Rare variants in single-minded 1 (SIM1) are associated with severe obesity

Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.Shwetha Ramachandrappa, Anne Raimondo, Anna M.G. Cali, Julia M. Keough, Elana Henning, Sadia Saeed, Amanda Thompson, Sumedha Garg, Elena G. Bochukova, Soren Brage, Victoria Trowse, Eleanor Wheeler, Adrienne E. Sullivan, Mehul Dattani, Peter E. Clayton, Vippan Datta, John B. Bruning, Nick J. Wareham, Stephen O'Rahilly, Daniel J. Peet, Ines Barroso, Murray L. Whielaw and I. Sadaf Farooq

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

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Testing For Human Papillomavirus Strains 16 And 18 Helps Predict The Presence Of Anal High-Grade Squamous Intraepithelial Lesions

BACKGROUND: More than 90% of anal cancers are caused by human papillomavirus, and human papillomavirus strains 16 and 18 are the most oncogenic. Anal high-grade squamous intraepithelial lesions are cancer precursors. Treating these high-grade intraepithelial lesions likely reduces the risk of cancer, but cytology is an imperfect screening test. OBJECTIVE: The purpose of this study was to determine whether human papillomavirus 16 and/or 18 testing better predicts the presence of high-grade squamous intraepithelial lesions. DESIGN: In this retrospective study, 894 consecutive patients underwent anal dysplasia screening with digital anorectal examination, anal cytology, high-risk human papillomavirus testing, and high-resolution anoscopy with biopsy. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value of each test and for a novel screening protocol. The absolute and relative risk of high-grade squamous intraepithelial lesions for all of the cytology/human papillomavirus combinations were also calculated. SETTINGS: The study was conducted at a single practice specializing in anal dysplasia. PATIENTS: Ninety-two percent of participants were men who have sex with men. Forty-four percent were HIV-positive individuals who were well controlled on antiretroviral therapy. The median age was 50 years. MAIN OUTCOME MEASURES: The presence of high-grade squamous intraepithelial lesions as a function of human papillomavirus and the cytology results were measured. RESULTS: High-risk human papillomavirus testing alone demonstrated better sensitivity (96% vs 89%; p = 0.03) and negative predictive value (99% vs 96%; p = 0.008) over cytology. Human papillomavirus 16/18 testing increased specificity (48% to 71%; p \u3c 0.0001) and positive predictive value (24% to 37%; p = 0.003) over testing for all of the high-risk strains. For each cytology category, high-grade squamous intraepithelial lesions were more prevalent when human papillomavirus 16/18 was detected. Benign cytology with 16/18 had a 31-fold increased risk of high-grade squamous intraepithelial lesions. LIMITATIONS: This study was conducted in a single private practice specializing in anal dysplasia screening with a mostly male population, and results might not be generalizable. CONCLUSIONS: Testing of high-risk human papillomavirus strains 16/18 improves specificity and positive predictive value over cytology for anal dysplasia screening. Patients testing positive for strains 16/18 are at a high risk for high-grade squamous intraepithelial lesions and should undergo high-resolution anoscopy regardless of the cytology result. See Video Abstract at http://links.lww.com/DCR/A654