HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management.

Human papillomavirus (HPV)-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the UICC/AJCC staging system separates HPV+ OPSCC from its HPV-negative (HPV-) counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment de-intensification as a means to improve quality of life while maintaining acceptable survival outcomes. In addition, owing to the distinct biology of HPV+ OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage owing to a lack of symptoms in the early stages; therefore, a need exists to identify and validate possible diagnostic biomarkers to aid in earlier detection. In this Review, we provide a summary of the epidemiology, molecular biology and clinical management of HPV+ OPSCC in an effort to highlight important advances in the field. Ultimately, a need exists for improved understanding of the molecular basis and clinical course of this disease to guide efforts towards early detection and precision care, and to improve patient outcomes

A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution

Bulk-tissue DNA methylomes represent an average over many different cell types, hampering our understanding of cell-type-specific contributions to disease development. As single-cell methylomics is not scalable to large cohorts of individuals, cost-effective computational solutions are needed, yet current methods are limited to tissues such as blood. Here we leverage the high-resolution nature of tissue-specific single-cell RNA-sequencing datasets to construct a DNA methylation atlas defined for 13 solid tissue types and 40 cell types. We comprehensively validate this atlas in independent bulk and single-nucleus DNA methylation datasets. We demonstrate that it correctly predicts the cell of origin of diverse cancer types and discovers new prognostic associations in olfactory neuroblastoma and stage 2 melanoma. In brain, the atlas predicts a neuronal origin for schizophrenia, with neuron-specific differential DNA methylation enriched for corresponding genome-wide association study risk loci. In summary, the DNA methylation atlas enables the decomposition of 13 different human tissue types at a high cellular resolution, paving the way for an improved interpretation of epigenetic data

Anosmia as a presenting symptom of SARS-CoV-2 infection in healthcare workers – A systematic review of the literature, case series, and recommendations for clinical assessment and management

Background: Healthcare workers are at the forefront of the ongoing COVID-19 pandemic and are at high risk for both the contraction and subsequent spread of virus. Understanding the role of anosmia as an early symptom of infection may improve monitoring and management of SARS-CoV2 infection. Methodology: We conducted a systematic review of the literature of SARS-CoV2 infection/COVID-19 and anosmia to help inform management of anosmia in healthcare works. We report a case series of healthcare workers, who presented with a loss of sense of smell secondary to COVID-19 infection to demonstrate management principles. RT-PCR was used to confirm COVID-19 positivity and psychophysical testing of olfaction was performed using the British version of the University of Pennsylvania Smell Identification Test, UPSIT. Results: The systematic literature search returned 31 articles eligible for inclusion in the study and informed our recommendations for clinical assessment and management. All three healthcare professionals who presented with loss of sense of smell subsequently tested positive for SARS-CoV-2. Psychophysical testing of olfaction using the UPSIT confirmed mild and moderate microsmia in two, respectively, and normosmia at day 17 in one. Conclusions: Olfactory (± gustatory) dysfunction is indicative of COVID-19 infection and thus has important implications in the context of healthcare workers, or key workers in general, who work in close contact with others if not recognised as suffering from COVID. This leads to a potentially higher likelihood of spreading the virus. In conjunction with our literature review these findings have helped with creating recommendations on the assessment and management of olfactory dysfunction during the ongoing COVID-19 pandemic, both for healthcare workers and patients

SSTR2 in Nasopharyngeal Carcinoma:Relationship with Latent EBV Infection and Potential as a Therapeutic Target

SIMPLE SUMMARY: Nasopharyngeal cancer (NPC) is a malignant epithelial tumor endemic to parts of Asia and associated with infection by the Epstein–Barr virus (EBV) in these regions. The cancer is often detected at a late stage which is associated with poor outcomes (63% 5-year survival). Advances for the management of this disease have remained largely stagnant and treatment relies primarily on radiotherapy and chemotherapy, as well as surgery when indicated. Nevertheless, our understanding of its underlying biology has grown rapidly in the past two decades, laying the foundation for the development of improved therapeutics which have the potential to improve outcomes. This review offers a comprehensive, up-to-date summary of this disease, with a focus on the role of somatostatin receptor 2 (SSTR2) in NPC and how this increased knowledge may lead to improved diagnosis and management of this disease. ABSTRACT: Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor, most commonly located in the pharyngeal recess and endemic to parts of Asia. It is often detected at a late stage which is associated with poor prognosis (5-year survival rate of 63%). Treatment for this malignancy relies predominantly on radiotherapy and/or systemic chemotherapy, which can be associated with significant morbidity and impaired quality of life. In endemic regions NPC is associated with infection by Epstein–Barr virus (EBV) which was shown to upregulate the somatostatin receptor 2 (SSTR2) cell surface receptor. With recent advances in molecular techniques allowing for an improved understanding of the molecular aetiology of this disease and its relation to SSTR2 expression, we provide a comprehensive and up-to-date overview of this disease and highlight the emergence of SSTR2 as a key tumor biomarker and promising target for imaging and therapy

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. There are 286 authors of this articles not all are listed in this record

Course of symptoms for loss of sense of smell and taste over time in one thousand forty-one healthcare workers during the Covid-19 pandemic: Our experience

On April 21, 2020, the Centers for Disease Control and Prevention (CDC) and on May 5, 2020, the World Health Organisation added 'new loss of taste or smell' to their list of symptoms related to Covid-19, respectively. Public Health England (PHE) only included loss of smell and taste as official symptoms on May 20th . However, whether individual hospitals were including smell and taste disturbances in their initial work-up for Covid-19 diagnosis is unknown

Retrieving the C and O Abundances of HR 7672~AB: a Solar-Type Primary Star with a Benchmark Brown Dwarf

A benchmark brown dwarf (BD) is a BD whose properties (e.g., mass and chemical composition) are precisely and independently measured. Benchmark BDs are valuable in testing theoretical evolutionary tracks, spectral synthesis, and atmospheric retrievals for sub-stellar objects. Here, we report results of atmospheric retrieval on a synthetic spectrum and a benchmark BD -- HR 7672~B -- with \petit. First, we test the retrieval framework on a synthetic PHOENIX BT-Settl spectrum with a solar composition. We show that the retrieved C and O abundances are consistent with solar values, but the retrieved C/O is overestimated by 0.13-0.18, which is $\sim$4 times higher than the formal error bar. Second, we perform retrieval on HR 7672~B using high spectral resolution data (R=35,000) from the Keck Planet Imager and Characterizer (KPIC) and near infrared photometry. We retrieve [C/H], [O/H], and C/O to be $-0.24\pm0.05$, $-0.19\pm0.04$, and $0.52\pm0.02$. These values are consistent with those of HR 7672~A within 1.5-$\sigma$. As such, HR 7672~B is among only a few benchmark BDs (along with Gl 570~D and HD 3651~B) that have been demonstrated to have consistent elemental abundances with their primary stars. Our work provides a practical procedure of testing and performing atmospheric retrieval, and sheds light on potential systematics of future retrievals using high- and low-resolution data.Comment: 29 pages, 17 figures, 5 tables, resubmitted to AAS journals after first revisio

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London