Background Welders are at increased risk of pneumococcal pneumonia. The mechanism for this association is not known. The capacity of pneumococci to adhere to and infect lower airway cells is mediated ...by host-expressed platelet-activating factor receptor (PAFR). Objective We sought to assess the effect of mild steel welding fumes (MS-WF) on PAFR-dependent pneumococcal adhesion and infection to human airway cells in vitro and on pneumococcal airway infection in a mouse model. Methods The oxidative potential of MS-WF was assessed by their capacity to reduce antioxidants in vitro . Pneumococcal adhesion and infection of A549, BEAS-2B, and primary human bronchial airway cells were assessed by means of quantitative bacterial culture and expressed as colony-forming units (CFU). After intranasal instillation of MS-WF, mice were infected with Streptococcus pneumoniae , and bronchoalveolar lavage fluid (BALF) and lung CFU values were determined. PAFR protein levels were assessed by using immunofluorescence and immunohistochemistry, and PAFR mRNA expression was assessed by using quantitative PCR. PAFR was blocked by CV-3988, and oxidative stress was attenuated by N-acetylcysteine. Results MS-WF exhibited high oxidative potential. In A549 and BEAS-2B cells MS-WF increased pneumococcal adhesion and infection and PAFR protein expression. Both CV-3988 and N-acetylcysteine reduced MS-WF–stimulated pneumococcal adhesion and infection of airway cells. MS-WF increased mouse lung PAFR mRNA expression and increased BALF and lung pneumococcal CFU values. In MS-WF–exposed mice CV-3988 reduced BALF CFU values. Conclusions Hypersusceptibility of welders to pneumococcal pneumonia is in part mediated by the capacity of welding fumes to increase PAFR-dependent pneumococcal adhesion and infection of lower airway cells.
Air pollution harms health across the life course. Children are at particular risk of adverse effects during development, which may impact on health in later life. Interventions that improve air ...quality are urgently needed both to improve public health now, and prevent longer-term increased vulnerability to chronic disease. Low Emission Zones are a public health policy intervention aimed at reducing traffic-derived contributions to urban air pollution, but evidence that they deliver health benefits is lacking. We describe a natural experiment study (CHILL: Children's Health in London and Luton) to evaluate the impacts of the introduction of London's Ultra Low Emission Zone (ULEZ) on children's health.
CHILL is a prospective two-arm parallel longitudinal cohort study recruiting children at age 6-9 years from primary schools in Central London (the focus of the first phase of the ULEZ) and Luton (a comparator site), with the primary outcome being the impact of changes in annual air pollutant exposures (nitrogen oxides NOx, nitrogen dioxide NO
, particulate matter with a diameter of less than 2.5micrograms PM
, and less than 10 micrograms PM
) across the two sites on lung function growth, measured as post-bronchodilator forced expiratory volume in one second (FEV
) over five years. Secondary outcomes include physical activity, cognitive development, mental health, quality of life, health inequalities, and a range of respiratory and health economic data.
CHILL's prospective parallel cohort design will enable robust conclusions to be drawn on the effectiveness of the ULEZ at improving air quality and delivering improvements in children's respiratory health. With increasing proportions of the world's population now living in large urban areas exceeding World Health Organisation air pollution limit guidelines, our study findings will have important implications for the design and implementation of Low Emission and Clean Air Zones in the UK, and worldwide.
GOV: NCT04695093 (05/01/2021).
Children with poorly controlled asthma have higher rates of unplanned healthcare use and school absences, as well as lower rates of medication adherence and knowledge. They also feel less comfortable ...using their medication at school, due to social fears and bullying. In this study, this was addressed through two school-based self-management interventions piloted to determine which one to use in a full trial.
We sought to assess the feasibility and acceptability of two school-based self-management intervention aimed at improving asthma control. Schools in London were randomised to (i) a theatre workshop for the whole year group aimed at raising awareness of asthma in schools, followed by self-management workshops for children (full intervention), (ii) theatre workshop alone (theatre only), or (iii) usual care (controls). Opt-out consent was obtained from parents. The study was a cluster randomised pilot trial, using London schools as the unit of allocation. Our primary aim was to assess the feasibility of delivering a self-management intervention in schools aimed at improving the asthma control test (ACT) score at 6 months. Secondary outcomes included acceptability of the school-based interventions, suitability of the theatre intervention and the full intervention with the self-management workshops, and generation of randomised data to inform future power calculations. Data were analysed by generalised mixed-effect models.
The recruitment strategy for this trial was effective. Five schools were randomised to full intervention (189 children), four to theatre only (103 children), and six to controls (83 children). Asthma control test (ACT) score at baseline and 6 months was obtained from 178/358 participating children. Compared with the controls, there were no large differences found in ACT score with the full intervention; knowledge and perception of asthma improved though. GP and hospital visits increased in the full intervention group. Compared with controls, ACT score was unchanged in the theatre only group.
The asthma self-management intervention trial in schools is feasible and acceptable. The full intervention consisting of both theatre and self-management workshop for asthmatics tended to be better suited to improve outcomes than the theatre intervention on its own. This full intervention should be the one carried forward into a main trial if funding for further research was sought. Further work is needed to understand why there was evidence that unscheduled visits to healthcare professionals increased with the full intervention.
The study was registered on the clinical trials database on 14th May 2018 (ID NCT03536416 ).
The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age ...group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype.
We did this multicentre, parallel-group, randomised, placebo-controlled trial between Oct 1, 2010, and Dec 20, 2013, at 21 primary care sites and 41 secondary care sites in England and Scotland. Children aged 10 months to 5 years with two or more wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) via a permuted block schedule (size ten), to receive intermittent montelukast or placebo given by parents at each wheeze episode over a 12 month period. Clinical investigators and parents were masked to treatment group and genotype strata. The primary outcome was number of unscheduled medical attendances for wheezing episodes. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01142505.
We randomly assigned 1358 children to receive montelukast (n=669) or placebo (n=677). Consent was withdrawn for 12 (1%) children. Primary outcome data were available for 1308 (96%) children. There was no difference in unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 SD 2·6 vs 2·3 2·7; incidence rate ratio IRR 0·88, 95% CI: 0·77–1·01; p=0·06). Compared with placebo, unscheduled medical attendances for wheezing episodes were reduced in children given montelukast in the 5/5 stratum (2·0 2·7 vs 2·4 3·0; IRR 0·80, 95% CI 0·68–0·95; p=0·01), but not in those in the 5/x+x/x stratum (2·0 2·5 vs 2·0 2·3; 1·03, 0·83–1·29; p=0·79, pinteraction=0·08). We recorded one serious adverse event, which was a skin reaction in a child allocated to placebo.
Our findings show no clear benefit of intermittent montelukast in young children with wheeze. However, the 5/5 ALOX5 promoter genotype might identify a montelukast-responsive subgroup.
Medical Research Council (UK) and National Institute for Health Research.
There is increasing evidence that vulnerability to pneumococcal pneumonia is mediated by the expression of adhesion receptors for bacteria on lower airway cells. A key bacterial adhesion receptor is ...the platelet-activating factor receptor (PAFR). In vitro and animal studies have shown that upregulation of PAFR increases vulnerability to infection and blocking PAFR and knockdown of PAFR attenuates infection. Blocking PAFR may therefore be a novel therapeutic strategy in acute and chronic airway infection.
Biologic plausibility for the association between exposure to particulate matter (PM) less than 10 μm in aerodynamic diameter (PM10) and coronavirus disease 2019 (COVID-19) morbidity in epidemiologic ...studies has not been determined. The upregulation of angiotensin-converting enzyme 2 (ACE2), the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) entry receptor on host cells, by PM10 is a putative mechanism.
We sought to assess the effect of PM10 on SARS-CoV-2 infection of cells in vitro.
PM10 from the curbside of London's Marylebone Road and from diesel exhaust emissions was collected by cyclone. A549 cells, human primary nasal epithelial cells (HPNEpCs), and SARS-CoV-2–susceptible Vero-E6 and Calu3 cells were cultured with PM10. ACE2 expression (as determined by median fluorescent intensity) was assessed by flow cytometry, and ACE2 mRNA transcript level was assessed by PCR. The role of oxidative stress was determined by N-acetyl cysteine. The cytopathic effect of SARS-CoV-2 (percentage of infection enhancement) and expression of SARS-CoV-2 genes' open reading frame (ORF) 1ab, S protein, and N protein (focus-forming units/mL) were assessed in Vero-E6 cells. Data were analyzed by either the Mann-Whitney U test or Kruskal-Wallis test with the Dunn multiple comparisons test.
Curbside PM10 at concentrations of 10 μg/mL or more increased ACE2 expression in A549 cells (P = .0021). Both diesel PM10 and curbside PM10 in a concentration of 10 μg/mL increased ACE2 expression in HPNEpCs (P = .0022 and P = .0072, respectively). ACE2 expression simulated by curbside PM10 was attenuated by N-acetyl cysteine in HPNEpCs (P = .0464). Curbside PM10 increased ACE2 expression in Calu3 cells (P = .0256). In Vero-E6 cells, curbside PM10 increased ACE2 expression (P = .0079), ACE2 transcript level (P = .0079), SARS-CoV-2 cytopathic effect (P = .0002), and expression of the SARS-CoV-2 genes' ORF 1ab, S protein, and N protein (P = .0079).
Curbside PM10 increases susceptibility to SARS-COV-2 infection in vitro.
Because randomized controlled trials of established pediatric asthma therapies are expensive and difficult to perform, observational studies may fill gaps in the evidence base.
To compare the ...effectiveness of representative small-particle inhaled corticosteroid (ICS) with that of standard size–particle ICS for children initiating or stepping up ICS therapy for asthma (analysis 1) and to compare the effectiveness of ICS dose step-up using small-particle ICS with adding long-acting β2-agonist (LABA) to the ICS (analysis 2).
These historical matched cohort analyses drew on electronic medical records of children with asthma aged 5 to 11 years. Variables measured during 2 consecutive years (1 baseline year for confounder definition and 1 outcome year) included risk-domain asthma control (no hospital attendance for asthma, acute oral corticosteroids, or lower respiratory tract infection requiring antibiotics) and rate of severe exacerbations (asthma-related emergency, hospitalization, or oral corticosteroids).
In the initiation population (n = 797 in each cohort), children prescribed small-particle ICS versus standard size–particle ICS experienced greater odds of asthma control (adjusted odds ratio, 1.49; 95% CI, 1.10-2.02) and lower severe exacerbation rate (adjusted rate ratio, 0.56; 95% CI, 0.35-0.88). Step-up outcomes (n = 206 in each cohort) were also significantly better for small-particle ICS, with asthma control adjusted odds ratio of 2.22 (95% CI, 1.23-4.03) and exacerbations adjusted rate ratio of 0.49 (95% CI, 0.27-0.89). The number needed to treat with small-particle ICS to achieve 1 additional child with asthma control was 17 (95% CI, 9-107) for the initiation population and 5 (95% CI, 3-78) for the step-up population. Outcomes were not significantly different for stepped-up small-particle ICS dose versus ICS/LABA combination (n = 185 in each cohort).
Initiating or stepping up the ICS dose with small-particle ICS rather than with standard size–particle ICS is more effective and shows similar effectiveness to add-on LABA in childhood asthma.
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