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Abstract Cerebral organoids co-cultured with patient derived glioma stem cells (GLICOs) are an experimentally tractable research tool useful for investigating the role of the human brain tumor microenvironment in glioblastoma. Here we describe long-term GLICOs, a novel model in which COs are grown from embryonic stem cell cultures containing low levels of GSCs and tumor development is monitored over extended durations (ltGLICOs). Single-cell profiling of ltGLICOs revealed an unexpectedly long latency period prior to GSC expansion, and that normal organoid development was unimpaired by the presence of low numbers of GSCs. However, as organoids age they experience chronic hypoxia and oxidative stress which remodels the tumor microenvironment to promote GSC expansion. Receptor-ligand modelling identified astrocytes, which secreted various pro-tumorigenic ligands including FGF1, as the primary cell type for GSC crosstalk and single-cell multi-omic analysis revealed these astrocytes were under the control of ischemic regulatory networks. Functional validation confirmed hypoxia as a driver of pro-tumorigenic astrocytic ligand secretion and that GSC expansion was accelerated by pharmacological induction of oxidative stress. When controlled for genotype, the close association between glioma aggressiveness and patient age has very few proposed biological explanations. Our findings indicate that age-associated increases in cerebral vascular insufficiency and associated regional chronic cerebral hypoxia may contribute to this phenomenon.

Abstract Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry- based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+ cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.

Background Overnight desaturation predicts poor prognosis across interstitial lung diseases (ILDs). The aim of the present study was to investigate whether nocturnal desaturation is associated with pulmonary vasculopathy and mortality. Methods A retrospective single centre study of 397 new ILD patients was carried out including patients with idiopathic pulmonary fibrosis (IPF) (n=107) and patients with non-IPF fibrotic ILD (n=290). This is the largest study to date of the effect of significant nocturnal desaturation (SND) (≥10% of total sleep time with oxygen saturation ≤90% measured by pulse oximetry). Results The prevalence of SND was 28/107 (26.2%) in IPF and 80/290 (27.6%) in non-IPF ILD. The prevalence of SND was higher in non-IPF ILDs than in IPF (p=0.025) in multivariate analysis. SND was associated with noninvasive markers of pulmonary hypertension (PH): tricuspid regurgitation velocity (TRV) (p4% in 6-min walking test (p

Myxopapillary ependymoma (MPE) is a primary tumor of the central nervous system (CNS), characteristically an indolent malignancy involving the spinal conus medullaris, Filum terminale or cauda equina. We present a rare case of MPE, recurrent in the pelvic soft tissue with eventual pleural and intra-pulmonary metastasis. Refractory to repeated gross resection, adjuvant radiotherapy, platinum-based chemotherapy and temozolomide exploitation of mutant somatic BRCA1 status with the addition of a poly (ADP-ribose); polymerase inhibitor (PARPi) in a novel combination regimen with olaparib-temozolomide (OT) has achieved stable radiological disease after 10 cycles.

Background: Coronavirus-2019 (COVID-19) is known to affect the heart and is associated with a pro-inflammatory state. Most studies to date have focused on clinically sick subjects. Here, we report cardiac and proinflammatory biomarkers levels in ambulatory young adults with asymptomatic or mild COVID-19 infection compared to those without infection 4–8 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) testing. Methods: 131 asymptomatic or mildly symptomatic subjects were enrolled following testing for SARS-COV-2. Fifty subjects tested negative, and 81 subjects tested positive. Serum samples were collected for measurement of C-reactive protein, ferritin, interleukin-6, NT-pro-B-type natriuretic peptide, and cardiac troponin 28–55 days after SARS-COV-2 RT-PCR testing. Results: Biomarker levels trended higher in SARS-COV-2-positive vs negative subjects, but differences in biomarker levels or proportion of subjects with elevated biomarkers were not statistically significant with respect to SARS-COV-2 status. Among individuals with ≥ 1 comorbidity, odds of elevated CRP were greater compared to individuals without any comorbidities (odds ratio [OR] = 2.90); this effect size was increased 1.4-fold among SARS-COV-2-positive subjects (OR = 4.03). Similarly, NT-pro-BNP was associated with CVD, with the strongest association in COVID-positive individuals (OR = 16.9). Conclusions: In a relatively young, healthy adult population, mild COVID-19 infection was associated with mild elevations in cardiac and proinflammatory biomarkers within 4–8 weeks of mild or asymptomatic COVID-19 infection in individuals with preexisting comorbidities, but not among individuals without comorbidities. For the general population of young adults, we did not find evidence of elevation of cardiac or proinflammatory biomarkers 4–8 weeks after COVID-19 infection.Clinical Perspective: This is a characterization of cardiac and proinflammatory biomarkers in ambulatory subjects following asymptomatic or mild COVID-19 infection. Young, ambulatory individuals did not have cardiac and proinflammatory biomarker elevation 4–8 weeks after mild COVID-19 infection. However, COVID-19 infection was associated with biomarker elevations in select individuals with comorbidities.Clinical study number: H-47423.

Abstract Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 and poor outcomes. Here the authors compare the transcriptomes of single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in these patients.

Abstract Environmental cues associated with an action can prime the motor system, decreasing response times and activating motor regions of the brain. However, when task goals change, the same responses to former go-associated cues are no longer required and motor priming needs to be inhibited to avoid unwanted behavioural errors. The present study tested whether the inhibition of motor system activity to presentations of former go cues is reliant on top-down, goal-directed cognitive control processes using a working memory (WM) load manipulation. Applying transcranial magnetic stimulation over the primary motor cortex to measure motor system activity during a Go/No-go task, we found that under low WM, corticospinal excitability was suppressed to former go and trained no-go cues relative to control cues. Under high WM, the cortical suppression to former go cues was reduced, suggesting that the underlying mechanism required executive control. Unexpectedly, we found a similar result for trained no-go cues and showed in a second experiment that the corticospinal suppression and WM effects were unrelated to local inhibitory function as indexed by short-interval intracortical inhibition. Our findings reveal that the interaction between former response cues and WM is complex and we discuss possible explanations of our findings in relation to models of response inhibition.

Abstract Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA–IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40–10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4–2.0, P = 1.2 × 10–10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.

Mutations in components of the MAP kinase pathway are associated with a group of syndromes known as RASopathies. Here, the authors identify gain-of-function mutations in BRAF in patients with RASopathies and congenital hypopituitarisms. This article demonstrates a central role for BRAF in the development of the hypothalamo-pituitary axis leading to endocrine deficiencies in patients with RASopathies.

Non-human primates are important animal models for studying SARS-CoV-2 infection. Here, Salguero et al. directly compare rhesus and cynomolgus macaques and show that both species represent COVID-19 disease of mild clinical cases, and provide a lung histopathology scoring system.

The presence of clinical, serological and/or radiological features suggestive, but not confirmatory, of a defined connective tissue disease in patients with interstitial lung disease is a relatively frequent occurrence. In 2015, the European Respiratory Society and the American Thoracic Society proposed classification criteria for the interstitial pneumonia with autoimmune features (IPAF) research entity to capture such patients in a standardised manner, with the intention of nurturing clinical research. This initiative resulted in the publication of several series of IPAF patients, with significant variation between cohorts in clinical characteristics, outcome and the application of IPAF criteria in patient selection. From this increasing body of published work, it has become apparent that revision of IPAF criteria is now required in order to justify the eventual designation of IPAF as a standalone diagnostic term, as opposed to a provisional entity put forward as a basis for clinical research. This review covers the current state of IPAF, conclusions that can and cannot be drawn from the IPAF evidence base, and ongoing uncertainties that require further expert group consideration.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019 in Wuhan, China, and then rapidly spread causing an unprecedented pandemic. A robust serological assay is needed to evaluate vaccine candidates and better understand the epidemiology of coronavirus disease (COVID-19).MethodsWe used the full-length spike (S) protein of SARS-CoV-2 for the development of qualitative and quantitative IgG and IgA anti-S enzyme linked immunosorbent assays (ELISA). A total of 320 sera used for assay development were comprised of pandemic sera from SARS-CoV-2 infected adults (n=51) and pre-pandemic sera (n=269) including sera from endemic human coronavirus infected adults. Reverse cumulative curves and diagnostic test statistics were evaluated to define the optimal serum dilution and OD cutoff value for IgG anti-S and IgA anti-S ELISAs. The IgG and IgA anti-S, and three functional antibodies (ACE-2 receptor blocking antibody, lentipseudovirus-S neutralizing antibody, and SARS-CoV-2 neutralizing antibody) were measured using additional SARS-CoV-2 PCR positive sera (n=76) and surveillance sera (n=25). Lastly, the IgG and IgA anti-S levels were compared in different demographic groups.ResultsThe optimal serum dilution for the qualitative IgG anti-S ELISA was at 1:1024 yielding a 99.6% specificity, 92.2% sensitivity, 92.9% positive predictive value (PPV), and 99.6% negative predictive value (NPV) at a SARS-CoV-2 seroprevalence of 5%. The optimal serum dilution for the qualitative IgA anti-S ELISA was at 1:128 yielding a 98.9% specificity, 76.5% sensitivity, 78.3% PPV, and 98.8% NPV at the same seroprevalence. Significant correlations were demonstrated between the IgG and IgA (r=0.833 for concentrations, r=0.840 for titers) as well as between IgG and three functional antibodies (r=0.811-0.924 for concentrations, r=0.795-0.917 for titers). The IgG and IgA anti-S levels were significantly higher in males than females (p

Lung cancer is the leading cause of cancer‐related deaths in the world. The most prevalent subtype, accounting for 85% of cases, is non‐small‐cell lung cancer (NSCLC). Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes. Despite recent advances in treatment, the low 5‐year survival rate of NSCLC patients (approximately 13%) reflects the lack of early diagnostic biomarkers and incomplete understanding of the underlying disease mechanisms. We hypothesized that integration of metabolomic, transcriptomic and genetic profiles of tumours and matched normal tissues could help to identify important factors and potential therapeutic targets that contribute to tumorigenesis. We integrated omics profiles in tumours and matched adjacent normal tissues of patients with LUSC (N = 20) and LUAD (N = 17) using multiple system biology approaches. We confirmed the presence of previously described metabolic pathways in NSCLC, particularly those mediating the Warburg effect. In addition, through our combined omics analyses we found that metabolites and genes that contribute to haemostasis, angiogenesis, platelet activation and cell proliferation were predominant in both subtypes of NSCLC. The important roles of adenosine diphosphate in promoting cancer metastasis through platelet activation and angiogenesis suggest this metabolite could be a potential therapeutic target.

Background Childhood interstitial and diffuse lung diseases (chILD) encompass a broad spectrum of rare pulmonary disorders. In most developing Middle Eastern countries, chILD is still underdiagnosed. Our objective was to describe and investigate patients diagnosed with chILD in a tertiary university hospital in Egypt. Methods We analysed data of consecutive subjects (aged

Abstract Cartilage defects repair poorly. Recent genetic studies suggest that WNT3a may contribute to cartilage regeneration, however the dense, avascular cartilage extracellular matrix limits its penetration and signalling to chondrocytes. Extracellular vesicles actively penetrate intact cartilage. This study investigates the effect of delivering WNT3a into large cartilage defects in vivo using exosomes as a delivery vehicle. Exosomes were purified by ultracentrifugation from conditioned medium of either L‐cells overexpressing WNT3a or control un‐transduced L‐cells, and characterized by electron microscopy, nanoparticle tracking analysis and marker profiling. WNT3a loaded on exosomes was quantified by western blotting and functionally characterized in vitro using the SUPER8TOPFlash reporter assay and other established readouts including proliferation and proteoglycan content. In vivo pathway activation was assessed using TCF/Lef:H2B‐GFP reporter mice. Wnt3a loaded exosomes were injected into the knees of mice, in which large osteochondral defects were surgically generated. The degree of repair was histologically scored after 8 weeks. WNT3a was successfully loaded on exosomes and resulted in activation of WNT signalling in vitro. In vivo, recombinant WNT3a failed to activate WNT signalling in cartilage, whereas a single administration of WNT3a loaded exosomes activated canonical WNT signalling for at least one week, and eight weeks later, improved the repair of osteochondral defects. WNT3a assembled on exosomes, is efficiently delivered into cartilage and contributes to the healing of osteochondral defects.

Summary: Background: Severe COVID-19 has a high mortality rate. Comprehensive pathological descriptions of COVID-19 are scarce and limited in scope. We aimed to describe the histopathological findings and viral tropism in patients who died of severe COVID-19. Methods: In this case series, patients were considered eligible if they were older than 18 years, with premortem diagnosis of severe acute respiratory syndrome coronavirus 2 infection and COVID-19 listed clinically as the direct cause of death. Between March 1 and April 30, 2020, full post-mortem examinations were done on nine patients with confirmed COVID-19, including sampling of all major organs. A limited autopsy was done on one additional patient. Histochemical and immunohistochemical analyses were done, and histopathological findings were reported by subspecialist pathologists. Viral quantitative RT-PCR analysis was done on tissue samples from a subset of patients. Findings: The median age at death of our cohort of ten patients was 73 years (IQR 52–79). Thrombotic features were observed in at least one major organ in all full autopsies, predominantly in the lung (eight [89%] of nine patients), heart (five [56%]), and kidney (four [44%]). Diffuse alveolar damage was the most consistent lung finding (all ten patients); however, organisation was noted in patients with a longer clinical course. We documented lymphocyte depletion (particularly CD8-positive T cells) in haematological organs and haemophagocytosis. Evidence of acute tubular injury was noted in all nine patients examined. Major unexpected findings were acute pancreatitis (two [22%] of nine patients), adrenal micro-infarction (three [33%]), pericarditis (two [22%]), disseminated mucormycosis (one [10%] of ten patients), aortic dissection (one [11%] of nine patients), and marantic endocarditis (one [11%]). Viral genomes were detected outside of the respiratory tract in four of five patients. The presence of subgenomic viral RNA transcripts provided evidence of active viral replication outside the respiratory tract in three of five patients. Interpretation: Our series supports clinical data showing that the four dominant interrelated pathological processes in severe COVID-19 are diffuse alveolar damage, thrombosis, haemophagocytosis, and immune cell depletion. Additionally, we report here several novel autopsy findings including pancreatitis, pericarditis, adrenal micro-infarction, secondary disseminated mucormycosis, and brain microglial activation, which require additional investigation to understand their role in COVID-19. Funding: Imperial Biomedical Research Centre, Wellcome Trust, Biotechnology and Biological Sciences Research Council.

Background Solitary fibrous tumours of the pleura (SFTP), or pleural fibromas, are rare tumours that generally, but not universally, follow a benign course. Surgical resection is the standard treatment, but there are no evidence-based guidelines regarding the management of these tumours. Methods Five databases were searched from inception to April 1, 2019 for studies reporting on SFTP management. Results Twenty-seven studies met the inclusion criteria (1542 patients, all non-comparative case series); 98% of these patients underwent resection and all SFTP included were pathologically diagnosed. 394 out of 1299 cases (30.5%, 95% CI 27.8–32.8%) were malignant with recurrence rates of between 0% and 42.9%. A pleural effusion was always associated with a negative outcome, but no other features were consistently reported to have negative associations. Preoperative biopsies incorrectly reported malignant histology in two studies. Over 25% of cases of recurrence occurred when a complete (R0) resection had been achieved. The first recurrence occurred >5 years after the initial resection in at least 23% of cases. Conclusions There is strong evidence to support long-term surveillance after surgical resection of SFTP, even where a complete (R0) resection has been achieved; however, there is no clear evidence to inform clinicians regarding the selection of patients who should undergo resection. The rates of malignant SFTP and SFTP recurrence are higher than previously reported. Only those that were pathologically diagnosed or resected were included, which may bias the data towards more aggressive tumours. Data collection on radiologically diagnosed SFTP is required to draw conclusions regarding the timing and need for intervention.

Background: UK COVID-19 mortality rates are amongst the highest globally. Controversy exists on the vulnerability of thoracic cancer patients. We describe the characteristics and sequelae of patients with thoracic cancer treated at a UK cancer centre infected with COVID-19. Methods: Patients undergoing care for thoracic cancer diagnosed with COVID-19 (RT-PCR/radiology/clinically) between March-June 2020 were included. Data were extracted from patient records. Results: Thirty-two patients were included: 14 (43%) diagnosed by RT-PCR, 18 (57%) by radiology and/or convincing symptoms. 88% had advanced thoracic malignancies. Eleven of 14 (79%) patients diagnosed by RT-PCR and 12 of 18 (56%) patients diagnosed by radiology/clinically were hospitalised, of which four (29%) and 2 (11%) patients required high-dependency/intensive care respectively. Three (21%) patients diagnosed by RT-PCR and 2 (11%) patients diagnosed by radiology/clinically required non-invasive ventilation; none were intubated. Complications included pneumonia and sepsis (43% and 14% respectively in patients diagnosed by RT-PCR; 17% and 11% respectively in patients diagnosed by radiology/clinically). In patients receiving active cancer treatment, therapy was delayed/ceased in 10/12 (83%) and 7/11 (64%) patients diagnosed by RT-PCR and radiology/clinically respectively. Nine (28%) patients died; all were smokers. Median time from symptom onset to death was 7 days (range 3–37). Conclusions: The immediate morbidity from COVID-19 is high in thoracic cancer patients. Hospitalisation and treatment interruption rates were high. Improved risk-stratification models for UK cancer patients are urgently needed to guide safe cancer-care delivery without compromising efficacy.

Over 40 years ago, abnormal enlargement of the nucleus of tubular epithelial cells was reported in a rare distinct hereditary chronic interstitial nephritis, karyomegalic interstitial nephritis (KIN). Here, we report the second case of systemic karyomegaly with pulmonary manifestations and present a detailed characterization of the karyomegalic cells in lung parenchyma. A 59-year-old woman who was diagnosed with KIN developed renal failure and eventually received a renal transplant later evaluated for chronic and progressive restrictive lung disease. The KIN diagnosis prompted us to carefully examine her lung parenchyma. Karyomegalic cells were identified in the alveolar epithelium, interstitium, as well as, in the vascular wall. Viral serological and biochemical blood analyses were negative. We consider that the pulmonary manifestations of karyomegaly expands the differential diagnosis of interstitial lung disease in patients with KIN. Keywords: Karyomegaly, Interstitial lung disease, Karyomegalic interstitial nephritis

Abstract Background COPD patients are at increased risk of developing non-small cell lung carcinoma that has a worse prognosis. Oxidative stress contributes to carcinogenesis and is increased in COPD patients due to mitochondrial dysfunction. We determined whether mitochondrial dysfunction is a contributing factor to the reduced survival of COPD patients with non-small cell lung carcinoma (NSCLC). Methods Using a transcriptomic database and outcome data of 3553 NSCLC samples, we selected mitochondrial-related genes whose levels in the tumour correlated with patient mortality. We further selected those genes showing a ≥ 2 fold expression in cancer compared to normal tissue. Cell-type specific expression of these proteins in lung tissue from NSCLC patients who were non-smokers or smokers with or without COPD (healthy smokers) was determined by immunohistochemistry. Gene set variation analysis was used in additional NSCLC datasets to determine the relative expression of specific macrophage transcriptomic signatures within lung cancer tissue. Results The expression of 14 mitochondrial-related genes was correlated with patient mortality and these were differentially expressed between cancer and normal lung tissue. We studied further the expression of one of these genes, PGAM5 which is a regulator of mitochondrial degradation by mitophagy. In background lung tissue, PGAM5 was only expressed in alveolar macrophages, with the highest expression in smokers with COPD compared to healthy smokers and non-smokers. In cancerous tissue, only the malignant epithelial cells and associated macrophages at the periphery of the cancer expressed PGAM5. Pre-neoplastic epithelium also showed the expression of PGAM5. There was no difference in expression in cancer tissue between COPD, healthy smoker and non-smoker groups. Macrophages at the edge of the cancer from COPD patients showed a trend towards higher expression of PGAM5 compared to those from the other groups. There was a significant correlation between PGAM5 expression in cancer tissue and the level of expression of 9 out of 49 previously-defined macrophage transcriptomic signatures with a particular one associated with patient mortality (p

Abstract Bioprinting is an emerging technique for the fabrication of living tissues that allows cells to be arranged in predetermined three-dimensional (3D) architectures. However, to date, there are limited examples of bioprinted constructs containing multiple cell types patterned at high-resolution. Here we present a low-cost process that employs 3D printing of aqueous droplets containing mammalian cells to produce robust, patterned constructs in oil, which were reproducibly transferred to culture medium. Human embryonic kidney (HEK) cells and ovine mesenchymal stem cells (oMSCs) were printed at tissue-relevant densities (107 cells mL−1) and a high droplet resolution of 1 nL. High-resolution 3D geometries were printed with features of ≤200 μm; these included an arborised cell junction, a diagonal-plane junction and an osteochondral interface. The printed cells showed high viability (90% on average) and HEK cells within the printed structures were shown to proliferate under culture conditions. Significantly, a five-week tissue engineering study demonstrated that printed oMSCs could be differentiated down the chondrogenic lineage to generate cartilage-like structures containing type II collagen.

Here we report a case of Pulmonary Hyalinising Granuloma (PHG) presenting with mild to moderate FDG positive nodules in an individual with a high risk of cancer. We explore the considerations in interpreting imaging findings and assess the benefits and risks of undertaking invasive investigations such as tissue biopsy. We highlight the importance of reaching an accurate diagnosis of this benign condition on our patients and their future outlook. Keywords: Pulmonary hyalinising granuloma, Lung nodules, FDG-avid, PET, Biopsy

The endocrine system coordinates a wide array of body functions mainly through secretion of hormones and their actions on target tissues. Over the last decades, a collective effort between developmental biologists, geneticists, and stem cell biologists has generated a wealth of knowledge related to the contribution of stem/progenitor cells to both organogenesis and self-renewal of endocrine organs. This review provides an up-to-date and comprehensive overview of the role of tissue stem cells in the development and self-renewal of endocrine organs. Pathways governing crucial steps in both development and stemness maintenance, and that are known to be frequently altered in a wide array of endocrine disorders, including cancer, are also described. Crucially, this plethora of information is being channeled into the development of potential new cell-based treatment modalities for endocrine-related illnesses, some of which have made it through clinical trials.

Summary: In a multi-center, prospective, observational study over two influenza seasons, we sought to quantify and correlate the amount of virus recovered from the nares of infected subjects with that recovered from their immediate environment in community and hospital settings. We recorded the symptoms of adults and children with A(H1N1)pdm09 infection, took nasal swabs, and sampled touched surfaces and room air. Forty-two infected subjects were followed up. The mean duration of virus shedding was 6.2 days by PCR (Polymerase Chain Reaction) and 4.2 days by culture. Surface swabs were collected from 39 settings; 16 (41%) subject locations were contaminated with virus. Overall, 33 of the 671 (4.9%) surface swabs were PCR positive for influenza, of which two (0.3%) yielded viable virus. On illness Day 3, subjects yielding positive surface samples had significantly higher nasal viral loads (geometric mean ratio 25.7; 95% CI 1.75, 376.0, p = 0.021) and a positive correlation (r = 0.47, p = 0.006) was observed between subject nasal viral loads and viral loads recovered from the surfaces around them. Room air was sampled in the vicinity of 12 subjects, and PCR positive samples were obtained for five (42%) samples. Influenza virus shed by infected subjects did not detectably contaminate the vast majority of surfaces sampled. We question the relative importance of the indirect contact transmission of influenza via surfaces, though our data support the existence of super-spreaders via this route. The air sampling results add to the accumulating evidence that supports the potential for droplet nuclei (aerosol) transmission of influenza. Keywords: Influenza, Environmental, Deposition, Infection, Control