Primary myxoid liposarcoma of the supraglottic larynx

Sarcomas are a rare occurrence accounting for roughly 1% of all cancer cases reported. Of these, 9–18% will be identified as liposarcoma. Overall, only 4–9% of all liposarcomas occur in the head and neck region. As such, it is a rare event to see a primary liposarcoma of the aerodigestive tract. These tumors are typically misdiagnosed secondary to their indolent, asymptomatic course and similarities in appearance to other benign lesions. An understanding of these lesions will help clinicians appropriately manage their patients. We present a case of a 60-year male with a primary supraglottic myxoid liposarcoma, and provide relevant information about liposarcomas

Preclinical evaluation of FLT190, a liver-directed AAV gene therapy for Fabry disease

Fabry disease is an X-linked lysosomal storage disorder caused by loss of alpha-galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of glycosphingolipids in multiple cells and tissues. FLT190, an investigational gene therapy, is currently being evaluated in a Phase 1/2 clinical trial in patients with Fabry disease (NCT04040049). FLT190 consists of a potent, synthetic capsid (AAVS3) containing an expression cassette with a codon-optimized human GLA cDNA under the control of a liver-specific promoter FRE1 (AAV2/S3-FRE1-GLAco). For mouse studies FLT190 genome was pseudotyped with AAV8 for efficient transduction. Preclinical studies in a murine model of Fabry disease (Gla-deficient mice), and non-human primates (NHPs) showed dose-dependent increases in plasma α-Gal A with steady-state observed 2 weeks following a single intravenous dose. In Fabry mice, AAV8-FLT190 treatment resulted in clearance of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in plasma, urine, kidney, and heart; electron microscopy analyses confirmed reductions in storage inclusion bodies in kidney and heart. In NHPs, α-Gal A expression was consistent with the levels of hGLA mRNA in liver, and no FLT190-related toxicities or adverse events were observed. Taken together, these studies demonstrate preclinical proof-of-concept of liver-directed gene therapy with FLT190 for the treatment of Fabry disease

Augmented Lung Inflammation Protects against Influenza A Pneumonia

Influenza pneumonia causes high mortality every year, and pandemic episodes kill millions of people. Influenza-related mortality has been variously ascribed to an ineffective host response that fails to limit viral replication, an excessive host inflammatory response that results in lung injury and impairment of gas exchange, or to bacterial superinfection. We sought to determine whether lung inflammation promoted or impaired host survival in influenza pneumonia.To distinguish among these possible causes of influenza-related death, we induced robust lung inflammation by exposing mice to an aerosolized bacterial lysate prior to challenge with live virus. The treatment induced expression of the inflammatory cytokines IL-6 and TNF in bronchoalveolar lavage fluid 8- and 40-fold greater, respectively, than that caused by lethal influenza infection. Yet, this augmented inflammation was associated with striking resistance to host mortality (0% vs 90% survival, p = 0.0001) and reduced viral titers (p = 0.004). Bacterial superinfection of virus infected lungs was not observed. When mice were repeatedly exposed to the bacterial lysate, as would be clinically desirable during an influenza epidemic, there was no tachyphylaxis of the induced viral resistance. When the bacterial lysate was administered after the viral challenge, there was still some mortality benefit, and when ribavirin was added to the aerosolized bacterial lysate, host survival was synergistically improved (0% vs 93.3% survival, p<0.0001).Together, these data indicate that innate immune resistance to influenza can be effectively stimulated, and suggest that ineffective rather than excessive inflammation is the major cause of mortality in influenza pneumonia

Fat, syn and disordered eating: The dangers and powers of excess

This is an accepted manuscript of an article published by Taylor & Francis in Fat Studies on 8 April 2015 available online: http://wwww.tandfonline.com/10.1080/21604851.2015.1016777This article draws on qualitative research inside one UK secular commercial weight loss group to show how ancient Christian suspicions of appetite and pleasure resurface in this group’s language of “Syn.” Following ancient Christian representations of sin, members assume that Syn depicts disorder and that fat is a visible sign of a body which has fallen out of place. Syn, though, is ambiguous, utilizing ancient theological meanings to discipline fat while containing within it the power to resist the very borders which hold women’s bodies and fat in place. Syn thus signals both the dangers and powers of disordered eating.This article draws on qualitative research inside one UK secular commercial weight loss group to show how ancient Christian suspicions of appetite and pleasure resurface in this group’s language of “Syn.” Following ancient Christian representations of sin, members assume that Syn depicts disorder and that fat is a visible sign of a body which has fallen out of place. Syn, though, is ambiguous, utilizing ancient theological meanings to discipline fat while containing within it the power to resist the very borders which hold women’s bodies and fat in place. Syn thus signals both the dangers and powers of disordered eating

Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

This corrects the article DOI: 10.1038/sdata.2017.179

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

Chronic Exposure to Beta-Blockers Attenuates Inflammation and Mucin Content in a Murine Asthma Model

Single-dose administration of beta-adrenoceptor agonists produces bronchodilation and inhibits airway hyperresponsiveness (AHR), and is the standard treatment for the acute relief of asthma. However, chronic repetitive administration of beta-adrenoceptor agonists may increase AHR, airway inflammation, and risk of death. Based upon the paradigm shift that occurred with the use of beta-blockers in congestive heart failure, we previously determined that chronic administration of beta-blockers decreased AHR in a murine model of asthma. To elucidate the mechanisms for the beneficial effects of beta-blockers, we examined the effects of chronic administration of several beta-adrenoceptor ligands in a murine model of allergic asthma. Administration of beta-blockers resulted in a reduction in total cell counts, eosinophils, and the cytokines IL-13, IL-10, IL-5, and TGF-β1 in bronchoalveolar lavage, and attenuated epithelial mucin content and morphologic changes. The differences in mucin content also occurred if the beta-blockers were administered only during the ovalbumin challenge phase, but administration of beta-blockers for 7 days was not as effective as administration for 28 days. These results indicate that in a murine model of asthma, chronic administration of beta-blockers reduces inflammation and mucous metaplasia, cardinal features of asthma that may contribute to airflow obstruction and AHR. Similar to heart failure, our results provide a second disease model in which beta-blockers producing an acutely detrimental effect may provide a therapeutically beneficial effect with chronic administration

Mixed-methods evaluation of the NHS Genomic Medicine Service for paediatric rare diseases: study protocol [version 2; peer review: 3 approved, 1 approved with reservations]

Background: A new nationally commissioned NHS England Genomic Medicine Service (GMS) was recently established to deliver genomic testing with equity of access for patients affected by rare diseases and cancer. The overarching aim of this research is to evaluate the implementation of the GMS during its early years, identify barriers and enablers to successful implementation, and provide recommendations for practice. The focus will be on the use of genomic testing for paediatric rare diseases. Methods: This will be a four-year mixed-methods research programme using clinic observations, interviews and surveys. Study 1 consists of qualitative interviews with designers/implementers of the GMS in Year 1 of the research programme, along with documentary analysis to understand the intended outcomes for the Service. These will be revisited in Year 4 to compare intended outcomes with what happened in practice, and to identify barriers and facilitators that were encountered along the way. Study 2 consists of clinic observations (pre-test counselling and results disclosure) to examine the interaction between health professionals and parents, along with follow-up interviews with both after each observation. Study 3 consists of a longitudinal survey with parents at two timepoints (time of testing and 12 months post-results) along with follow-up interviews, to examine parent-reported experiences and outcomes. Study 4 consists of qualitative interviews and a cross-sectional survey with medical specialists to identify preparedness, facilitators and challenges to mainstreaming genomic testing. The use of theory-based and pre-specified constructs will help generalise the findings and enable integration across the various sub-studies. Dissemination: We will disseminate our results to policymakers as findings emerge, so any suggested changes to service provision can be considered in a timely manner. A workshop with key stakeholders will be held in Year 4 to develop and agree a set of recommendations for practice

Mixed-methods evaluation of the NHS Genomic Medicine Service for paediatric rare diseases: study protocol [version 2; peer review: 3 approved, 1 approved with reservations]

Background: A new nationally commissioned NHS England Genomic Medicine Service (GMS) was recently established to deliver genomic testing with equity of access for patients affected by rare diseases and cancer. The overarching aim of this research is to evaluate the implementation of the GMS during its early years, identify barriers and enablers to successful implementation, and provide recommendations for practice. The focus will be on the use of genomic testing for paediatric rare diseases. Methods: This will be a four-year mixed-methods research programme using clinic observations, interviews and surveys. Study 1 consists of qualitative interviews with designers/implementers of the GMS in Year 1 of the research programme, along with documentary analysis to understand the intended outcomes for the Service. These will be revisited in Year 4 to compare intended outcomes with what happened in practice, and to identify barriers and facilitators that were encountered along the way. Study 2 consists of clinic observations (pre-test counselling and results disclosure) to examine the interaction between health professionals and parents, along with follow-up interviews with both after each observation. Study 3 consists of a longitudinal survey with parents at two timepoints (time of testing and 12 months post-results) along with follow-up interviews, to examine parent-reported experiences and outcomes. Study 4 consists of qualitative interviews and a cross-sectional survey with medical specialists to identify preparedness, facilitators and challenges to mainstreaming genomic testing. The use of theory-based and pre-specified constructs will help generalise the findings and enable integration across the various sub-studies.   Dissemination: We will disseminate our results to policymakers as findings emerge, so any suggested changes to service provision can be considered in a timely manner. A workshop with key stakeholders will be held in Year 4 to develop and agree a set of recommendations for practice