Chlorine activation and enhanced ozone depletion induced by wildfire aerosol.

Remarkable perturbations in the stratospheric abundances of chlorine species and ozone were observed over Southern Hemisphere mid-latitudes following the 2020 Australian wildfires1,2. These changes in atmospheric chemical composition suggest that wildfire aerosols affect stratospheric chlorine and ozone depletion chemistry. Here we propose that wildfire aerosol containing a mixture of oxidized organics and sulfate3-7 increases hydrochloric acid solubility8-11 and associated heterogeneous reaction rates, activating reactive chlorine species and enhancing ozone loss rates at relatively warm stratospheric temperatures. We test our hypothesis by comparing atmospheric observations to model simulations that include the proposed mechanism. Modelled changes in 2020 hydrochloric acid, chlorine nitrate and hypochlorous acid abundances are in good agreement with observations1,2. Our results indicate that wildfire aerosol chemistry, although not accounting for the record duration of the 2020 Antarctic ozone hole, does yield an increase in its area and a 3-5% depletion of southern mid-latitude total column ozone. These findings increase concern2,12,13 that more frequent and intense wildfires could delay ozone recovery in a warming world.

Antimicrobial therapies for prevention of recurrent acute exacerbations of COPD (AECOPD): beyond the guidelines.

BACKGROUND: Unfortunately, many COPD patients continue to exacerbate despite good adherence to GOLD Class D recommended therapy. Acute exacerbations lead to an increase in symptoms, decline in lung function and increased mortality rate. The purpose of this review is to do a literature search for any prophylactic anti-microbial treatment trials in GOLD class D patients who 'failed' recommended therapy and discuss the role of COPD phenotypes, lung and gut microbiota and co-morbidities in developing a tailored approach to anti-microbial therapies for high frequency exacerbators. MAIN TEXT: There is a paucity of large, well-conducted studies in the published literature to date. Factors such as single-centre, study design, lack of well-defined controls, insufficient patient numbers enrolled and short follow-up periods were significant limiting factors in numerous studies. One placebo-controlled study involving more than 1000 patients, who had 2 or more moderate exacerbations in the previous year, demonstrated a non-significant reduction in exacerbations of 19% with 5 day course of moxifloxacillin repeated at 8 week intervals. In Pseudomonas aeruginosa (Pa) colonised COPD patients, inhaled antimicrobial therapy using tobramycin, colistin and gentamicin resulted in significant reductions in exacerbation frequency. Viruses were found to frequently cause acute exacerbations in COPD (AECOPD), either as the primary infecting agent or as a co-factor. However, other, than the influenza vaccination, there were no trials of anti-viral therapies that resulted in a positive effect on reducing AECOPD. Identifying clinical phenotypes and co-existing conditions that impact on exacerbation frequency and severity is essential to provide individualised treatment with targeted therapies. The role of the lung and gut microbiome is increasingly recognised and identification of pathogenic bacteria will likely play an important role in personalised antimicrobial therapies. CONCLUSION: Antimicrobial therapeutic options in patients who continue to exacerbate despite adherence to guidelines-directed therapy are limited. Phenotyping patients, identification of co-existing conditions and assessment of the microbiome is key to individualising antimicrobial therapy. Given the impact of viruses on AECOPD, anti-viral therapeutic agents and targeted anti-viral vaccinations should be the focus of future research studies.

Recurrent asthma exacerbations: co-existing asthma and common variable immunodeficiency.

Common variable immunodeficiency is characterized by impaired B-cell differentiation and defective immunoglobulin production manifesting as recurrent respiratory tract infections. While the condition can masquerade as asthma, late diagnosis of CVID in known asthmatic is rarely reported.We present the case of a 43-year-old lady with recurrent episodes of wheeze, cough, sinusitis and multiple lower respiratory tract infections. Transiently responsive to antibiotics and steroids. These episodes had been occurring for many years and she had a longstanding clinical diagnosis of asthma.As part of her work up for recurrent respiratory tract infections a CT thorax was performed and demonstrated bronchiectasis. Further tests including Immunoglobulin levels revealed critically low IgG, IgM, and IgA levels. Immunoglobulin replacement therapy was commenced with a reduction in exacerbation frequency and severity, and objective improvement of asthma control. Subsequent lung function tests demonstrated reversible airflow limitation (obstructive lung function with 13% reversibility in FEV1 post-bronchodilator) consistent with asthma.Our case illustrates the importance of searching for alternate and co-existent diagnoses in patients diagnosed with asthma who are unresponsive to conventional therapy. We believe that serum immunoglobulin measurement should form a component of such a workup.

Trends and patterns in the contributions to cumulative radiative forcing from different regions of the world.

Different regions of the world have had different historical patterns of emissions of carbon dioxide, other greenhouse gases, and aerosols as well as different land-use changes. One can estimate the net cumulative contribution by each region to the global mean radiative forcing due to past greenhouse gas emissions, aerosol precursors, and carbon dioxide from land-use changes. Several patterns stand out from such calculations. Some regions have had a common historical pattern in which the short-term offsets between the radiative forcings from carbon dioxide and sulfate aerosols temporarily led to near-zero radiative forcing during periods of exponential emissions growth with few emission controls. This happened for North America and Europe in the mid-20th century and China in the 1990s and 2000s. However, these same periods lead to a commitment to future radiative forcing from the carbon dioxide and other greenhouse gases that stay in the atmosphere long after the aerosols. For every region, this commitment to future radiative forcing (2018-2100) from emissions already in the atmosphere is larger than the cumulative radiative forcing to date (1900-2017). This comparison again highlights how the full radiative forcing from greenhouse gases is unmasked once the aerosol emissions are reduced to improve air quality. The relative contributions from various regions to global climate forcing depends more on the time the contributions are compared (e.g., now or 2100) and future development scenarios than on whether cumulative radiative forcing, ocean heat content, or temperature is used to compare regional contributions.

Outcomes Post Thrombolysis for Acute Pulmonary Embolism.

Background Pulmonary embolism (PE) remains a significant cause of mortality in Europe1. Thrombolytic therapy is often utilised as a therapeutic strategy in massive and sub-massive PE. There is a dearth of research on short term complications and subsequent outcomes in patients who have received thrombolysis for PE in Ireland. Methods This retrospective study examined patients who underwent thrombolysis for acute sub massive PE whilst under the care of the respiratory service in Cork University Hospital (CUH) from 2010-2018. All patients had CTPA done for diagnosis of PE. Alteplase was used as a thrombolytic agent. Patient records were perused. Follow-up pulmonary functions tests (PFTs) and trans-thoracic echocardiogram (TTE) results were assessed for evidence of impairment of diffusing capacity (DLCO) and pulmonary hypertension (PH) respectively. Results Twenty five patients were included in the study. Nine patients (36%) were women and 64% men. Average age was 55.1 years. Four patients suffered complications related to thrombolysis (average age 63.3 years). Twenty-Two patients (88%) underwent a follow-up echocardiography (mean 30 weeks post PE). Three patients (13%) had echocardiographic evidence of possible mild PH (i.e. RVSP >40mmhg) at initial follow-up. Fourteen patients (56%) who underwent thrombolysis had follow-up PFTs (mean 11.8 months post PE). The diffusing capacity (DLCO) was normal in all patients. Conclusion Thrombolysis was a relatively safe intervention in this small study.

The effectiveness of Reslizumab in severe asthma treatment: a real-world experience.

BACKGROUND: Increased numbers of blood and sputum eosinophils are associated with higher exacerbation frequency and increased asthma severity. In clinical trials, targeting Interleukin-5 has been shown to be a useful therapeutic strategy for patients with severe eosinophilic asthma. METHODS: Twenty-six patients have been commenced on Reslizumab in our institution since early 2017. Safety and clinical efficacy parameters were recorded at regular intervals. RESULTS: Mean ACQ-6 score at the start of treatment was 3.5. The average number of exacerbations in the year preceding treatment was 8.3 per person. 30% of patients had been admitted to hospital at least once over the 12 months preceding therapy. 54% of our patients were on long term oral steroid. Our data showed sustained improvement of Asthma control (Mean improvement in ACQ-6 was 1.7 at 1 year, and 2.0 at 2 years, P = 0.0001). Of the patients who were on long term systemic steroids, 35.7% discontinued steroids completely, with a mean reduction of prednisolone dose of 5.2 mg at 1 year. There was a 79% reduction in the annual exacerbation frequency at 1 year, and 88% at 2 years (P = < 0.0001). Modest, albeit statistically significant increases in creatine kinase which seemed to plateau by 1 year were noted. CONCLUSIONS: Overall, Reslizumab was well tolerated with discontinuation of treatment due to side effects recorded in only one patient. Our data confirm the utility of anti-IL5 therapy in a carefully selected phenotype of severe asthma with evidence of eosinophilic airway inflammation.

A Study To Assess The Prevalence Of Exercise-Induced Bronchoconstriction In Inter-County Hurling.

Exercise-Induced Bronchoconstriction (EIB) is an acute, transient airway narrowing occurring after exercise which may impact athletic performance. Studies report 10% of the general population and up to 90% of asthmatics experience EIB. Ninety-two players from three elite hurling squads underwent a spirometric field-based provocation test with real-time heart rate monitoring and lactate measurements to ensure adequate exertion. Players with a new diagnosis of EIB and those with a negative field-test but with a previous label of EIB or asthma underwent further reversibility testing and if negative, methacholine challenge. Eight (8.7%) of players had EIB, with one further athlete having asthma with a negative field test. Interestingly, only three out of 12 players who had previously been physician-labelled with EIB or asthma had their diagnosis objectively confirmed. Our study highlights the role of objective testing in EIB.

T cell-mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells.

BACKGROUND: Inhaled peptide challenge has been shown to induce T cell-mediated, isolated late asthmatic reaction (LAR), characterized by recruitment of CD4(+) T cells and increased levels of thymus and activation-regulated chemokine (TARC; CCL17). Epithelial-derived thymic stromal lymphopoietin (TSLP) has been shown to modulate dendritic cell function to promote TH 2 responses via CCL17 production. OBJECTIVES: To elucidate the mechanisms involved in allergen-specific T cell-induced LAR and recruitment of CD4(+) T cells by examining the effects of T cell-derived factors on the induction of TSLP in primary bronchial epithelial cells (PBEC). METHODS: PBEC grown at air-liquid interface from healthy individuals and patients with asthma were stimulated with double-stranded RNA (dsRNA) or supernatants from activated allergen-specific T cells. TSLP was measured in PBEC culture supernatants. Neutralizing antibodies and signalling inhibitors were used to examine the mechanisms responsible for the induction of epithelial-derived TSLP. The functional activity of PBEC-derived TSLP was measured using a bioassay involving the induction of CCL17 production from monocyte-derived dendritic cells (moDC). RESULTS: Both dsRNA and allergen-specific T cells induced enhanced TSLP secretion from asthmatic PBEC compared to healthy PBEC. Activated PBEC culture supernatant induced TSLP-dependent CCL17 production from moDC in a manner related to clinical asthmatic status. IL-1ß, IL-6, and CXCL8, rather than TH 2 cytokines (IL-4/5/13), appeared to be the principle mediators of allergen-specific T cell-dependent induction of epithelial-derived TSLP, which was regulated by the MEK, MAPK, and NFκB pathways. CONCLUSION AND CLINICAL RELEVANCE: Our data reveal a novel effect of allergen-specific T cells as a positive regulator of TSLP production by epithelial cells, suggesting T cell-airway epithelium interactions that may lead to maintenance and amplification of allergic inflammation. TSLP is currently a candidate for therapeutic intervention in asthma, but the factors that drive TSLP expression (T cell-derived factors) may be equally relevant in the treatment of allergic inflammation.

A study to assess inhaler technique and its potential impact on asthma control in patients attending an asthma clinic.

OBJECTIVES: The aim of this study was to evaluate inhaler technique and symptom control in patients with poorly controlled asthma at baseline and at follow-up in a dedicated asthma clinic in a tertiary hospital. We also investigated the impact of asthma on these patients' quality of life. METHODS: Patients referred to a newly established asthma clinic in Cork University Hospital were prospectively recruited over a 6-month period. Their inhaler technique was assessed by a pulmonary nurse specialist using a validated scoring system. They received instruction on inhaler usage when scores were suboptimal. Patients completed a validated asthma control questionnaire (ACQ) and asthma quality of life questionnaire (AQLQ). At follow-up 3-4 months later, the inhaler technique was reassessed and the ACQ questionnaire repeated. RESULTS: Forty-six patients were recruited (female = 74%), and 40/46 were followed up. Mean [SD] FEV1 % predicted at baseline = 76.5% [21.5]. About 63% of the patients were classified as incorrectly using their inhaler at their initial assessment. This decreased to 20% at follow-up, indicating an overall significant improvement in inhaler usage post-training (p = 0.003). ACQ scores improved significantly from median [interquartile range] 2.70 [1.66] to 2.00 [1.90] (p = 0.002). Baseline measurement indicated that patients' quality of life was moderately affected by asthma, with a median AQLQ score of 4.75 [1.97]. CONCLUSION: This study demonstrates the importance of educating and formally assessing inhaler technique in patients with asthma as a part of their ongoing clinical review.

A 76 year old female diagnosed with cystic fibrosis.

The diagnosis of Cystic Fibrosis (CF) requires a high clinical suspicion in patients presenting at all ages. Early recognition permits referral to a specialist centre and may reduce the morbidity and mortality associated with CF. We report the case of the oldest patient in Ireland diagnosed with CF at 76 years of age and highlight the clinical features of her presentation.

Contribution of isoprene-derived organosulfates to free tropospheric aerosol mass.

Recent laboratory studies have demonstrated that isoprene oxidation products can partition to atmospheric aerosols by reacting with condensed phase sulfuric acid, forming low-volatility organosulfate compounds. We have identified organosulfate compounds in free tropospheric aerosols by single particle mass spectrometry during several airborne field campaigns. One of these organosulfates is identified as the sulfate ester of IEPOX, a second generation oxidation product of isoprene. The patterns of IEPOX sulfate ester in ambient data generally followed the aerosol acidity and NO(x) dependence established by laboratory studies. Detection of the IEPOX sulfate ester was most sensitive using reduced ionization laser power, when it was observed in up to 80% of particles in the tropical free troposphere. Based on laboratory mass calibrations, IEPOX added > 0.4% to tropospheric aerosol mass in the remote tropics and up to 20% in regions downwind of isoprene sources. In the southeastern United States, when acidic aerosol was exposed to fresh isoprene emissions, accumulation of IEPOX increased aerosol mass by up to 3%. The IEPOX sulfate ester is therefore one of the most abundant single organic compounds measured in atmospheric aerosol. Our data show that acidity-dependent IEPOX uptake is a mechanism by which anthropogenic SO(2) and marine dimethyl sulfide emissions generate secondary biogenic aerosol mass throughout the troposphere.

Pyrocumulonimbus affect average stratospheric aerosol composition.

Pyrocumulonimbus (pyroCb) are wildfire-generated convective clouds that can inject smoke directly into the stratosphere. PyroCb have been tracked for years, yet their apparent rarity and episodic nature lead to highly uncertain climate impacts. In situ measurements of pyroCb smoke reveal its distinctive and exceptionally stable aerosol properties and define the long-term influence of pyroCb activity on the stratospheric aerosol budget. Analysis of 13 years of airborne observations shows that pyroCb are responsible for 10 to 25% of the black carbon and organic aerosols in the "present-day" lower stratosphere, with similar impacts in both the North and South Hemispheres. These results suggest that, should pyroCb increase in frequency and/or magnitude in future climates, they could generate dominant trends in stratospheric aerosol.

Modulation, microbiota and inflammation in the adult CF gut: A prospective study.

BACKGROUND: Cystic Fibrosis (CF) has prominent gastrointestinal and pancreatic manifestations. The aim of this study was to determine the effect of Cystic fibrosis transmembrane conductance regulator (CFTR) modulation on, gastrointestinal inflammation, pancreatic function and gut microbiota composition in people with cystic fibrosis (CF) and the G551D-CFTR mutation. METHODS: Fourteen adult patients with the G551D-CFTR mutation were assessed clinically at baseline and for up to 1 year after treatment with ivacaftor. The change in gut inflammatory markers (calprotectin and lactoferrin), exocrine pancreatic status and gut microbiota composition and structure were assessed in stool samples. RESULTS: There was no significant change in faecal calprotectin nor lactoferrin in patients with treatment while all patients remained severely pancreatic insufficient. There was no significant change in gut microbiota diversity and richness following treatment. CONCLUSION: There was no significant change in gut inflammation after partial restoration of CFTR function with ivacaftor, suggesting that excess gut inflammation in CF is multi-factorial in aetiology. In this adult cohort, exocrine pancreatic function was irreversibly lost. Longer term follow-up may reveal more dynamic changes in the gut microbiota and possible restoration of CFTR function.

A bolt from the blue; A case report of an unusual asthma exacerbation.

BACKGROUND: We describe this case of a young gentleman presenting with acute dyspnoea on a background history of known, long-standing asthma. His dramatic presentation, notable for profound hypoxia and cyanosis, led to an unexpected additional diagnosis of type one congenital methaemoglobinaemia. CASE PRESENTATION: A 26-year-old Irish gentleman was transferred urgently to the emergency department resuscitation room with marked cyanosis and tachypnoea. His oxygen saturation was 70% on 100% high flow oxygen. His arterial blood gas (On Fi02 90%) demonstrated a PaO2 = 76.8 kPa, SpO2 = 99%, pCO2 = 3 kPa and pH = 7.51. A saturation gap was evident and on further analysing the arterial blood gas, the methaemoglobin level was noted to be 28%. No contributing drugs were identified. Our patient was diagnosed with type one congenital methaemoglobinaemia. He recovered well from this admission, however, has had recurrent presentations to hospital since with high methaemoglobin levels noted on each occasion. DISCUSSION: Congenital methemoglobinemia is a rare, often overlooked differential diagnosis in patients presenting with cyanosis and dyspnoea. This is the only case, to our knowledge, of a patient with both asthma and congenital methaemoglobinaemia. Congenital methaemoglobinaemia was first described in 1943 by Dr Deeny who described two siblings as suffering from 'Familial Idiopathic Methaemoglobinaemia'. The case we present is the first reported Irish case of congenital methaemoglobinaemia, we are aware of, since 1943.Current treatment strategies include high-flow oxygen, methylene blue infusion (contraindicated in glucose-6-phosphate-dehydrogenase deficiency) and red cell exchange transfusions in the emergency setting whilst oral ascorbic acid and riboflavin are preventative.

Targeting allograft injury and inflammation in the management of post-lung transplant bronchiolitis obliterans syndrome.

Chronic allograft dysfunction, manifesting as bronchiolitis obliterans syndrome (BOS), is the major cause of morbidity and mortality in human lung transplant recipients. While alloimmunity has a definite role, there is increasing interest in overall allograft injury and subsequent inflammation and remodeling. This review deals with nonalloimmune factors that may potentiate alloimmune injury. We discuss infection and reflux/aspiration as examples of allograft injury, which may lead to chronic loss of graft function and BOS. Surgical and nonsurgical treatments aimed at preventing these insults and improving survival are considered. The need for further evidence, including randomized-controlled trials, to evaluate the role of medical and surgical therapies is emphasized by the current literature.

Distinct protein sorting and localization to premelanosomes, melanosomes, and lysosomes in pigmented melanocytic cells.

Melanosomes and premelanosomes are lysosome-related organelles with a unique structure and cohort of resident proteins. We have positioned these organelles relative to endosomes and lysosomes in pigmented melanoma cells and melanocytes. Melanosome resident proteins Pmel17 and TRP1 localized to separate vesicular structures that were distinct from those enriched in lysosomal proteins. In immunogold-labeled ultrathin cryosections, Pmel17 was most enriched along the intralumenal striations of premelanosomes. Increased pigmentation was accompanied by a decrease in Pmel17 and by an increase in TRP1 in the limiting membrane. Both proteins were largely excluded from lysosomal compartments enriched in LAMP1 and cathepsin D. By kinetic analysis of fluid phase uptake and immunogold labeling, premelanosomal proteins segregated from endocytic markers within an unusual endosomal compartment. This compartment contained Pmel17, was accessed by BSA-gold after 15 min, was acidic, and displayed a cytoplasmic planar coat that contained clathrin. Our results indicate that premelanosomes and melanosomes represent a distinct lineage of organelles, separable from conventional endosomes and lysosomes within pigmented cells. Furthermore, they implicate an unusual clathrin-coated endosomal compartment as a site from which proteins destined for premelanosomes and lysosomes are sorted.

Ablation, flux, and atmospheric implications of meteors inferred from stratospheric aerosol.

Single-particle analyses of stratospheric aerosol show that about half of the particles contain 0.5 to 1.0 weight percent meteoritic iron by mass, requiring a total extraterrestrial influx of 8 to 38 gigagrams per year. The sodium/iron ratio in these stratospheric particles is higher and the magnesium/iron and calcium/iron ratios are lower than in chondritic meteorites, implying that the fraction of material that is ablated must lie at the low end of previous estimates and that the extraterrestrial component that resides in the mesosphere and stratosphere is not of chondritic composition.