon, Pauline, Nouroudine, Mariama, Quintin, Caroline, Thy, Michael, Vignali, Valérie, Chahine, Abir, Waucquier, Nawal, Migaud, Maria-Claire, Djossou, Félix, Mergeay-Fabre, Mayka, Lucarelli, Aude, Demar, Magalie, Bruneau, Léa, Gérardin, Patrick, Maillot, Adrien, Payet, Christine, Laviolle, Bruno, Paris, Christophe, Desille-Dugast, Mireille, Fouchard, Julie, Pistone, Thierry, Perreau, Pauline, Gissot, Valérie, Le Goas, Carole, Montagne, Samatha, Richard, Lucie, Bouiller, Kévin, Desmarets, Maxime, Meunier, Alexandre, Bourgeon, Marilou, Lefèvre, Benjamin, Jeulin, Hélène, Legrand, Karine, Lomazzi, Sandra, Tardy, Bernard, Gagneux-Brunon, Amandine, Bertholon, Frédérique, Botelho-Nevers, Elisabeth, Kouakam, Christelle, Leturque, Nicolas, Roufai, Layidé, Amat, Karine, Espérou, Hélène, Hendou, Samia, van Agtmael, Michiel, Algera, Anne Geke, Appelman, Brent, van Baarle, Frank, Bax, Diane, Beudel, Martijn, Bogaard, Harm Jan, Bomers, Marije, Bonta, Peter, Bos, Lieuwe, Botta, Michela, de Brabander, Justin, de Bree, Godelieve, de Bruin, Sanne, Buis, David, Bugiani, Marianna, Bulle, Esther, Chouchane, Osoul, Cloherty, Alex, Dijkstra, Mirjam, Dongelmans, Dave, Dujardin, Romein, Elbers, Paul, Fleuren, Lucas, Geerlings, Suzanne, Geijtenbeek, Theo, Girbes, Armand, Goorhuis, Bram, Grobusch, Martin, Hafkamp, Florianne, Hagens, Laura, Hamann, Jorg, Harris, Vanessa, Hemke, Robert, Hermans, Sabine, Heunks, Leo, Hollmann, Markus, Horn, Janneke, Hovius, Joppe, de Jong, Menno, Lim, Endry, van Mourik, Niels, Nellen, Jeaninne, Nossent, Esther, Paulus, Frederique, Peters, Edgar, Pina-Fuentes, Dan, van der Poll, Tom, Preckel, Bennedikt, Prins, Jan, Raasveld, Jorinde, Reijnders, Tom, de Rotte, Maurits, Schinkel, Michiel, Schultz, Marcus, Schrauwen, Femke, Schuurman, Alex, Schuurmans, Jaap, Sigaloff, Kim, Slim, Marleen, Smeele, Patrick, Smit, Marry, Stijnis, Cornelis, Stilma, Willemke, Teunissen, Charlotte, Thoral, Patrick, Tsonas, Anissa, Tuinman, Pieter, van der Valk, Marc, Veelo, Denise, Volleman, Carolien, de Vries, Heder, Vught, Lonneke, van Vugt, Michèle, Wouters, Dorien, Zwinderman, A., Brouwer, Matthijs, Wiersinga, W. Joost, Vlaar, Alexander, Al-Muhsen, Saleh, Al-Mulla, Fahd, Arias, Andrés, Bogunovic, Dusan, Bolze, Alexandre, Bryceson, Yenan, Bustamante, Carlos, Butte, Manish, Chakravorty, Samya, Christodoulou, John, Constantinescu, Stefan, Cooper, Megan, Desai, Murkesh, Drolet, Beth, El Baghdadi, Jamila, Espinosa-Padilla, Sara, Froidure, Antoine, Henrickson, Sarah, Hsieh, Elena, Husebye, Eystein, Imai, Kohsuke, Itan, Yuval, Jarvis, Erich, Karamitros, Timokratis, Ku, Cheng-Lung, Ling, Yun, Lucas, Carrie, Maniatis, Tom, Maródi, László, Milner, Joshua, Mironska, Kristina, Novelli, Antonio, Novelli, Giuseppe, de Diego, Rebeca Perez, Perez-Tur, Jordi, Arkin, Lisa, Asano, Takaki, Oriol, Roger Colobran, Renia, Laurent, Resnick, Igor, Sancho-Shimizu, Vanessa, Seppänen, Mikko R.J., Shahrooei, Mohammed, Slaby, Ondrej, Tayoun, Ahmad Abou, Ramaswamy, Sathishkumar, Turvey, Stuart, Uddin, K., Uddin, Mohammed, von Bernuth, Horst, Zawadzki, Pawel, Grimbacher, Bodo, Pape, Jean, Perlin, David, Pesole, Graziano, García, Paula Andrea Gaviria, López, Gustavo Andrés Salguero, Rojas-Villaraga, Adriana, Vélez, Verónica Posada, Landinez, Lina Marcela Acevedo, Correales, Luisa Paola Duarte, Gómez, Oscar, Guaqueta, Jeser Santiago Grass, Pérez, Cristian Alejandro Ricaurte, Carrillo, Jorge, Vergara, José Alejandro Daza, Landinez, Sandra, Mantilla, Rubén, Yepes, Jairo David Torres, Ricaurte, Oscar Andrés Briceño, Pérez-Díaz, Carlos, Mateus, Yady Nataly, Navarro, Laura Mancera, Rodríguez, Yhojan, Acosta-Ampudia, Yeny, Monsalve, Diana, Rojas, Manuel, Nadif, Rachel, Goldberg, Marcel, Ozguler, Anna, Henny, Joseph, Lemonnier, Sylvie, Coeuret-Pellicer, Mireille, Got, Stéphane Le, Tzourio, Christophe, Dufouil, Carole, Soumaré, Aïcha, Lachaize, Morgane, Fievet, Nathalie, Flaig, Amandine, Martin, Fernando, Bonneaudeau, Brigitte, Cannet, Dorothée, Gallian, Pierre, Jeanne, Michel, Perroquin, Magali, Hamzeh-Cognasse, Hind, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Rockefeller University [New York], Hiroshima University, Vall d’Hebron Research Institute (VHIR), University of Tartu, CHU Henri Mondor, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang [La Plaine Saint-Denis] (EFS), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hospital Universitario Infanta Leonor [Madrid], Hospices Civils de Lyon (HCL), Grand Hôpital de l'Est Francilien (GHEF), Vall d'Hebron University Hospital [Barcelona], Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Assistance Publique - Hôpitaux de Marseille (APHM), National Institutes of Health [Bethesda] (NIH), Tokyo Medical and Dental University [Japan] (TMDU), Universitat de Barcelona (UB), Institut National de la Santé et de la Recherche Médicale (INSERM), Biomedical Research Foundation of the Academy of Athens (BRFAA), Institute for Systems Biology [Seattle] (ISB), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidad del Rosario [Bogota], Hospital Universitario de Gran Canaria Dr Negrin, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), Uniformed Services University of the Health Sciences (USUHS), University of British Columbia (UBC), CHU Necker - Enfants Malades [AP-HP], Spanish National Research Council (CSIC), Ghent University Hospital, Goce Delchev University (UGD), Invitae Corporation, Bilkent University [Ankara], Necmettin Erbakan University [Konya, Turquie], Centre Hospitalier Universitaire Hassan II (CHU HII), CHU Ibn Rochd [Casablanca], Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institute, Réseau International des Instituts Pasteur (RIIP), Tel Aviv Sourasky Medical Center [Te Aviv], The Feinstein Institute for Medical Research, IRCCS San Raffaele Scientific Institute [Milan, Italie], IRCCS Ospedale San Raffaele [Milan, Italy], Universidade de São Paulo = University of São Paulo (USP), Fundacion Rioja Salud, Amsterdam Neuroscience [Pays-Bas], Vrije Universiteit Amsterdam [Amsterdam] (VU)-University of Amsterdam [Amsterdam] (UvA)-VU University Medical Center [Amsterdam], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Shupyk National Medical Academy of Postgraduate Education [Kiev] (SNMAPE), I.Horbachevsky Ternopil State Medical University, Ternopil, Ukraine, Hospital Donostia, Garvan Institute of medical research, Sorbonne Université (SU), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Charles University [Prague] (CU), University Hospital Motol [Prague], Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology [Moscow, Russia], The University of Hong Kong (HKU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of La Sabana = Universitad de la Sabana, Hôpital Robert Ballanger [Aulnay-sous-Bois], Sackler Faculty of Medicine, Tel Aviv University (TAU), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Tallaght Hospital, Trinity College Dublin, University of Sharjah (UoS), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire CERBA [Saint Ouen l'Aumône], King Fahad University, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), McGill University = Université McGill [Montréal, Canada], Aarhus University [Aarhus], Instituto de Pesquisa Pelé Pequeno Principe, Hôpital Jean Verdier [AP-HP], Ecole Polytechnique Fédérale de Lausanne (EPFL), Yale University [New Haven], University of California [San Francisco] (UC San Francisco), University of California (UC), Academy of Athens, Institució Catalana de Recerca i Estudis Avançats (ICREA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Hôpital Bichat, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), IrsiCaixa (Institut de Recerca de la Sida), Hôpital Foch [Suresnes], Etablissement Français du Sang, EFS, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, National Institutes of Health (US), George Mason University, Yale University, National Human Genome Research Institute (US), Fisher Center for Alzheimer's Research Foundation, Meyer Foundation, JPB Foundation, Agence Nationale de la Recherche (France), Fondation pour la Recherche Médicale, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (France), Scientific Committee on Oceanic Research, Ministre de l'Enseignement Supérieur, de la Recherche et de l'Innovation (France), Institut National de la Santé et de la Recherche Médicale (France), Université de Paris, Fondation Bettencourt Schueller, Centro de Investigación Biomédica en Red Enfermedades Raras (España), European Commission, G. Harold & Leila Y. Mathers Foundation, Hospital Universitario Infanta Leonor, National Institute of Allergy and Infectious Diseases (US), National Institute of Dental and Craniofacial Research (US), Estonian Research Council, Al Jalila Foundation, American University of Sharjah, National Health and Medical Research Council (Australia), University of New South Wales (Australia), Regione Lombardia, Instituto de Salud Carlos III, Japan Agency for Medical Research and Development, Sorbonne Université, Université de Bordeaux, National Cancer Institute (US), Research Foundation - Flanders, Hellenic Foundation for Research and Innovation, Sao Paulo Research Foundation, The Meath Foundation, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), INSERM UMRS-1144, Université Paris Cité, Réanimation Médicale et Toxicologique, Hôpital Lariboisière, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, The Rockefeller University, the St. Giles Foundation, the NIH (Grants R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Awards program (Grant UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956), the Yale High Performance Computing Center (Grant S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (Grant ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (Grant EQU201903007798), the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05), the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects, the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, and the University Paris Cité. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (Grant ANR-10-LABX-69-01). K.K.’s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project 'Risposta immune in pazienti con COVID-19 e co-morbidità'). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés, Direction générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Program 'Cohortes et collections de données biologiques.' S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under Contract 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation - Flanders (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1, AEI/FEDER, European Union), Fundación DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants CGIEU0000219140 and 'Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19'). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health Professional-Investigator Award. P.Q.H. and L. Hammarström were funded by the European Union’s Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation de la Coopération Scientifique (ECOS) Nord - Coopération Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies (PID), by the Katholieke Universiteit Leuven C1 Grant C16/18/007, by a Flanders Institute for Biotechnology-Grand Challenges - PID grant, by the FWO Grants G0C8517N, G0B5120N, and G0E8420N, and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union’s Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the São Paulo Research Foundation (Grant 2020/09702-1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation., HGID Lab, COVID Clinicians, COVID-STORM Clinicians, NIAID Immune Response to COVID Group, NH-COVAIR Study Group, Danish CHGE, Danish Blood Donor Study, St. James's Hospital, SARS CoV2 Interest Group, French COVID Cohort Study Group, Imagine COVID-Group, Milieu Intérieur Consortium, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank Investigators, COVID Human Genetic Effort, CP-COVID-19 Group, CONSTANCES cohort, 3C-Dijon Study, Cerba Health-Care, Etablissement Français du Sang Study group, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-19-CE15-0009,CNSVIRGEN,Déficits immunitaires innés dans les infections sévères du tronc cérébral(2019), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), European Project: 948959,ERC-2020-STG,MORE2ADA2(2021), Manry, J, Bastard, P, Gervais, A, Le Voyer, T, Rosain, J, Philippot, Q, Michailidis, E, Hoffmann, H, Eto, S, Garcia-Prat, M, Bizien, L, Parra-Martínez, A, Yang, R, Haljasmägi, L, Migaud, M, Särekannu, K, Maslovskaja, J, de Prost, N, Tandjaoui-Lambiotte, Y, Luyt, C, Amador-Borrero, B, Gaudet, A, Poissy, J, Morel, P, Richard, P, Cognasse, F, Troya, J, Trouillet-Assant, S, Belot, A, Saker, K, Garçon, P, Rivière, J, Lagier, J, Gentile, S, Rosen, L, Shaw, E, Morio, T, Tanaka, J, Dalmau, D, Tharaux, P, Sene, D, Stepanian, A, Mégarbane, B, Triantafyllia, V, Fekkar, A, Heath, J, Franco, J, Anaya, J, Solé-Violán, J, Imberti, L, Biondi, A, Bonfanti, P, Castagnoli, R, Delmonte, O, Zhang, Y, Snow, A, Holland, S, Biggs, C, Moncada-Vélez, M, Arias, A, Lorenzo, L, Boucherit, S, Anglicheau, D, Planas, A, Haerynck, F, Duvlis, S, Ozcelik, T, Keles, S, Bousfiha, A, El Bakkouri, J, Ramirez-Santana, C, Paul, S, Pan-Hammarström, Q, Hammarström, L, Dupont, A, Kurolap, A, Metz, C, Aiuti, A, Casari, G, Lampasona, V, Ciceri, F, Barreiros, L, Dominguez-Garrido, E, Vidigal, M, Zatz, M, van de Beek, D, Sahanic, S, Tancevski, I, Stepanovskyy, Y, Boyarchuk, O, Nukui, Y, Tsumura, M, Vidaur, L, Tangye, S, Burrel, S, Duffy, D, Quintana-Murci, L, Klocperk, A, Kann, N, Shcherbina, A, Lau, Y, Leung, D, Coulongeat, M, Marlet, J, Koning, R, Reyes, L, Chauvineau-Grenier, A, Venet, F, Monneret, G, Nussenzweig, M, Arrestier, R, Boudhabhay, I, Baris-Feldman, H, Hagin, D, Wauters, J, Meyts, I, Dyer, A, Kennelly, S, Bourke, N, Halwani, R, Sharif-Askari, F, Dorgham, K, Sallette, J, Sedkaoui, S, Alkhater, S, Rigo-Bonnin, R, Morandeira, F, Roussel, L, Vinh, D, Erikstrup, C, Condino-Neto, A, Prando, C, Bondarenko, A, Spaan, A, Gilardin, L, Fellay, J, Lyonnet, S, Bilguvar, K, Lifton, R, Mane, S, Anderson, M, Boisson, B, Béziat, V, Zhang, S, Andreakos, E, Hermine, O, Pujol, A, Peterson, P, Mogensen, T, Rowen, L, Mond, J, Debette, S, de Lamballerie, X, Burdet, C, Bouadma, L, Zins, M, Soler-Palacin, P, Colobran, R, Gorochov, G, Solanich, X, Susen, S, Martinez-Picado, J, Raoult, D, Vasse, M, Gregersen, P, Piemonti, L, Rodríguez-Gallego, C, Notarangelo, L, Su, H, Kisand, K, Okada, S, Puel, A, Jouanguy, E, Rice, C, Tiberghien, P, Zhang, Q, Casanova, J, Abel, L, Cobat, A, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Neurology, AII - Infectious diseases, ANS - Neuroinfection & -inflammation, Graduate School, Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Gunst, Jan, Acibadem University Dspace, Manry, Jérémy, Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Michailidis, Eleftherio, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martínez, Alba, Yang, Rui, Haljasmägi, Lii, Migaud, Mélanie, Särekannu, Karita, Maslovskaja, Julia, de Prost, Nicola, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesú, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garçon, Pierre, Rivière, Jacques G, Lagier, Jean-Christophe, Gentile, Stéphanie, Rosen, Lindsey B, Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Loui, Sene, Damien, Stepanian, Alain, Mégarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James R, Franco, José Lui, Anaya, Juan-Manuel, Solé-Violán, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia M, Zhang, Yu, Snow, Andrew L, Holland, Steven M, Biggs, Catherine M, Moncada-Vélez, Marcela, Arias, Andrés Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Anglicheau, Dany, Planas, Anna M, Haerynck, Filomeen, Duvlis, Sotirija, Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed A, El Bakkouri, Jalila, Ramirez-Santana, Carolina, Paul, Stéphane, Pan-Hammarström, Qiang, Hammarström, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine N, Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila A, Dominguez-Garrido, Elena, Vidigal, Mateu, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart G, Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Llui, Klocperk, Adam, Kann, Nelli Y, Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angélique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel C, Arrestier, Romain, Boudhabhay, Idri, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam H, Kennelly, Sean P, Bourke, Nollaig M, Halwani, Rabih, Sharif-Askari, Fatemeh Saheb, Dorgham, Karim, Sallette, Jérôme, Sedkaoui, Souad Mehlal, Alkhater, Suzan, Rigo-Bonnin, Raúl, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald C, Erikstrup, Christian, Condino-Neto, Antonio, Prando, Carolina, Bondarenko, Anastasiia, Spaan, András N, Gilardin, Laurent, Fellay, Jacque, Lyonnet, Stanisla, Bilguvar, Kaya, Lifton, Richard P, Mane, Shrikant, Anderson, Mark S, Boisson, Bertrand, Béziat, Vivien, Zhang, Shen-Ying, Andreakos, Evangelo, Hermine, Olivier, Pujol, Aurora, Peterson, Pärt, Mogensen, Trine H, Rowen, Lee, Mond, Jame, Debette, Stéphanie, de Lamballerie, Xavier, Burdet, Charle, Bouadma, Lila, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter K, Piemonti, Lorenzo, Rodríguez-Gallego, Carlo, Notarangelo, Luigi D, Su, Helen C, Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles M, Tiberghien, Pierre, Zhang, Qian, Casanova, Jean-Laurent, Abel, Laurent, Cobat, Aurélie, Vougny, Marie-Christine, and Amsterdam Neuroscience - Neuroinfection & -inflammation

Subjects
Adult, Male, Risk, infection fatality rate, [SDV.IMM] Life Sciences [q-bio]/Immunology, autoantibodies, chronic mucocutaneous candidiasis, CHRONIC MUCOCUTANEOUS CANDIDIASIS, Autoimmunity, IMMUNITY, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Article, DISEASE, Basic medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, INFECTION, Medicine and Health Sciences, Humans, IMUNOLOGIA, Aged, Autoantibodies, Aged, 80 and over, disease, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Multidisciplinary, SARS-CoV-2, type I IFNs, Age Factors, COVID-19, Type I IFNs, Middle Aged, autoantibodie, immunity, Antibodies, Neutralizing, infection, Infection fatality rate, Relative risk, relative risk, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, type I IFN
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged 4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals, The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute; The Rockefeller University; the St. Giles Foundation; the NIH (Grants R01AI088364 and R01AI163029); the National Center for Advancing Translational Sciences; NIH Clinical and Translational Science Awards program (Grant UL1 TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at George Mason University; the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956); the Yale High Performance Computing Center (Grant S10OD018521); the Fisher Center for Alzheimer’s Research Foundation; the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the “Investments for the Future” program (Grant ANR-10-IAHU-01); the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (Grant EQU201903007798); the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05); the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects; the Square Foundation; Grandir–Fonds de solidarité pour l’Enfance; the Fondation du Souffle; the SCOR Corporate Foundation for Science; The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19); Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM; and the University Paris Cité. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (Grant ANR-10-LABX-69-01). K.K.’s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e co-morbidità”). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés, Direction générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Program “Cohortes et collections de données biologiques.” S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under Contract 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation - Flanders (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1; AEI/FEDER, European Union), Fundación DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health Professional-Investigator Award. P.Q.H. and L. Hammarström were funded by the European Union’s Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation de la Coopération Scientifique (ECOS) Nord - Coopération Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies (PID); by the Katholieke Universiteit Leuven C1 Grant C16/18/007; by a Flanders Institute for Biotechnology-Grand Challenges - PID grant; by the FWO Grants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union’s Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the São Paulo Research Foundation (Grant 2020/09702-1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation.

Published
2022

44. Anatomical study of the clitoris and its implications on female genital mutilation and surgical repair

Author

Cécile Philandrianos, Valentin Massin, Baptiste Bertrand, Maxime Abellan-Lopez, Olivier Camuzard, Dominique Casanova, Anne-Sophie Perchenet, Arthur Klein, and Fanny Blayney

Subjects
Clitoridectomy, medicine.medical_specialty, Clitoris, 030230 surgery, Glans Clitoris, Vulva, 03 medical and health sciences, 0302 clinical medicine, Cadaver, medicine, Humans, 030219 obstetrics & reproductive medicine, business.industry, Suspensory ligament, Plastic Surgery Procedures, Neurovascular bundle, Surgery, Dissection, medicine.anatomical_structure, Dorsal artery of clitoris, Circumcision, Female, Female, Dorsal nerve of clitoris, business
Abstract

Summary Background Worldwide, 200 million girls and women have been subjected to female genital mutilation. To restore the clitoral function and vulvar anatomy, clitoral repair has been performed since the 2000s. Nevertheless, there is a lack of precise and comprehensive data on the clitoral anatomy during surgical repair. This study aimed to precisely describe the terminal anatomies of the dorsal nerve and artery of the clitoris, and the clitoral neurovascular flap advancement for reconstruction in patients with female genital mutilation. Methods This study was performed on seven fresh female cadavers. The site of origin, diameter, length, and trajectory of each nerve and artery were recorded. The clitoral neurovascular flap advancement was measured after a midline transection of the suspensory ligament was performed and after extensive liberation of the dorsal bundles at their emergence from the pubic rami. Results At the distal point of the clitoral body, the width of the dorsal nerve and artery was 1.9 ± 0.3 mm and 0.9 ± 0.2 mm, respectively. The total length of the dorsal bundles was 6.6 cm (± 0.4). The midpart of the suspensory ligament was sectioned, which allowed a mean anteroposterior mobility of 2.7 cm (± 0.2). Extensive dissection of the neurovascular bundles up to their point of emergence from the suspensory ligament allowed a mean mobility of 3.4 ± 0.2 cm. Conclusion We described the anatomical characteristics of the dorsal nerve and artery of the clitoris and the mobility of the clitoral neurovascular flap for reconstruction post clitoridectomy. This was done to restore the anatomic position of the glans clitoris while preserving and potentially restoring clitoral function in patients with female genital mutilation.

Published
2021

45. Ceritinib in paediatric patients with anaplastic lymphoma kinase-positive malignancies: an open-label, multicentre, phase 1, dose-escalation and dose-expansion study

Author

Johannes H. Schulte, C. Michel Zwaan, David S. Ziegler, Michela Casanova, Matthias Fischer, Mario Stegert, Beate Wulff, Constantino Sábado, Meredith S. Irwin, Luojun Wang, Birgit Geoerger, Fabrice Branle, Felipe K. Hurtado, Lynley V. Marshall, Lucas Moreno, and Pediatrics

Subjects
Male, Oncology, medicine.medical_specialty, Adolescent, Maximum Tolerated Dose, Antineoplastic Agents, Pharmacokinetics, Refractory, Neoplasms, hemic and lymphatic diseases, Internal medicine, Neuroblastoma, medicine, Humans, Anaplastic lymphoma kinase, Anaplastic Lymphoma Kinase, Sulfones, Child, Rhabdomyosarcoma, Anaplastic large-cell lymphoma, Ceritinib, business.industry, Inflammatory myofibroblastic tumour, Infant, Prognosis, medicine.disease, Survival Rate, Pyrimidines, Child, Preschool, Mutation, Female, business, Follow-Up Studies, medicine.drug
Abstract

Background: Several paediatric malignancies, including anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumour (IMT), neuroblastoma, and rhabdomyosarcoma, harbour activation of anaplastic lymphoma kinase (ALK) through different mechanisms. Here, we report the safety, pharmacokinetics, and efficacy of ceritinib in paediatric patients with ALK-positive malignancies. Methods: This multicentre, open-label, phase 1 trial was done at 23 academic hospitals in ten countries. Children (aged ≥12 months to 2 daily and for the fed state was 320 mg/m2 daily. The primary objective of this study was to establish the maximum tolerated dose (ie, RDE) of ceritinib in the fasted and fed states. The RDE was established on the basis of the incidence of dose-limiting toxicities in patients who completed a minimum of 21 days of treatment with safety assessments and at least 75% drug exposure, or who discontinued treatment earlier because of dose-limiting toxicity. Overall response rate (defined as the proportion of patients with a best overall response of complete response or partial response) was a secondary endpoint. Activity and safety analyses were done in all patients who received at least one dose of ceritinib. This trial is registered with ClinicalTrials.gov (NCT01742286) and is completed. Findings: Between Aug 28, 2013, and Oct 17, 2017, 83 children with ALK-positive malignancies were enrolled to the dose-escalation (n=40) and dose-expansion (n=43) groups. The RDE of ceritinib was established as 510 mg/m2 (fasted) and 500 mg/m2 (fed). 55 patients (30 with neuroblastoma, ten with IMT, eight with ALCL, and seven with other tumour types) were treated with ceritinib at the RDE (13 patients at 510 mg/m2 fasted and 42 patients at 500 mg/m2 fed). The median follow-up was 33·3 months (IQR 24·8–39·3) for patients with neuroblastoma, 33·2 months (27·9–35·9) for those with IMT, 34·0 months (21·9–46·4) for those with ALCL, and 27·5 months (22·4–36·9) for patients with other tumour types. An overall response was recorded in six (20%; 95% CI 8–39) of 30 patients with neuroblastoma, seven (70%; 33–93) of ten patients with IMT, six (75%; 35–97) of eight patients with ALCL, and one (14%; 2 once daily with food is the recommended dose for paediatric patients with ALK-positive malignancies. Ceritinib showed promising preliminary antitumour activity in patients with ALK-positive refractory or recurrent IMT or ALCL, and in a subset of patients with relapsed or refractory neuroblastoma, with a manageable safety profile. Our data support the notion that ALK inhibitors should be considered in therapeutic strategies for paediatric patients with malignancies with genetic ALK alterations. Funding: Novartis Pharmaceutical Corporation.

Published
2021

46. Clinical Impact of Next-Generation Sequencing Multi-Gene Panel Highlighting the Landscape of Germline Alterations in Ovarian Cancer Patients

Author

Giorgia Gurioli, Gianluca Tedaldi, Alberto Farolfi, Elisabetta Petracci, Claudia Casanova, Giuseppe Comerci, Rita Danesi, Valentina Arcangeli, Mila Ravegnani, Daniele Calistri, Valentina Zampiga, Ilaria Cangini, Eugenio Fonzi, Alessandra Virga, Davide Tassinari, Marta Rosati, Paola Ulivi, and Ugo De Giorgi

Subjects
Ovarian Neoplasms, BRCA1 Protein, Genes, BRCA2, Organic Chemistry, High-Throughput Nucleotide Sequencing, Breast Neoplasms, General Medicine, Catalysis, Computer Science Applications, ovarian cancer, BRCA1/2, cancer predisposition, platinum sensitivity, PARP inhibitors, platelets, Inorganic Chemistry, Mutation, Humans, Female, Genetic Predisposition to Disease, Physical and Theoretical Chemistry, Molecular Biology, Germ-Line Mutation, Spectroscopy
Abstract

BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations in genes other than BRCA1/2 that could be associated with a high risk of developing OC and permit patients to enter the most appropriate treatment and surveillance program. Next-generation sequencing analysis with a 94-gene panel was performed on germline DNA of 219 OC patients. We identified 34 pathogenic/likely pathogenic variants in BRCA1/2 and 38 in other 21 genes. The patients with pathogenic/likely pathogenic variants in the non-BRCA1/2 genes mainly developed OC alone compared to the other groups that also developed breast cancer or other tumors (p = 0.001). Clinical correlation analysis showed that the low-risk patients were significantly associated with platinum sensitivity (p < 0.001). Regarding PARP inhibitors (PARPi) response, the patients with pathogenic mutations in the non-BRCA1/2 genes had worse PFS and OS. Moreover, a statistically significantly worse PFS was found for every increase of one thousand platelets before PARPi treatment. To conclude, knowledge about molecular alterations in genes beyond BRCA1/2 in OC could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies for OC patients.

Published
2022
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47. Assessment of patient navigation programs for breast cancer patients across the city of Boston

Author

Katelyn R Mullikin, Stephenie C. Lemon, Ellen Ohrenberger, JoEllen Ross, Susan K. Parsons, Amy M LeClair, Naomi Y. Ko, Tracy A. Battaglia, Jennifer S. Haas, Nicole Casanova, Beverly Moy, and Karen M. Freund

Subjects
medicine.medical_specialty, Operationalization, business.industry, Nursing research, Breast Neoplasms, Continuity of Patient Care, medicine.disease, Care Continuum, Article, Health equity, Clinical trial, Workflow, Breast cancer, Oncology, Intervention (counseling), Family medicine, Humans, Patient Navigation, Medicine, Female, business, Delivery of Health Care, Boston
Abstract

PURPOSE: Healthcare systems contribute to disparities in breast cancer outcomes. Patient navigation is a widely cited systembased approach to improve outcomes among populations at risk for delays in care. Patient navigation programs exist in all major Boston hospitals, yet disparities in outcomes persist. The objective of this study was to conduct a baseline assessment of navigation processes at six Boston hospitals that provide breast cancer care in preparation for an implementation trial of standardized navigation across the city. METHODS: We conducted a mixed methods study in six hospitals that provide treatment to breast cancer patients in Boston. We administered a web-based survey to clinical champions (n = 7) across six sites to collect information about the structure of navigation programs. We then conducted in-person workflow assessments at each site using a semi-structured interview guide to understand site-specific implementation processes for patient navigation programs. The target population included administrators, supervisors, and patient navigators who provided breast cancer treatment-focused care. RESULTS: All sites offered patient navigation services to their patients undergoing treatment for breast cancer. We identified wide heterogeneity in terms of how programs were funded/resourced, which patients were targeted for navigation, the type of services provided, and the continuity of those services relative to the patient’s cancer treatment. CONCLUSIONS: The operationalization of patient navigation varies widely across hospitals especially in relation to three core principles in patient navigation: providing patient support across the care continuum, targeting services to those patients most likely to experience delays in care, and systematically screening for and addressing patients’ health-related social needs. Gaps in navigation across the care continuum present opportunities for intervention. TRIAL REGISTRATION: Clinical Trial Registration Number NCT03514433, 5/2/2018

Published
2021

48. Infant Metabolome in Relation to Prenatal DHA Supplementation and Maternal Single-Nucleotide Polymorphism rs174602: Secondary Analysis of a Randomized Controlled Trial in Mexico

Author

Aryeh D. Stein, Hans Demmelmair, Albino Barraza-Villarreal, Dean P. Jones, Berthold Koletzko, Isabelle Romieu, Usha Ramakrishnan, Sonia Tandon, and Ines Gonzalez-Casanova

Subjects
medicine.medical_specialty, Docosahexaenoic Acids, Offspring, Mothers, Medicine (miscellaneous), Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, chemistry.chemical_compound, Child Development, Double-Blind Method, Pregnancy, Polymorphism (computer science), Internal medicine, medicine, Metabolome, Humans, Genomics, Proteomics, and Metabolomics, Mexico, chemistry.chemical_classification, Nutrition and Dietetics, Fatty acid metabolism, biology, business.industry, Infant, Fatty acid, Minor allele frequency, Endocrinology, Fatty acid desaturase, chemistry, Dietary Supplements, biology.protein, Female, business
Abstract

BACKGROUND: Although DHA (22:6n–3) is critical for fetal development, results from randomized controlled trials (RCTs) of prenatal DHA supplementation report inconsistent effects on offspring health. Variants in fatty acid desaturase (FADS) genes that regulate the conversion of n–3 and n–6 essential fatty acids into their biologically active derivatives may explain this heterogeneity. OBJECTIVES: We investigated the effect of prenatal DHA supplementation on the offspring metabolome at age 3 mo and explored differences by maternal FADS single-nucleotide polymorphism (SNP) rs174602. METHODS: Data were obtained from a double-blind RCT in Mexico [POSGRAD (Prenatal Omega-3 Fatty Acid Supplementation and Child Growth and Development)] in which women (18–35 y old) received DHA (400 mg/d) or placebo from mid-gestation until delivery. Using high-resolution MS with LC, untargeted metabolomics was performed on 112 offspring plasma samples. Discriminatory metabolic features were selected via linear regression (P

Published
2021

49. Structural and functional connectivity of the ascending arousal network for prediction of outcome in patients with acute disorders of consciousness

Author

Carol J. Zarate-Ardila, Diana Andrea Vera Rivera, Mayra A. Hurtado, Cesar O Enciso-Olivera, Cristian Pulido, Francisco Gómez, Jorge H. Marín-Muñoz, José L. Hernández, Natalia Guerrero, Edgar G. Ordóñez-Rubiano, Jorge Rudas, Rosangela Casanova-Libreros, Darwin Martínez, Clara P. Hernández-Torres, and Natalia Aguilera-Bustos

Subjects
Adult, Male, medicine.medical_specialty, Consciousness, Traumatic brain injury, Science, Functional magnetic resonance imaging, Article, Arousal, White matter, Magnetic resonance imaging, Internal medicine, Brain Injuries, Traumatic, Neural Pathways, Image Processing, Computer-Assisted, Medicine, Humans, Coma, Stroke, Aged, Univariate analysis, Multidisciplinary, business.industry, Minimally conscious state, Brain, Middle Aged, medicine.disease, Prognosis, Heart Arrest, medicine.anatomical_structure, Diffusion Tensor Imaging, nervous system, Oxygen Saturation, Brain Injuries, Cardiology, Consciousness Disorders, Wakefulness, Female, business, Neurological disorders, Biomarkers, Diffusion MRI
Abstract

Object: To determine the role of early acquisition of blood oxygen level-dependent (BOLD) signals and diffusion tensor imaging (DTI) for analysis of the connectivity of the ascending arousal network (AAN) in predicting neurological outcomes after acute traumatic brain injury (TBI), cardiopulmonary arrest (CPA), or stroke.Methods: A prospective analysis of 50 comatose patients was performed during their ICU stay. Image processing was conducted to assess structural and functional connectivity of the AAN. Outcomes were evaluated after 3 and 6 months.Results: Nineteen patients (38%) had stroke, 18 (36%) CPA, and 13 (26%) TBI. Twenty-three patients were comatose (44%), 11 were in a minimally conscious state (20%), and 16 had unresponsive wakefulness syndrome (32%). Univariate analysis demonstrated that measurements of diffusivity, functional connectivity, and numbers of fibers in the gray matter, white matter, whole brain, midbrain reticular formation, and pontis oralis nucleus may serve as predictive biomarkers of outcome depending on the diagnosis. Multivariate analysis demonstrated a correlation of the predicted value and the real outcome for each separate diagnosis and for all the etiologies together.Conclusion: Findings suggest that the above imaging biomarkers may have a predictive role for the outcome of comatose patients after acute TBI, CPA, or stroke.

Published
2021

50. Measles Sclerosing Subacute PanEncephalitis (SSPE), an intriguing and ever-present disease: Data, assumptions and new perspectives

Author

A. Gelot, Pierre Lebon, Jean-Laurent Casanova, Shen-Ying Zhang, and J.-J. Hauw

Subjects
Adult, Pediatrics, medicine.medical_specialty, Neurological complication, Fulminant, Disease, Communicable Diseases, Measles, Subacute sclerosing panencephalitis, Measles virus, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, medicine, Humans, 030212 general & internal medicine, Epidemics, Exome sequencing, biology, business.industry, Vaccination, biology.organism_classification, medicine.disease, Neurology, Female, Subacute Sclerosing Panencephalitis, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background Subacute sclerosing panencephalitis (SSPE) is a rare, non-treatable and fatal neurological complication of measles , still present due to the return of the epidemic linked to the loosening of vaccination policies. Its mechanism remains unexplained. Objective The main objective was to investigate explanatory variables relating to the risk of developing SSPE and its pathophysiology . Methods Literature analysis was focused on different varieties of SSPE: perinatal forms, short-incubation forms similar to acute measles inclusion body encephalitis (MIBE), rapidly evolving forms, forms occurring in the immunosuppressed, adult forms, and family forms. In addition, several studies on the parameters of innate immunity and interferon responses of patients were analyzed. Results Two main data were highlighted: a relationship between the so-called fulminant forms and the prescription of corticosteroids was established. In familial SSPE, two groups were individualized according to the duration of the latency period, prompting an analysis of patient exomes . Conclusion Treatment with corticosteroids should be banned. Knowledge of the genes involved and epigenetics should be useful for understanding the pathophysiology of SSPE and other late-onset neurological infections with RNA viruses .

Published
2021

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