Body dissatisfaction and body change strategies among adolescents : a longitudinal investigation

This thesis examined body dissatisfaction and body change behaviors among adolescent girls and boys from a biopsychosocial framework. The contribution of biological, psychological and sociocultural factors were examined in relation to body dissatisfaction, weight loss, weight gain and increased muscle tone behaviors among early adolescent girls and boys. In particular, pubertal maturation, body mass index (BMI), perception of body shape and size and psychological factors, such as depression, anxiety, ineffectiveness, self-esteem and perfectionism, were examined as possible factors that may precipitate or maintain body dissatisfaction and engagement in body change strategies. The sociocultural factors evaluated were the quality of family and peer relationships, as well as the influence of family and peers in predicting the adoption of specific body change strategies. The specific mechanisms by which these influences were transmitted were also examined. These included perceived discussion, encouragement and modelling of various body change strategies, as well as perceived teasing about body shape and size. A number of separate cross-sectional and longitudinal studies were conducted to examine the above relationships and identify the factors that contribute to weight loss, weight gain and increased muscle tone behaviors in adolescents. Study 1 examined the psychometric properties and principal components structure of the Bulimia Test Revised (BULIT-R; Thelen, Farmer, Wonderlich, & Smith, 1991) to assess its applicability to adolescent samples. Study 2 investigated the nature of body dissatisfaction and weight loss behaviors among 603 adolescents (306 girls and 297 boys) using a standardised questionnaire. This preliminary study was conducted to ascertain whether variables previously found to be relevant to adolescent girls, could also be related to the development of body dissatisfaction and weight loss behaviors among adolescent boys. Studies 3 and 4 described the development and validation of a body modification scale that measured weight loss, weight gain and increased muscle tone behaviors. Studies 5 and 6 were designed to modify an Excessive Exercise Scale developed by Long, Smith, Midgley, and Cassidy (1993) into a shorter form, and validate this scale with an adolescent sample. Study 7 investigated the factors that contribute to weight loss, weight gain and increased muscle among adolescent girls and boys both cross-sectionally and longitudinally (over one year). Structural equation modelling was used to examine associations among self-reported body dissatisfaction, body change strategies and a range of biological, psychological and sociocultural variables both cross-sectionally and longitudinally. Overall, the results suggested that both girls and boys experience body dissatisfaction and engage in a number of different body change strategies in order to achieve an ideal size. A number of gender similarities and differences were identified in the expression of body dissatisfaction and the adoption of body change strategies for both girls and boys. Girls were more likely than boys to report body dissatisfaction and engage in weight loss behaviors, while boys were more likely than girls to engage in weight gain and increased muscle tone behaviors. Generally, the same factors were found to contribute to weight loss, and more specifically, bulimic symptomatology, ad weight gain in both adolescent girls and boys. While a combination of biological, psychological and sociocultural factors contributed to bulimic symptomatology, only biological and psychological factors were found to contribute to weight gain in adolescents. The most notable gender differences were found in the model of increased muscle tone. Sociocultural and biological factors contributed to increased muscle tone behaviors in girls, while sociocultural and psychological factors were implicated in these behaviors in adolescent boys. With the exception of the model of increased muscle tone for boys, body dissatisfaction was a consistent factor in the adoption of body change behaviors. Consistent with previous investigations, the present thesis provides empirical support for the need to examine the etiology and maintenance of such concerns and behaviors from a multifaceted perspective

Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-β production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses

Genotype-phenotype features of germline variants of the TMEM127 pheochromocytoma susceptibility gene: A 10-year update

Purpose: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). Design: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. Main Outcome Analysis: Clinical, genetic, and functional associations were determined. Results: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P <. 001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P <. 001) and clustered disproportionately within transmembrane regions (P <. 01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. Conclusions: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.Fil: Armaiz Pena, Gustavo. University Of Texas Health Science Center At San Antonio;; Estados UnidosFil: Flores, Shahida K.. No especifíca;Fil: Cheng, Zi Ming. No especifíca;Fil: Zhang, Xhingyu. No especifíca;Fil: Esquivel, Emmanuel. No especifíca;Fil: Poullard, Natalie. No especifíca;Fil: Vaidyanathan, Anusha. No especifíca;Fil: Liu, Qianqian. No especifíca;Fil: Michalek, Joel. No especifíca;Fil: Santillan Gomez, Alfredo A.. No especifíca;Fil: Liss, Michael. No especifíca;Fil: Ahmadi, Sara. No especifíca;Fil: Katselnik, Daniel. No especifíca;Fil: Maldonado, Enrique. No especifíca;Fil: Salgado, Sarimar Agosto. No especifíca;Fil: Jimenez, Camilo. No especifíca;Fil: Fishbein, Lauren. No especifíca;Fil: Hamidi, Oksana. No especifíca;Fil: Else, Tobias. No especifíca;Fil: Lechan, Ron. Tufts Medical Center; Estados UnidosFil: Tischler, Art S.. Tufts Medical Center; Estados UnidosFil: Benn, Diana E.. No especifíca;Fil: Dwight, Trisha. University of Technology Sydney; AustraliaFil: Clifton Bligh, Rory. University of Technology Sydney; AustraliaFil: Sanso, Elsa Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Barontini, Marta Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Vincent, Deepa. Massachusetts Institute of Technology; Estados UnidosFil: Aronin, Neil. Massachusetts Institute of Technology; Estados UnidosFil: Biondi, Bernadette. University of Naples Federico II; ItaliaFil: Koops, Maureen. University of Texas Health San Antonio; Estados UnidosFil: Bowhay Carnes, Elizabeth. No especifíca;Fil: Gimenez Roqueplo, Anne Paule. No especifíca;Fil: Alvarez Eslava, Andrea. No especifíca;Fil: Bruder, Jan M.. No especifíca;Fil: Kitano, Mio. No especifíca;Fil: Burnichon, Nelly. No especifíca;Fil: Ding, Yanli. No especifíca;Fil: Dahia, Patricia L. M.. No especifíca

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

A year of genomic surveillance reveals how the SARS-CoV-2 pandemic unfolded in Africa.

The progression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in Africa has so far been heterogeneous, and the full impact is not yet well understood. In this study, we describe the genomic epidemiology using a dataset of 8746 genomes from 33 African countries and two overseas territories. We show that the epidemics in most countries were initiated by importations predominantly from Europe, which diminished after the early introduction of international travel restrictions. As the pandemic progressed, ongoing transmission in many countries and increasing mobility led to the emergence and spread within the continent of many variants of concern and interest, such as B.1.351, B.1.525, A.23.1, and C.1.1. Although distorted by low sampling numbers and blind spots, the findings highlight that Africa must not be left behind in the global pandemic response, otherwise it could become a source for new variants

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance.

Investment in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing in Africa over the past year has led to a major increase in the number of sequences that have been generated and used to track the pandemic on the continent, a number that now exceeds 100,000 genomes. Our results show an increase in the number of African countries that are able to sequence domestically and highlight that local sequencing enables faster turnaround times and more-regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and illuminate the distinct dispersal dynamics of variants of concern-particularly Alpha, Beta, Delta, and Omicron-on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve while the continent faces many emerging and reemerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century