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Misfolding, polymerization, and defective secretion of functional alpha-1 antitrypsin underlies the predisposition to severe liver and lung disease in alpha-1 antitrypsin deficiency. We have identified a novel (Ala336Pro, Baghdad) deficiency variant and characterized it relative to the wild-type (M) and Glu342Lys (Z) alleles. The index case is a homozygous individual of consanguineous parentage, with levels of circulating alpha-1 antitrypsin in the moderate deficiency range, but is a biochemical phenotype that could not be classified by standard methods. The majority of the protein was present as functionally inactive polymer, and the remaining monomer was 37% active relative to the wild-type protein. These factors combined indicate an 85 to 95% functional deficiency, similar to that seen with ZZ homozygotes. Biochemical, biophysical, and computational studies further defined the molecular basis of this deficiency. These studies demonstrated that native Ala336Pro alpha-1 antitrypsin could populate the polymerogenic intermediate-and therefore polymerize-more readily than either wild-type alpha-1 antitrypsin or the Z variant. In contrast, folding was far less impaired in Ala336Pro alpha-1 antitrypsin than in the Z variant. The data are consistent with a disparate contribution by the \"breach\" region and \"shutter\" region of strand 5A to folding and polymerization mechanisms. Moreover, the findings demonstrate that, in these variants, folding efficiency does not correlate directly with the tendency to polymerize in vitro or in vivo. They therefore differentiate generalized misfolding from polymerization tendencies in missense variants of alpha-1 antitrypsin. Clinically, they further support the need to quantify loss-of-function in alpha-1 antitrypsin deficiency to individualize patient care.

There is controversy regarding the significance of radiological consolidation in the context of COPD exacerbation (eCOPD). While some studies into eCOPD exclude these cases, consolidation is a common feature of eCOPD admissions in real practice. This study aims to address the question of whether consolidation in eCOPD is a distinct clinical phenotype with implications for management decisions and outcomes. The European COPD Audit was carried out in 384 hospitals from 13 European countries between 2010 and 2011 to analyze guideline adherence in eCOPD. In this analysis, admissions were split according to the presence or not of consolidation on the admission chest radiograph. Groups were compared in terms of clinical and epidemiological features, existing treatment, clinical care utilized and mortality. 14,111 cases were included comprising 2,714 (19.2%) with consolidation and 11,397 (80.8%) without. The risk of radiographic consolidation increased with age, female gender, cardiovascular diseases, having had two or more admissions in the previous year, and sputum color change. Previous treatment with inhaled steroids was not associated. Patients with radiographic consolidation were significantly more likely to receive antibiotics, oxygen and non-invasive ventilation during the admission and had a lower survival from admission to 90-day follow-up. Patients admitted for COPD exacerbation who have radiological consolidation have a more severe illness course, are treated more intensively by clinicians and have a poorer prognosis. We recommend that these patients be considered a distinct subset in COPD exacerbation.

Neither the intention to treat analysis nor the per protocol analysis found any significant difference between the treatment and control arms in terms of health-related quality of life, anxiety or depression.

It is not fully understood why COVID-19 is typically milder in children 1 – 3 . Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n  = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children. Mechanisms explaining the milder clinical syndrome that is observed in children with SARS-CoV-2 infection.

A 27-year-old woman was referred from her general practitioner (GP) 6 weeks postpartum with weight loss, dyspnoea and bilateral leg swelling. She had been treated by the GP for a chest infection the week before. On admission she was tachycardic, hypotensive and hypoxic with bilateral leg oedema and bibasal crackles. A chest radiograph showed diffuse multinodular opacification. A CT pulmonary angiogram showed dilated pulmonary artery. Echocardiogram confirmed right ventricular strain and dilation. Sputum microscopy was positive for acid-fast bacilli. The patient developed confusion and low-grade fever and the CT head scan showed meningeal involvement. One year of antituberculous therapy was started and she made a clinical recovery after 10 days and was discharged with regular follow-up. An echocardiogram showed resolution of the right heart strain 4 months later.

Children infected with SARS-CoV-2 rarely progress to respiratory failure. However, the risk of mortality in infected people over 85 years of age remains high. Here we investigate differences in the cellular landscape and function of paediatric (<12 years), adult (30–50 years) and older adult (>70 years) ex vivo cultured nasal epithelial cells in response to infection with SARS-CoV-2. We show that cell tropism of SARS-CoV-2, and expression of ACE2 and TMPRSS2 in nasal epithelial cell subtypes, differ between age groups. While ciliated cells are viral replication centres across all age groups, a distinct goblet inflammatory subtype emerges in infected paediatric cultures and shows high expression of interferon-stimulated genes and incomplete viral replication. In contrast, older adult cultures infected with SARS-CoV-2 show a proportional increase in basaloid-like cells, which facilitate viral spread and are associated with altered epithelial repair pathways. We confirm age-specific induction of these cell types by integrating data from in vivo COVID-19 studies and validate that our in vitro model recapitulates early epithelial responses to SARS-CoV-2 infection. Age-specific differences upon SARS-CoV-2 infection are marked by emergence of goblet 2 inflammatory cells expressing antiviral interferon stimulating genes in paediatric nasal cultures, and basaloid-like cells with increased viral spread in cultures from older adults.

Perhaps, also, the treatment was started too late; there was a 4-day average delay between the symptom onset and the start of therapy. [...]the authors note that NSAIDs may be prescribed to reduce other symptoms such as chest discomfort-the decision not to collect data examining this perhaps represents a missed opportunity. [...]it is clear that antibiotics and NSAIDs should not be used routinely to treat cough in acute bronchitis in patients under the age of 70 without comorbidity.

A 27-year-old woman was referred from her general practitioner (GP) 6 weeks postpartum with weight loss, dyspnoea and bilateral leg swelling. She had been treated by the GP for a chest infection the week before. On admission she was tachycardic, hypotensive and hypoxic with bilateral leg oedema and bibasal crackles. A chest radiograph showed diffuse multinodular opacification. A CT pulmonary angiogram showed dilated pulmonary artery. Echocardiogram confirmed right ventricular strain and dilation. Sputum microscopy was positive for acid-fast bacilli. The patient developed confusion and low-grade fever and the CT head scan showed meningeal involvement. One year of antituberculous therapy was started and she made a clinical recovery after 10 days and was discharged with regular follow-up. An echocardiogram showed resolution of the right heart strain 4 months later.

Children infected with SARS-CoV-2 rarely progress to respiratory failure, but the risk of mortality in infected people over 85 years of age remains high, despite vaccination and improving treatment options. Here, we take a comprehensive, multidisciplinary approach to investigate differences in the cellular landscape and function of paediatric (<11y), adult (30-50y) and elderly (>70y) nasal epithelial cells experimentally infected with SARS-CoV-2. Our data reveal that nasal epithelial cell subtypes show different tropism to SARS-CoV-2, correlating with age, ACE2 and TMPRSS2 expression. Ciliated cells are a viral replication centre across all age groups, but a distinct goblet inflammatory subtype emerges in infected paediatric cultures, identifiable by high expression of interferon stimulated genes and truncated viral genomes. In contrast, infected elderly cultures show a proportional increase in ITGB6hi progenitors, which facilitate viral spread and are associated with dysfunctional epithelial repair pathways. A video explaining this work can be found here - https://youtu.be/uExP4bx6D_A .Competing Interest StatementIn the past three years, SAT has received remuneration for consulting and Scientific Advisory Board Membership from GlaxoSmithKline, Foresite Labs and Qiagen. SAT is a co-founder, board member and holds equity in Transition Bio. All other authors declare no conflicts of interest.Footnotes* Main Figure file order has been updated. Previous version had Figure duplication