Continuous negative extrathoracic pressure and bronchiolitis

Bronchiolitis is the commonest cause of acute respiratory failure in infancy and several hundred children need respiratory support for the condition each year in the United Kingdom. Continuous negative extrathoracic pressure (CNEP) has been used to support such children but concerns about its possible association with significant harm prompted a government enquiry into the conduct of research at a UK centre using the technique. This retrospective study was designed to address these concerns by careful evaluation of outcome in two matched cohorts. Fifty children who had received CNEP for bronchiolitis as infants were compared with 50 controls who were treated in another hospital during the same period. Pre-treatment variables, demographics and neonatal factors were well matched in the two groups. In all subjects questionnaires and clinical examination were used to assess respiratory symptoms, disability and health-related quality of life whilst respiratory function was assessed by measuring airway resistance using the interrupter technique (Rint), by spirometry and by bronchodilator responsiveness. CNEP was associated with reduced need for, and shorter duration of, positive pressure ventilation but with longer periods in oxygen and hospital. Median Rint was 16.5% higher in the CNEP cohort (p<0.001) and median FEF25-75 was 9.3% lower (p=0.029). There were no significant differences between the groups in FEV1, FVC, bronchodilator responses or respiratory symptoms, or in the prevalence of moderate or severe disability (Mantel-Haenszel statistic 1.40, 95% confidence intervals: 0.64 -3.04, p=0.39). Median health utility indices were similar; CNEP 1.00 (interquartile range: 0.85-1.00), controls 0.99 (interquartile range: 0.81 -1.00), n=48 pairs, p= 0.37. The higher Rint and lower FEF25-75 in the CNEP group represent a small difference in respiratory function that may be attributable to population differences but a CNEP effect cannot be excluded. Further evaluation of the use of CNEP in bronchiolitis requires a prospective, controlled study

Continuous negative extrathoracic pressure and bronchiolitis

Bronchiolitis is the commonest cause of acute respiratory failure in infancy and several hundred children need respiratory support for the condition each year in the United Kingdom. Continuous negative extrathoracic pressure (CNEP) has been used to support such children but concerns about its possible association with significant harm prompted a government enquiry into the conduct of research at a UK centre using the technique. This retrospective study was designed to address these concerns by careful evaluation of outcome in two matched cohorts. Fifty children who had received CNEP for bronchiolitis as infants were compared with 50 controls who were treated in another hospital during the same period. Pre-treatment variables, demographics and neonatal factors were well matched in the two groups. In all subjects questionnaires and clinical examination were used to assess respiratory symptoms, disability and health-related quality of life whilst respiratory function was assessed by measuring airway resistance using the interrupter technique (Rint), by spirometry and by bronchodilator responsiveness. CNEP was associated with reduced need for, and shorter duration of, positive pressure ventilation but with longer periods in oxygen and hospital. Median Rint was 16.5% higher in the CNEP cohort (p<0.001) and median FEF25-75 was 9.3% lower (p=0.029). There were no significant differences between the groups in FEV1, FVC, bronchodilator responses or respiratory symptoms, or in the prevalence of moderate or severe disability (Mantel-Haenszel statistic 1.40, 95% confidence intervals: 0.64 -3.04, p=0.39). Median health utility indices were similar; CNEP 1.00 (interquartile range: 0.85-1.00), controls 0.99 (interquartile range: 0.81 -1.00), n=48 pairs, p= 0.37. The higher Rint and lower FEF25-75 in the CNEP group represent a small difference in respiratory function that may be attributable to population differences but a CNEP effect cannot be excluded. Further evaluation of the use of CNEP in bronchiolitis requires a prospective, controlled study

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. METHODS: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. FINDINGS: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. INTERPRETATION: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. FUNDING: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Polycyclic Aromatic Hydrocarbons with Corannulene Subunits

The study of polycyclic aromatic hydrocarbons (PAHs) with curved surfaces, also known as buckybowls or fullerene fragments, represent an area which is under intense investigation by organic chemists and material scientists. This dissertation describes research that contributes to this field. The availability of multi-gram quantities of the smallest buckybowl, corannulene, has led to the synthesis of several larger systems with buckybowl subunits. Cyclotrimerization of corannulyne using palladium(0) as the catalyst is described. The resulting product, C60H24, is a highly nonplanar hydrocarbon with very interesting conformational dynamics. The X-ray crystallography of the cyclotrimer confirms the “twist” conformation with C1 symmetry. The cyclotrimer also shows three distinct corannulene bowls with very different inversion barriers as confirmed by both experiment and calculations. The bowl to bowl inversion of the corannulene bowl with the lowest inversion barrier results in pseudorotation of the cyclotrimer, which gives rise to a symmetrized 1H NMR spectrum exhibiting 12 distinct proton signals. 1H NMR line shape analysis gives an estimation of the inversion barrier at 8.5 – 8.6 kcal/mol. The tetrameric hydrocarbon C80H32 was synthesized through the Diels-Alder reaction of the cyclotrimer and 1,2-didehydrocorannulene. The six membered rings adjacent to the central ring in the cyclotrimer are activated enough to react with another corannulyne. The tetramer exhibits different conformational and optical absorption properties when compared to the cyclotrimer. The tetramer (C80H32), which is highly nonplanar and sterically congested, represents the largest fully characterized oligomer of corannulyne reported to date. This is also the first reported example of a cycloaddition reaction in which a corannulene subunit acts as a diene. A tripodal molecular receptor (C87H54O6) with three corannulene pincers and a cyclotriveratrylene tether was synthesized. The molecular receptor was evaluated by 1H NMR titration in toluene-d8 for its ability to bind fullerenes. The experiment demonstrates the formation of 1:1 inclusion complexes of the molecular receptor with fullerenes and provides the association constants of 1500 plus or minus 50 and 1180 plus or minus 30 M-1 for C60 and C70, respectively

Continuous negative extrathoracic pressure and bronchiolitis

Bronchiolitis is the commonest cause of acute respiratory failure in infancy and several hundred children need respiratory support for the condition each year in the United Kingdom. Continuous negative extrathoracic pressure (CNEP) has been used to support such children but concerns about its possible association with significant harm prompted a government enquiry into the conduct of research at a UK centre using the technique. This retrospective study was designed to address these concerns by careful evaluation of outcome in two matched cohorts. Fifty children who had received CNEP for bronchiolitis as infants were compared with 50 controls who were treated in another hospital during the same period. Pre-treatment variables, demographics and neonatal factors were well matched in the two groups. In all subjects questionnaires and clinical examination were used to assess respiratory symptoms, disability and health-related quality of life whilst respiratory function was assessed by measuring airway resistance using the interrupter technique (Rint), by spirometry and by bronchodilator responsiveness. CNEP was associated with reduced need for, and shorter duration of, positive pressure ventilation but with longer periods in oxygen and hospital. Median Rint was 16.5% higher in the CNEP cohort (p<0.001) and median FEF25-75 was 9.3% lower (p=0.029). There were no significant differences between the groups in FEV1, FVC, bronchodilator responses or respiratory symptoms, or in the prevalence of moderate or severe disability (Mantel-Haenszel statistic 1.40, 95% confidence intervals: 0.64 -3.04, p=0.39). Median health utility indices were similar; CNEP 1.00 (interquartile range: 0.85-1.00), controls 0.99 (interquartile range: 0.81 -1.00), n=48 pairs, p= 0.37. The higher Rint and lower FEF25-75 in the CNEP group represent a small difference in respiratory function that may be attributable to population differences but a CNEP effect cannot be excluded. Further evaluation of the use of CNEP in bronchiolitis requires a prospective, controlled study.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A 2:1 receptor/C60 complex as a nanosized universal joint

Buckycatcher II, a C51 H24 hydrocarbon with two corannulene pincers on a dibenzonorbornadiene tether, exhibits an affinity toward C60 in organic solvents that is dramatically higher than the original buckycatcher C60 H28 and other corannulene-based molecular receptors for fullerenes. In addition to the formation of an usual 1:1 C60 @catcher inclusion complex, a trimeric C60 @(catcher)2 assembly is detected in solutions and in the solid state. X-ray structure determination reveals a remarkable universal joint solvent-free crystal arrangement of the trimer, with a single fullerene cage wrapped by four corannulene subunits of two cooperating catcher receptors

Corannulene Subunit Acts as a Diene in a Cycloaddition Reaction: Synthesis of C₈₀H₃₂ Corannulyne Tetramer

Distortion of six-membered rings in corannulene subunits of corannulyne (1,2-didehydrocorannulene) cyclotrimer activates the system for a cycloaddition reaction with another corannulyne unit. This unprecedented cycloaddition in which a corannulene fragment acts as a diene produces the largest oligomer of corannulyne reported to date. X-ray crystallography reveals the highly nonplanar structure of the tetramer which exhibits conformational and optical absorption properties very different from those of the cyclotrimer

Thermodynamics of Host–Guest Interactions between Fullerenes and a Buckycatcher

¹H NMR and isothermal titration calorimetry (ITC) experiments were employed to obtain reliable thermodynamic data for the formation of the 1:1 inclusion complexes of fullerenes C₆₀ and C₇₀ with the buckycatcher (C₆₀H₂₈). NMR measurements were done in toluene-<i>d</i>₈ and chlorobenzene-<i>d</i>₅ at 288, 298, and 308 K, while the ITC titrations were performed in toluene, chlorobenzene, <i>o</i>-dichlorobenzene, anisole, and 1,1,2,2-tetrachloroethane at temperatures from 278 to 323 K. The association constants, <i>K</i>_a, obtained with both techniques are in very good agreement. The thermodynamic data obtained by ITC indicate that generally the host–guest association is enthalpy-driven. Interestingly, the entropy contributions are, with rare exceptions, slightly stabilizing or close to zero. Neither Δ<i>H</i> nor Δ<i>S</i> is constant over the temperature range studied, and these thermodynamic functions exhibit classical enthalpy/entropy compensation. The Δ<i>C</i>_<i>p</i> values calculated from the temperature dependence of the calorimetric Δ<i>H</i> values are negative for the association of both fullerenes with the buckycatcher in toluene. The negative Δ<i>C</i>_<i>p</i> values are consistent with some desolvation of the host-cavity and the guest in the inclusion complexes, C₆₀@C₆₀H₂₈ and C₇₀@C₆₀H₂₈