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Introduction\ud \ud Otitis media is an umbrella term for middle ear inflammation; ranging from acute infection to chronic mucosal disease. It is a leading cause of antimicrobial therapy prescriptions and surgery in children. Despite this, treatments have changed little in over 50 years. Research has been limited by the lack of physiological models of middle ear epithelium.\ud \ud \ud Methods\ud \ud We develop a novel human middle ear epithelial culture using an air-liquid interface (ALI) system; akin to the healthy ventilated middle ear in vivo. We validate this using immunohistochemistry, immunofluorescence, scanning and transmission electron microscopy, and membrane conductance studies. We also utilize this model to perform a pilot challenge of middle ear epithelial cells with SARS-CoV-2.\ud \ud \ud Results\ud \ud We demonstrate that human middle ear epithelial cells cultured at an ALI undergo mucociliary differentiation to produce diverse epithelial subtypes including basal (p63+), goblet (MUC5AC+, MUC5B+), and ciliated (FOXJ1+) cells. Mature ciliagenesis is visualized and tight junction formation is shown with electron microscopy, and confirmed by membrane conductance. Together, these demonstrate this model reflects the complex epithelial cell types which exist in vivo. Following SARS-CoV-2 challenge, human middle ear epithelium shows positive viral uptake, as measured by polymerase chain reaction and immunohistochemistry.\ud \ud \ud Conclusion\ud \ud We describe a novel physiological system to study the human middle ear. This can be utilized for translational research into middle ear diseases. We also demonstrate, for the first time under controlled conditions, that human middle ear epithelium is susceptible to SARS-CoV-2 infection, which has important clinical implications for safe otological surgery.\ud \ud \ud Level of Evidence\ud \ud NA.

Objective Otitis media (OM) is a common reason for children to be prescribed antibiotics and undergo surgery but a thorough understanding of disease mechanisms is lacking. We evaluate the evidence of a dysregulated immune response in the pathogenesis of OM. Methods A comprehensive systematic review of the literature using search terms [otitis media OR glue ear OR AOM OR OME] OR [middle ear AND (infection OR inflammation)] which were run through Medline and Embase via Ovid, including both human and animal studies. In total, 82 955 studies underwent automated filtering followed by manual screening. One hundred studies were included in the review. Results Most studies were based on in vitro or animal work. Abnormalities in pathogen detection pathways, such as Toll-like receptors, have confirmed roles in OM. The aetiology of OM, its chronic subgroups (chronic OM, persistent OM with effusion) and recurrent acute OM is complex; however, inflammatory signalling mechanisms are frequently implicated. Host epithelium likely plays a crucial role, but the characterisation of human middle ear tissue lags behind that of other anatomical subsites. Conclusions Translational research for OM presently falls far behind its clinical importance. This has likely hindered the development of new diagnostic and treatment modalities. Further work is urgently required; particularly to disentangle the respective immune pathologies in the clinically observed phenotypes and thereby work towards more personalised treatments.

Shifts in cellular metabolic phenotypes have the potential to cause disease-driving processes in respiratory disease. The respiratory epithelium is particularly susceptible to metabolic shifts in disease, but our understanding of these processes is limited by the incompatibility of the technology required to measure metabolism in real-time with the cell culture platforms used to generate differentiated respiratory epithelial cell types. Thus, to date, our understanding of respiratory epithelial metabolism has been restricted to that of basal epithelial cells in submerged culture, or via indirect end point metabolomics readouts in lung tissue. Here we present a novel methodology using the widely available Seahorse Analyzer platform to monitor real-time changes in the cellular metabolism of fully differentiated primary human airway epithelial cells grown at air-liquid interface (ALI). We show increased glycolytic, but not mitochondrial, ATP production rates in response to physiologically relevant increases in glucose availability. We also show that pharmacological inhibition of lactate dehydrogenase is able to reduce glucose-induced shifts toward aerobic glycolysis. This method is timely given the recent advances in our understanding of new respiratory epithelial subtypes that can only be observed in vitro through culture at ALI and will open new avenues to measure real-time metabolic changes in healthy and diseased respiratory epithelium, and in turn the potential for the development of novel therapeutics targeting metabolic-driven disease phenotypes.

Rationale:\ud Aspiration of infective subglottic secretions causes ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Mechanisms underlying subglottic colonization in critical illness have not been defined, limiting strategies for targeted prevention of VAP.\ud \ud Objectives:\ud To characterize subglottic host defense dysfunction in mechanically ventilated patients in the intensive care unit (ICU). To determine whether subglottic mucin contributes to neutrophil phagocytic impairment and bacterial growth.\ud \ud Methods:\ud Prospective subglottic sampling in mechanically ventilated patients (intubated for four or more days), and newly intubated control patients (intubated for less than 30 minutes). Isolation and culture of primary subglottic epithelial cells from controls. Laboratory analysis of host innate immune defenses.\ud \ud Measurements and Main Results:\ud Twenty-four patients in the ICU and 27 newly intubated control patients were studied. Subglottic ICU samples had significantly reduced microbiological diversity and contained potential respiratory pathogens. The subglottic microenvironment in ICU was characterized by neutrophilic inflammation, significantly increased pro-inflammatory cytokines and neutrophil proteases, and altered physical properties of subglottic secretions, including accumulation of mucins. Subglottic mucin from ICU patients impaired the capacity of neutrophils to phagocytose and kill bacteria. Phagocytic function was reversible upon treatment with a mucolytic agent. Subglottic mucus promoted growth and invasion of bacterial pathogens in a novel air-liquid interface model of primary human subglottic epithelium.\ud \ud Conclusions:\ud Mechanical ventilation in ICU is characterized by substantial mucin secretion and neutrophilic inflammation. Mucin impairs neutrophil dysfunction and promotes bacterial growth. Mucolytic agents reverse mucin-mediated neutrophil dysfunction. Enhanced mucus disruption and removal has potential to augment preventive benefits of subglottic drainage.

With the number of individuals diagnosed with type 2 diabetes on the rise, it has become more important to ensure these patients are effectively treated. The Centers for Disease Control and Prevention estimated that 8.3% of all Americans were diagnosed with diabetes in 2011 and this number will likely continue to rise. With lifestyle interventions, such as proper diet and exercise, continuing to be an essential component of diabetes treatment, more patients are requiring medication therapy to help them reach their therapeutic goals. It is important for the clinician, when determining the treatment strategy for these individuals, to find a balance between reaching treatment goals and limiting the adverse effects of the treatments themselves. Of all the adverse events associated with treatment of diabetes, the risk of hypoglycemia is one that most therapies have in common. This risk is often a limiting factor when attempting to aggressively treat diabetic patients. This manuscript will review how hypoglycemia is defined and categorized, as well as discuss the prevalence of hypoglycemia among the many different treatment options.

Type 2 diabetes and obesity commonly occur together. Obesity contributes to insulin resistance, a main cause of type 2 diabetes. Modest weight loss reduces glucose, lipids, blood pressure, need for medications, and cardiovascular risk. A number of approaches can be used to achieve weight loss, including lifestyle modification, surgery, and medication. Lorcaserin, a novel antiobesity agent, affects central serotonin subtype 2A receptors, resulting in decreased food intake and increased satiety. It has been studied in obese patients with type 2 diabetes and results in an approximately 5.5 kg weight loss, on average, when used for one year. Headache, back pain, nasopharyngitis, and nausea were the most common adverse effects noted with lorcaserin. Hypoglycemia was more common in the lorcaserin groups in the clinical trials, but none of the episodes were categorized as severe. Based on the results of these studies, lorcaserin was approved at a dose of 10 mg twice daily in patients with a body mass index ≥30 kg/m(2) or ≥27 kg/m(2) with at least one weight-related comorbidity, such as hypertension, type 2 diabetes mellitus, or dyslipidemia, in addition to a reduced calorie diet and increased physical activity. Lorcaserin is effective for weight loss in obese patients with and without type 2 diabetes, although its specific role in the management of obesity is unclear at this time. This paper reviews the clinical trials of lorcaserin, its use from the patient perspective, and its potential role in the treatment of obesity.

Institutions, at state and local level, have been perceived as a mechanism of supporting the vulnerable within society. The processes of globalisation within an economic, political and social context have played a fundamental role in institutions. The 'State' that administers institutions has experienced involvement and adjustment by central government's policy of privatisation and deregulation. The aim of this paper is to critically explore the current debates on institutions within British society. We frame the debates within Foucault's notion of 'governmentality', which highlights how government provides governance of 'action at a distance' in order to detract blame from government and its policies and place this blame onto individuals and communities themselves (1978, p. 33).

The nasal epithelium is a plausible entry point for SARS-CoV-2, a site of pathogenesis and transmission, and may initiate the host response to SARS-CoV-2. Antiviral interferon (IFN) responses are critical to outcome of SARS-CoV-2. Yet little is known about the interaction between SARS-CoV-2 and innate immunity in this tissue. Here we apply single-cell RNA sequencing and proteomics to a primary cell model of human nasal epithelium differentiated at air-liquid interface. SARS-CoV-2 demonstrates widespread tropism for nasal epithelial cell types. The host response is dominated by type I and III IFNs and interferon-stimulated gene products. This response is notably delayed in onset relative to viral gene expression and compared to other respiratory viruses. Nevertheless, once established, the paracrine IFN response begins to impact on SARS-CoV-2 replication. When provided prior to infection, recombinant IFNβ or IFNλ1 induces an efficient antiviral state that potently restricts SARS-CoV-2 viral replication, preserving epithelial barrier integrity. These data imply that the IFN-I/III response to SARS-CoV-2 initiates in the nasal airway and suggest nasal delivery of recombinant IFNs to be a potential chemoprophylactic strategy., The innate immune response in epithelial cells after SARS-CoV-2 infection is not fully understood. Here the authors use human air-liquid interface culture and show single cell transcription changes and delayed type I Interferon responses after SARS-CoV-2 infection compared with other respiratory viruses.