6 research outputs found
ILâ1β prevents ILC2 expansion, type 2 cytokine secretion, and mucus metaplasia in response to earlyâlife rhinovirus infection in mice
BackgroundEarlyâlife wheezingâassociated respiratory infection with human rhinovirus (RV) is associated with asthma development. RV infection of 6âdayâold immature mice causes mucous metaplasia and airway hyperresponsiveness which is associated with the expansion of ILâ13âproducing type 2 innate lymphoid cells (ILC2s) and dependent on ILâ25 and ILâ33. We examined regulation of this asthmaâlike phenotype by ILâ1β.MethodsSixâdayâold wildâtype or NRLP3â/â mice were inoculated with sham or RVâA1B. Selected mice were treated with ILâ1 receptor antagonist (ILâ1RA), antiâILâ1β, or recombinant ILâ1β.ResultsRhinovirus infection induced Il25, Il33, Il4, Il5, Il13, muc5ac, and gob5 mRNA expression, ILC2 expansion, mucus metaplasia, and airway hyperresponsiveness. RV also induced lung mRNA and protein expression of proâILâ1β and NLRP3 as well as cleavage of caspaseâ1 and proâILâ1β, indicating inflammasome priming and activation. Lung macrophages were a major source of ILâ1β. Inhibition of ILâ1β signaling with ILâ1RA, antiâILâ1β, or NLRP3 KO increased RVâinduced type 2 cytokine immune responses, ILC2 number, and mucus metaplasia, while decreasing ILâ17 mRNA expression. Treatment with ILâ1β had the opposite effect, decreasing ILâ25, ILâ33, and mucous metaplasia while increasing ILâ17 expression. ILâ1β and ILâ17 each suppressed Il25, Il33, and muc5ac mRNA expression in cultured airway epithelial cells. Finally, RVâinfected 6âdayâold mice showed reduced ILâ1β mRNA and protein expression compared to mature mice.ConclusionMacrophage ILâ1β limits type 2 inflammation and mucous metaplasia following RV infection by suppressing epithelial cell innate cytokine expression. Reduced ILâ1β production in immature animals provides a mechanism permitting asthma development after earlyâlife viral infection.Earlyâlife rhinovirus infection increases epithelial expression of the innate cytokines ILâ25 and ILâ33, expands (type 2 innate lymphoid cells) ILC2s, and enhances development of an asthmaâlike phenotype. Rhinovirus causes macrophage (NLR family, pyrin domain containing 3) NLRP3 inflammasome activation and bioactive ILâ1β production. ILâ1β production, which is deficient in immature mice, attenuates production of ILâ25 and ILâ33, thereby protecting against rhinovirusâinduced asthma development.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156197/3/all14241_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156197/2/all14241.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156197/1/all14241-sup-0001-FigS1.pd
Using outbreak science to strengthen the use of models during epidemics.
Infectious disease modeling has played a prominent role in recent outbreaks, yet integrating these analyses into public health decision-making has been challenging. We recommend establishing âoutbreak scienceâ as an inter-disciplinary field to improve applied epidemic modeling
LEARN: A multi-centre, cross-sectional evaluation of Urology teaching in UK medical schools
OBJECTIVE: To evaluate the status of UK undergraduate urology teaching against the British Association of Urological Surgeons (BAUS) Undergraduate Syllabus for Urology. Secondary objectives included evaluating the type and quantity of teaching provided, the reported performance rate of General Medical Council (GMC)-mandated urological procedures, and the proportion of undergraduates considering urology as a career. MATERIALS AND METHODS: LEARN was a national multicentre cross-sectional study. Year 2 to Year 5 medical students and FY1 doctors were invited to complete a survey between 3rd October and 20th December 2020, retrospectively assessing the urology teaching received to date. Results are reported according to the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). RESULTS: 7,063/8,346 (84.6%) responses from all 39 UK medical schools were included; 1,127/7,063 (16.0%) were from Foundation Year (FY) 1 doctors, who reported that the most frequently taught topics in undergraduate training were on urinary tract infection (96.5%), acute kidney injury (95.9%) and haematuria (94.4%). The most infrequently taught topics were male urinary incontinence (59.4%), male infertility (52.4%) and erectile dysfunction (43.8%). Male and female catheterisation on patients as undergraduates was performed by 92.1% and 73.0% of FY1 doctors respectively, and 16.9% had considered a career in urology. Theory based teaching was mainly prevalent in the early years of medical school, with clinical skills teaching, and clinical placements in the later years of medical school. 20.1% of FY1 doctors reported no undergraduate clinical attachment in urology. CONCLUSION: LEARN is the largest ever evaluation of undergraduate urology teaching. In the UK, teaching seemed satisfactory as evaluated by the BAUS undergraduate syllabus. However, many students report having no clinical attachments in Urology and some newly qualified doctors report never having inserted a catheter, which is a GMC mandated requirement. We recommend a greater emphasis on undergraduate clinical exposure to urology and stricter adherence to GMC mandated procedures
Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study
Introduction:
The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures.
Methods:
In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged âĽ18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025.
Findings:
Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5¡0 months (IQR 4¡2â6¡3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0¡0001) and independently associated with COVID-19 status (odds ratio [OR] 2¡9 [95% CI 1¡5â5¡8]; padjusted=0¡0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0¡0001; parenchymal abnormalities), brain abnormalities (p<0¡0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0¡014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4â10]; mean age of 59¡8 years [SD 11¡7] with multiorgan abnormalities vs mean age of 52¡8 years [11¡9] without multiorgan abnormalities; p<0¡0001), more likely to have three or more comorbidities (OR 2¡47 [1¡32â4¡82]; padjusted=0¡0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3¡55 [1¡23â11¡88]; padjusted=0¡025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation.
Interpretation:
After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification
Small Animal Models of Respiratory Viral Infection Related to Asthma
Respiratory viral infections are strongly associated with asthma exacerbations. Rhinovirus is most frequently-detected pathogen; followed by respiratory syncytial virus; metapneumovirus; parainfluenza virus; enterovirus and coronavirus. In addition; viral infection; in combination with genetics; allergen exposure; microbiome and other pathogens; may play a role in asthma development. In particular; asthma development has been linked to wheezing-associated respiratory viral infections in early life. To understand underlying mechanisms of viral-induced airways disease; investigators have studied respiratory viral infections in small animals. This report reviews animal models of human respiratory viral infection employing mice; rats; guinea pigs; hamsters and ferrets. Investigators have modeled asthma exacerbations by infecting mice with allergic airways disease. Asthma development has been modeled by administration of virus to immature animals. Small animal models of respiratory viral infection will identify cell and molecular targets for the treatment of asthma