Ethnic differences in cellular and humoral immune responses to SARS-CoV-2 vaccination in UK healthcare workers: a cross-sectional analysis.

Background: Few studies have compared SARS-CoV-2 vaccine immunogenicity by ethnic group. We sought to establish whether cellular and humoral immune responses to SARS-CoV-2 vaccination differ according to ethnicity in UK Healthcare workers (HCWs). Methods: In this cross-sectional analysis, we used baseline data from two immunological cohort studies conducted in HCWs in Leicester, UK. Blood samples were collected between March 3, and September 16, 2021. We excluded HCW who had not received two doses of SARS-CoV-2 vaccine at the time of sampling and those who had serological evidence of previous SARS-CoV-2 infection. Outcome measures were SARS-CoV-2 spike-specific total antibody titre, neutralising antibody titre and ELISpot count. We compared our outcome measures by ethnic group using univariable (t tests and rank-sum tests depending on distribution) and multivariable (linear regression for antibody titres and negative binomial regression for ELISpot counts) tests. Multivariable analyses were adjusted for age, sex, vaccine type, length of interval between vaccine doses and time between vaccine administration and sample collection and expressed as adjusted geometric mean ratios (aGMRs) or adjusted incidence rate ratios (aIRRs). To assess differences in the early immune response to vaccination we also conducted analyses in a subcohort who provided samples between 14 and 50 days after their second dose of vaccine. Findings: The total number of HCWs in each analysis were 401 for anti-spike antibody titres, 345 for neutralising antibody titres and 191 for ELISpot. Overall, 25.4% (19.7% South Asian and 5.7% Black/Mixed/Other) were from ethnic minority groups. In analyses including the whole cohort, neutralising antibody titres were higher in South Asian HCWs than White HCWs (aGMR 1.47, 95% CI [1.06-2.06], P = 0.02) as were T cell responses to SARS-CoV-2 S1 peptides (aIRR 1.75, 95% CI [1.05-2.89], P = 0.03). In a subcohort sampled between 14 and 50 days after second vaccine dose, SARS-CoV-2 spike-specific antibody and neutralising antibody geometric mean titre (GMT) was higher in South Asian HCWs compared to White HCWs (9616 binding antibody units (BAU)/ml, 95% CI [7178-12,852] vs 5888 BAU/ml [5023-6902], P = 0.008 and 2851 95% CI [1811-4487] vs 1199 [984-1462], P < 0.001 respectively), increments which persisted after adjustment (aGMR 1.26, 95% CI [1.01-1.58], P = 0.04 and aGMR 2.01, 95% CI [1.34-3.01], P = 0.001). SARS-CoV-2 ELISpot responses to S1 and whole spike peptides (S1 + S2 response) were higher in HCWs from South Asian ethnic groups than those from White groups (S1: aIRR 2.33, 95% CI [1.09-4.94], P = 0.03; spike: aIRR, 2.04, 95% CI [1.02-4.08]). Interpretation: This study provides evidence that, in an infection naïve cohort, humoral and cellular immune responses to SARS-CoV-2 vaccination are stronger in South Asian HCWs than White HCWs. These differences are most clearly seen in the early period following vaccination. Further research is required to understand the underlying mechanisms, whether differences persist with further exposure to vaccine or virus, and the potential impact on vaccine effectiveness. Funding: DIRECT and BELIEVE have received funding from UK Research and Innovation (UKRI) through the COVID-19 National Core Studies Immunity (NCSi) programme (MC_PC_20060).

Predictors of adverse outcome in the first and second waves of the COVID-19 pandemic: results from a UK centre.

BACKGROUND/AIMS: Data concerning differences in demographics/disease severity between the first and second waves of COVID-19 are limited. We aimed to examine prognosis in patients presenting to hospital with COVID-19 amongst different ethnic groups between the first and second waves in the UK. METHODS: In this retrospective cohort study, we included 1763 patients presenting to a regional hospital centre in Leicester (UK) and compared those in the first (n = 956) and second (n = 807) waves. Admission National Early Warning Scores, mechanical ventilation and mortality rate were lower in the second wave compared with the first. RESULTS: Thirty-day mortality risk in second wave patients was approximately half that of first wave patients [adjusted hazard ratio (aHR) 0.55, 95% confidence interval (CI) 0.40-0.75]. In the second wave, Black patients were at higher risk of 30-day mortality than White patients (4.73, 1.56-14.3). CONCLUSION: We found that disporportionately higher risks of death in patients from ethnic minority groups were not equivalent across consecutive waves of the pandemic. This suggests that risk factors for death in those from ethnic minority groups are malleable and potentially reversible. Our findings need urgent investigation in larger studies.

No cases of asymptomatic SARS-CoV-2 infection among healthcare staff in a city under lockdown restrictions: lessons to inform 'Operation Moonshot'.

BACKGROUND: Leicester was the first city in the UK to have 'local lockdown' measures imposed in response to high community rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. As part of this response, a directive was issued by NHS England to offer testing of asymptomatic healthcare workers (HCWs) at University Hospitals of Leicester NHS Trust (UHL) for SARS-CoV-2 infection. METHODS: Between 20 July and 14 August 2020, we invited all HCWs at UHL to attend for SARS-CoV-2 testing by nucleic acid amplification (NAAT). We combined the result of this assay with demographic information from the electronic staff record. RESULTS: A total of 1150 staff (~8% of the workforce) volunteered. The median age was 46 years (IQR 34-55), 972 (84.5%) were female; 234 (20.4%) were of South Asian and 58 (5.0%) of Black ethnicity; 564 (49.0%) were nurses/healthcare assistants. We found no cases of asymptomatic infection. In comparison, average community test positivity rate in Leicester city was 2.6%. CONCLUSIONS: Within the context of local lockdowns due to high community transmission rates, voluntary testing of asymptomatic staff has low uptake and low yield and thus its premise and cost-effectiveness should be re-considered.

Socio-demographic heterogeneity in the prevalence of COVID-19 during lockdown is associated with ethnicity and household size: Results from an observational cohort study.

BACKGROUND: Accumulating evidence indicates that COVID-19 causes adverse outcomes in ethnic minority groups. However, little is known about the impact of ethnicity and household size on acquiring infection with SARS-CoV-2. METHODS: We undertook a retrospective cohort study, in Leicester (UK), of all individuals assessed for COVID-19 with polymerase chain reaction (PCR) testing at University Hospitals of Leicester NHS Trust between 1st March and 28th April 2020. We used logistic regression to identify sociodemographic, clinical and temporal factors associated with SARS-CoV-2 PCR positivity before/after lockdown. FINDINGS: 971/4051 (24.0%) patients with suspected COVID-19 were found to be PCR positive for SARS-CoV-2. PCR positivity was more common amongst individuals from ethnic minortiy backgrounds than their White counterparts (White 20.0%, South Asian 37.5%, Black 36.1%, Other 32.2%; p<0.001 for all ethnic minority groups vs White). After adjustment, compared to White ethnicity, South Asian (aOR 2.44 95%CI 2.01, 2.97), Black (aOR 2.56 95%CI 1.71, 3.84) and Other (aOR 2.53 95%CI 1.74, 3.70) ethnicities were more likely to test positive, as were those with a larger estimated household size (aOR 1.06 95%CI 1.02, 1.11). We saw increasing proportions of positive tests in the three weeks post-lockdown amongst the ethnic minority , but not the White, cohort. Estimated household size was associated with PCR positivity after, but not before, lockdown (aOR 1.10 95%CI 1.03, 1.16). INTERPRETATION: In individuals presenting with suspected COVID-19, those from ethnic minority communities and larger households had an increased likelihood of SARS-CoV-2 PCR positivity. Pandemic control measures may have more rapid impact on slowing viral transmission amongst those of White ethnicity compared to ethnic minority groups, Research is urgently required to understand the mechanisms underlying these disparities and whether public health interventions have differential effects on individuals from ethnic minority groups. FUNDING: 10.13039/100006662 NIHR.

Quantitative IFN-γ Release Assay and Tuberculin Skin Test Results to Predict Incident Tuberculosis. A Prospective Cohort Study.

Rationale: Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority.Objectives: We evaluated whether implementing higher diagnostic thresholds than currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB, and the tuberculin skin test (TST) might improve prediction of incident TB.Methods: Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by relinkage to national TB surveillance records (median follow-up 4.7 yr). Incidence rates and rate ratios, sensitivities, specificities, and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB, and TST (with adjustment for prior bacillus Calmette-Guérin [BCG] vaccination).Measurements and Main Results: For all tests, incidence rates and rate ratios increased with the magnitude of the test result (P < 0.0001). Over 3 years' follow-up, there was a modest increase in positive predictive value with the higher thresholds (3.0% for QFT-GIT ≥0.35 IU/ml vs. 3.6% for ≥4.00 IU/ml; 3.4% for T-SPOT.TB ≥5 spots vs. 5.0% for ≥50 spots; and 3.1% for BCG-adjusted TST ≥5 mm vs. 4.3% for ≥15 mm). As thresholds increased, sensitivity to detect incident TB waned for all tests (61.0% for QFT-GIT ≥0.35 IU/ml vs. 23.2% for ≥4.00 IU/ml; 65.4% for T-SPOT.TB ≥5 spots vs. 27.2% for ≥50 spots; 69.7% for BCG-adjusted TST ≥5 mm vs. 28.1% for ≥15 mm).Conclusions: Implementation of higher thresholds for QFT-GIT, T-SPOT.TB, and TST modestly increases positive predictive value for incident TB, but markedly reduces sensitivity. Novel biomarkers or validated multivariable risk algorithms are required to improve prediction of incident TB.

Prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study.

BACKGROUND: Tackling tuberculosis requires testing and treatment of latent tuberculosis in high-risk groups. The aim of this study was to estimate the predictive values of the tuberculin skin test (TST) and two interferon-γ release assays (IGRAs) for the development of active tuberculosis in high-risk groups-ie, people in recent contact with active tuberculosis cases and from high-burden countries. METHOD: In this prospective cohort study, we recruited participants from 54 centres (eg, clinics, community settings) in London, Birmingham, and Leicester in the UK. Participants were eligible if they were aged 16 years or older and at high risk for latent tuberculosis infection (ie, recent contact with someone with active tuberculosis [contacts] or a migrant who had arrived in the UK in the past 5 years from-or who frequently travelled to-a country with a high burden of tuberculosis [migrants]). Exclusion criteria included prevalent cases of tuberculosis, and participants who were treated for latent tuberculosis after a positive test result in this study. Each participant received three tests (QuantiFERON-TB Gold-In Tube, T-SPOT.TB, and a Mantoux TST). A positive TST result was reported using three thresholds: 5 mm (TST-5), 10 mm (TST-10), and greater than 5 mm in BCG-naive or 15 mm in BCG-vaccinated (TST-15) participants. Participants were followed up from recruitment to development of tuberculosis or censoring. Incident tuberculosis cases were identified by national tuberculosis databases, telephone interview, and review of medical notes. Our primary objective was to estimate the prognostic value of IGRAs compared with TST, assessed by the ratio of incidence rate ratios and predictive values for tuberculosis development. The study was registered with ClinicalTrials.gov, NCT01162265, and is now complete. FINDINGS: Between May 4, 2010, and June 1, 2015, 10 045 people were recruited, of whom 9610 were eligible for inclusion. Of this cohort, 4861 (50·6%) were contacts and 4749 (49·4%) were migrants. Participants were followed up for a median of 2·9 years (range 21 days to 5·9 years). 97 (1·0%) of 9610 participants developed active tuberculosis (77 [1·2%] of 6380 with results for all three tests). In all tests, annual incidence of tuberculosis was very low in those who tested negatively (ranging from 1·2 per 1000 person-years, 95% CI 0·6-2·0 for TST-5 to 1·9 per 1000 person-years, 95% CI 1·3-2·7, for QuantiFERON-TB Gold In-Tube). Annual incidence in participants who tested positively were highest for T-SPOT.TB (13·2 per 1000 person-years, 95% CI 9·9-17·4), TST-15 (11·1 per 1000 person-years, 8·3-14·6), and QuantiFERON-TB Gold In-Tube (10·1 per 1000 person-years, 7·4-13·4). Positive results for these tests were significantly better predictors of progression than TST-10 and TST-5 (eg, ratio of test positivity rates in those progressing to tuberculosis compared with those not progressing T-SPOT.TB vs TST-5: 1·99, 95% CI 1·68-2·34; p<0·0001). However, TST-5 identified a higher proportion of participants who progressed to active tuberculosis (64 [83%] of 77 tested) than all other tests and TST thresholds (≤75%). INTERPRETATION: IGRA-based or BCG-stratified TST strategies appear most suited to screening for potential disease progression among high-risk groups. Further work will be needed to assess country-specific cost-effectiveness of each screening test, and in the absence of highly specific diagnostic tests, cheap non-toxic treatments need to be developed that could be given to larger groups of people at potential risk. FUNDING: National Institute for Health Research Health Technology Assessment Programme 08-68-01.

A validated chiral LC method for enantiomeric separation of nebivolol stereoisomers in bulk drugs and dosage forms on amylose-based stationary phase.

A novel and reproducible isocratic normal phase liquid chromatographic method was developed for the quantitative determination of 10 stereoisomers of Nebivolol in pharmaceutical bulk drugs and dosage forms. The method was developed using an amylose-based chiral stationary phase, Chiralpak AD-3 (250 × 4.6 mm, 3 µm) column with mobile phase containing n-hexane-ethanol-isopropanol-diethanolamine in the ratio 42:45:13:0.1 (v/v/v/v). The eluted compounds were monitored at 280 nm. Ten stereoisomers of Nebivolol were well separated with resolution >2.0 for all pair of components. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, linearity (R(2) value >0.999), limit of detection, limit of quantification, accuracy (recovery range 95.8-103.2%), precision (relative standard deviation, RSD, <2.5%) and robustness. Nebivolol sample solutions were found to be stable when characterized over a period of 48 h. Forced degradation studies were also performed to demonstrate the stability-indicating power of the developed HPLC method. The method was found to be rugged and robust.

Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes.

BACKGROUND: Severe asthma is a heterogeneous condition. Airway remodelling is a feature of severe asthma and can be determined by the assessment of high-resolution computed tomography (HRCT) scans. The aim of this study was to assess whether airway remodelling is restricted to specific subphenotypes of severe asthma. METHODS: A retrospective analysis was performed of HRCT scans from subjects who had attended a single-centre severe asthma clinic between 2003 and 2008. The right upper lobe apical segmental bronchus (RB1) dimensions were measured and the clinical and sputum inflammatory characteristics associated with RB1 geometry were assessed by univariate and multivariate regression analyses. Longitudinal sputum data were available and were described as area under the time curve (AUC). Comparisons were made in RB1 geometry across subjects in four subphenotypes determined by cluster analysis, smokers and non-smokers, and subjects with and without persistent airflow obstruction. RESULTS: Ninety-nine subjects with severe asthma and 16 healthy controls were recruited. In the subjects with severe asthma the RB1 percentage wall area (%WA) was increased (p=0.009) and lumen area (LA)/body surface area (BSA) was decreased (p=0.008) compared with controls but was not different across the four subphenotypes. Airway geometry was not different between smokers and non-smokers and RB1 %WA was increased in those with persistent airflow obstruction. RB1 %WA in severe asthma was best associated with airflow limitation and persistent neutrophilic airway inflammation (model R(2)=0.27, p=0.001). CONCLUSIONS: Airway remodelling of proximal airways occurs in severe asthma and is associated with impaired lung function and neutrophilic airway inflammation.

Ciliary dysfunction and ultrastructural abnormalities are features of severe asthma.

BACKGROUND: Epithelial dysfunction has been implicated in asthma pathophysiology, but no studies have directly assessed ciliary function in asthma. OBJECTIVE: To study the ciliary function and epithelial ultrastructure of patients with asthma and healthy controls. METHODS: We studied ciliary beat frequency and beat pattern by using digital high-speed video imaging and ultrastructure by transmission electron microscopy of bronchial epithelial strips from 7 subjects with mild, 7 with moderate, and 19 with severe asthma and 9 healthy controls. RESULTS: The median (interquartile range) ciliary beat frequency was decreased in moderate (6.5 [4.4-8.5] Hz) and severe asthma (6.7 [6.1-7.6] Hz) compared with controls (10.5 [9.7-11.8] Hz; P < .01). Dyskinesia and immotility indices were higher in severe asthma (65% [43%-75%]; 6.3% [1%-9.5%], respectively) compared with controls (4% [0%-6.7%; 0%, respectively; P < .01). These abnormalities were related to disease severity (ciliary beat frequency, r(s) = -0.68; dyskinesia index, r(s) = 0.86; immotility index, r(s) = 0.65; P < .0001). The ultrastructure of the epithelium was abnormal in severe asthma with a reduction in ciliated cells, an increase in dead cells, and ciliary disorientation compared with all other groups (P < .05). Compared with patients with mild asthma and healthy controls, patients with severe asthma showed increased ciliary depletion, microtubular defects, mitochondrial damage, and cytoplasmic blebbing (P < .01). All of these changes were related to disease severity. CONCLUSION: Ciliary dysfunction and ultrastructural abnormalities are closely related to asthma severity. Ciliary dysfunction is a feature of moderate to severe asthma, and profound ultrastructural abnormalities are restricted to severe disease. Whether these changes contribute to the development of severe asthma phenotype remains to be determined.

Eosinophil protein in airway macrophages: a novel biomarker of eosinophilic inflammation in patients with asthma.

BACKGROUND: Noneosinophilic asthma is common across asthma severities. However, in patients with moderate-to-severe disease, the absence of sputum eosinophilia cannot distinguish between asthmatic subjects with eosinophilic inflammation controlled by corticosteroids versus those in whom eosinophilic inflammation is not a component of the disease. OBJECTIVES: We sought to develop a method to quantify eosinophil proteins in airway macrophages as a novel biomarker of eosinophilic airway inflammation. METHODS: Eosinophil proteins in airway macrophages were assessed by means of flow cytometry, immunofluorescence, and cytoplasmic hue change after ingestion of apoptotic eosinophils. Airway macrophage median percentage of red-hued area in stained sputum cytospin preparations was assessed by means of image analysis from (1) subjects with mild-to-severe asthma, subjects with nonasthmatic eosinophilic bronchitis, and healthy control subjects; (2) subjects with eosinophilic severe asthma after treatment with prednisolone; and (3) subject with noneosinophilic asthma before corticosteroid withdrawal. RESULTS: Eosinophil proteins were detected in airway macrophages, and cytoplasmic red hue increased after ingestion of apoptotic eosinophils. Airway macrophage percentage redhued area was increased in subjects with moderate-to-severe asthma compared with that seen in subjects with mild asthma and healthy control subjects, was similar in those with or without a sputum eosinophilia, and was increased after corticosteroid therapy. In asthmatic subjects without sputum eosinophilia, the airway macrophage percentage red-hued area was increased in subjects who did versus those who did not have sputum eosinophilia after corticosteroid withdrawal. CONCLUSIONS: Eosinophil proteins can be reliably measured in airway macrophages. In combination with sputum eosinophilia, the macrophage eosinophil protein content might further define the asthma phenotype and provide an additional tool to direct therapy.

1-(3-Chloro-4-fluoro-phen-yl)-5-(2-diazo-acet-yl)-4-phenyl-pyrrolidin-2-one.

In the title compound, C(18)H(13)ClFN(3)O(2), the pyrrolidine ring adopts an envelope conformation and the planar part is rotated by 4.3 (6)° from the plane of the benzene ring and is almost perperdicular both to the diazo-acetyl unit [dihedral angle = 78.93 (7)°] and the phenyl ring [dihedral angle = 86.07 (7)°]. In the crystal, mol-ecules are linked into a three-dimensional framework by C-H⋯O inter-actions. The mol-ecular conformation is stabilized by an intra-molecular C-H⋯O hydrogen bond.

Qualitative analysis of high-resolution CT scans in severe asthma.

BACKGROUND: High-resolution CT (HRCT) scanning is part of the management of severe asthma, but its application varies between centers. We sought to describe the HRCT scan abnormalities of a large severe asthma cohort and to determine the utility of clinical features to direct the use of HRCT scanning in this group of patients. METHODS: Subjects attending our Difficult Asthma Clinic (DAC) between February 2000 and November 2006 (n = 463) were extensively re-characterized and 185 underwent HRCT scan. The HRCT scans were analyzed qualitatively and the interobserver variability was assessed. Using logistic regression we defined clinical parameters that were associated with bronchiectasis (BE) and bronchial wall thickening (BWT) alone or in combination. RESULTS: HRCT scan abnormalities were present in 80% of subjects and often coexisted with BWT (62%), BE (40%), and emphysema (8%). The interobserver agreement for BE (kappa = 0.76) and BWT (kappa = 0.63) was substantial. DAC patients who underwent HRCT scanning compared with those who did not were older, had longer disease duration, had poorer lung function, were receiving higher doses of corticosteroids, and had increased neutrophilic airway inflammation. The sensitivity and specificity of detecting BE clinically were 74% and 45%, respectively. FEV(1)/FVC ratio emerged as an important predictor for both BE and BWT but had poor discriminatory utility for subjects who did not have airway structural changes (FEV(1)/FVC ratio, >or= 75%; sensitivity, 67%; specificity, 65%). CONCLUSION: HRCT scan abnormalities are common in patients with severe asthma. Nonradiologic assessments fail to reliably predict important bronchial wall changes; therefore, CT scan acquisition may be required in all patients with severe asthma.

Cluster analysis and clinical asthma phenotypes.

RATIONALE: Heterogeneity in asthma expression is multidimensional, including variability in clinical, physiologic, and pathologic parameters. Classification requires consideration of these disparate domains in a unified model. OBJECTIVES: To explore the application of a multivariate mathematical technique, k-means cluster analysis, for identifying distinct phenotypic groups. METHODS: We performed k-means cluster analysis in three independent asthma populations. Clusters of a population managed in primary care (n = 184) with predominantly mild to moderate disease, were compared with a refractory asthma population managed in secondary care (n = 187). We then compared differences in asthma outcomes (exacerbation frequency and change in corticosteroid dose at 12 mo) between clusters in a third population of 68 subjects with predominantly refractory asthma, clustered at entry into a randomized trial comparing a strategy of minimizing eosinophilic inflammation (inflammation-guided strategy) with standard care. MEASUREMENTS AND MAIN RESULTS: Two clusters (early-onset atopic and obese, noneosinophilic) were common to both asthma populations. Two clusters characterized by marked discordance between symptom expression and eosinophilic airway inflammation (early-onset symptom predominant and late-onset inflammation predominant) were specific to refractory asthma. Inflammation-guided management was superior for both discordant subgroups leading to a reduction in exacerbation frequency in the inflammation-predominant cluster (3.53 [SD, 1.18] vs. 0.38 [SD, 0.13] exacerbation/patient/yr, P = 0.002) and a dose reduction of inhaled corticosteroid in the symptom-predominant cluster (mean difference, 1,829 mug beclomethasone equivalent/d [95% confidence interval, 307-3,349 mug]; P = 0.02). CONCLUSIONS: Cluster analysis offers a novel multidimensional approach for identifying asthma phenotypes that exhibit differences in clinical response to treatment algorithms.

Simple glycosylation reaction of allyl glycosides.

A simple glycosylation strategy employing only allyl glycosides is described. In a one-pot fashion, an allyl glycoside is first isomerized to the reactive 1-prop-en-yl glycoside intermediate, which subsequently undergoes glycosylation with a glycosyl acceptor, promoted by NIS at room temperature.

Noneosinophilic asthma: a distinct clinical and pathologic phenotype.

The use of induced sputum to assess airway inflammation in large and diverse populations with asthma has led to the recognition that significant numbers of patients do not have evidence of eosinophilic airway inflammation. The absence of a sputum eosinophilia has been noted in patients across the range of asthma severity; it has also been reported in patients presenting with an asthma exacerbation. However, whether noneosinophilic asthma represents a pathologically distinct and clinically important asthma phenotype remains unclear. In this review, we present recent evidence suggesting that noneosinophilic asthma represents a stable phenotype associated with a distinct lower airway pathology and structure. We suggest that this lower airway inflammation develops in response to etiologic factors acting through the innate immune pathway and that elements of this immune response contribute to airway dysfunction. Finally, we argue that noneosinophilic asthma is associated with clinically important differences in natural history and treatment response. We particularly highlight evidence that noneosinophilic asthma is associated with a reduced short-term and long-term response to corticosteroid therapy.

NaBH4-InCl3-mediated one-pot chemo- and stereoselective decarboxylative reduction of alpha-aza gem-dicarboxylic esters to monoalcohols.

[reaction: see text] The combination of NaBH4 and a catalytic amount of InCl3 provides a one-pot method for chemo- and stereoselective decarboxylative reduction of gem-dicarboxylic esters 1 to monoalcohols 2 in the presence of the lactam carbonyl in refluxing acetonitrile under inert atmosphere.

Diethyl 1-(4-fluorophenyl)-3-(2-furyl)-5-oxopyrrolidine-2,2-dicarboxylate and diethyl 1-(3,4-dichlorophenyl)-3-(2-furyl)-5-oxopyrrolidine-2,2-dicarboxylate.

The title compounds, C20H20FNO6 and C20H19Cl2NO6, respectively, may exhibit bioactivity. In these compounds, the pyrrolidine ring adopts a conformation intermediate between envelope and half-chair. Only one of the two ethoxycarbonyl side chains is nearly planar. Centrosymmetric pairs are formed, and the crystal structure is stabilized by weak C-H.O hydrogen bonds and van der Waals interactions.