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Sickle cell disease is the commonest genetic disorder in Nigeria, affecting 2-3% of an estimated population of 160 million people. The role of genetic mutations in folate cycle genes, and the variable phenotypic expressions constituting disease severity, needs to be critically examined.This study was carried out to establish the pattern of methionine synthase gene mutations (rs1805087 SNP), and its possible association with disease severity in adults with sickle cell anaemia in Lagos, Nigeria.This is a cross-sectional study of seventy (70) subjects with sickle cell disease (HbSS) matched for age and gender with known apparently healthy haemoglobin genotype AA (HbAA) subjects, as cases and controls respectively. Structured questionnaires were used to obtain demographic, clinical and other phenotypic data needed to compute disease severity. Pattern of MTR A2756G gene mutation and homocysteine assay (Hcy) were assessed by Polymerase Chain Reaction and Enzyme- linked Immunosorbent Assay respectively. Full blood count analysis of participants was done using the KX-21 Automated Analyzer (Sysmex Corporation, Japan).The mutant genotypes MTR 2756 AG/GG were recorded in 46.4% (n =55) of subjects with disease severity score7. Elevated plasma homocysteine (HHcy) was significantly associated with disease severity among HbSS subjects (OR=17.2, CI: 3.490-86.079; p=0.0001). Conversely, no significant association was observed with the mutant genotypes MTR 2756 AG/GG and disease severity (p0.05).While HHcy is significantly associated with phenotypic expression of HbSS, the MTR 2756 SNPs did not appear to independently influence homocysteine level or disease severity in HbSS subjects.La drépanocytose est la maladie génétique la plus répandue au Nigeria, affectant 2 à 3 % d’une population estimée à 160 millions de personnes. Le rôle des mutations génétiques dans les gènes du cycle du folate, et les expressions phénotypiques variables constituant la gravité de la maladie, doivent être examinés de façon critique.Cette étude a été menée pour établir le schéma des mutations du gène de la méthionine synthase (rs1805087 SNP), et son association possible avec la gravité de la maladie chez les adultes atteints de drépanocytose à Lagos, au Nigeria.Il s’agit d’une étude transversale de soixantedix (70) sujets atteints de drépanocytose (HbSS) appariés pour l’âge et le sexe avec des sujets connus apparemment sains de génotype d’hémoglobine AA (HbAA), comme cas et contrôles respectivement. Des questionnaires structurés ont été utilisés pour obtenir des données démographiques, cliniques et autres données phénotypiques nécessaires au calcul de la gravité de la maladie. Le profil de la mutation du gène MTR A2756G et le dosage de l’homocystéine (Hcy) ont été évalués respectivement par réaction en chaîne par polymérase et par test immunologique enzymatique. L’analyse de la formule sanguine complète des participants a été effectuée à l’aide de l’analyseur automatisé KX-21 (Sysmex Corporation, Japon).Les génotypes mutants MTR 2756 AG/GG ont été enregistrés chez 46,4 % (n =55) des sujets présentant un score de gravité de la maladie7. L’homocystéine plasmatique élevée (HHcy) était significativement associée à la gravité de la maladie chez les sujets HbSS (OR=17,2, CI : 3,490–86,079 ; p=0,0001). À l’inverse, aucune association significative n’a été observée entre les génotypes mutants MTR 2756 AG/GG et la gravité de la maladie (p0,05).Alors que l’HHcy est significativement associée à l’expression phénotypique de l’HbSS, les SNP MTR 2756 ne semblent pas influencer indépendamment le niveau d’homocystéine ou la gravité de la maladie chez les sujets HbSS.

We investigated the dynamics of seroconversion in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During March 29-May 22, 2020, we collected serum samples and associated clinical data from 177 persons in London, UK, who had SARS-CoV-2 infection. We measured IgG against SARS-CoV-2 and compared antibody levels with patient outcomes, demographic information, and laboratory characteristics. We found that 2.0%-8.5% of persons did not seroconvert 3-6 weeks after infection. Persons who seroconverted were older, were more likely to have concurrent conditions, and had higher levels of inflammatory markers. Non-White persons had higher antibody concentrations than those who identified as White; these concentrations did not decline during follow-up. Serologic assay results correlated with disease outcome, race, and other risk factors for severe SARS-CoV-2 infection. Serologic assays can be used in surveillance to clarify the duration and protective nature of humoral responses to SARS-CoV-2 infection.

BackgroundThe best strategy for maintaining clinical remission in patients with axial spondyloarthritis (axSpA) has not been defined. C-OPTIMISE compared dose continuation, reduction and withdrawal of the tumour necrosis factor inhibitor certolizumab pegol (CZP) following achievement of sustained remission in patients with early axSpA.MethodsC-OPTIMISE was a two-part, multicentre phase 3b study in adults with early active axSpA (radiographic or non-radiographic). During the 48-week open-label induction period, patients received CZP 200 mg every 2 weeks (Q2W). At Week 48, patients in sustained remission (Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.5 at any time point) during the double-blind period.ResultsAt Week 48, 43.9% (323/736) patients achieved sustained remission, of whom 313 were randomised to CZP full maintenance dose, CZP reduced maintenance dose or placebo. During Weeks 48 to 96, 83.7% (87/104), 79.0% (83/105) and 20.2% (21/104) of patients receiving the full maintenance dose, reduced maintenance dose or placebo, respectively, were flare-free (pConclusionsPatients with early axSpA who achieve sustained remission at 48 weeks can reduce their CZP maintenance dose; however, treatment should not be completely discontinued due to the high risk of flare following CZP withdrawal.Trial registration numberNCT02505542, ClinicalTrials.gov.

Background Emergency abdominal surgery is associated with a high risk of postoperative pulmonary complications (PPCs). The primary aim of this study was to determine whether patients undergoing emergency laparotomy are ventilated using a lung-protective ventilation strategy employing tidal volume ≤8 ml kg−1 ideal body weight−1, PEEP >5 cm H2O, and recruitment manoeuvres. The secondary aim was to investigate the association between ventilation factors (lung-protective ventilation strategy, intraoperative FiO2, and peak inspiratory pressure) and the occurrence of PPCs. Methods Data were collected prospectively in 28 hospitals across London as part of routine National Emergency Laparotomy Audit (NELA). Patients were followed for 7 days. Complications were defined according to the European Perioperative Clinical Outcome definition. Results Data were collected from 568 patients. The median [inter-quartile range (IQR)] tidal volume observed was 500 ml (450–540 ml), corresponding to a median tidal volume of 8 ml kg−1 ideal body weight−1 (IQR: 7.2–9.1 ml). A lung-protective ventilation strategy was employed in 4.9% (28/568) of patients, and was not protective against the occurrence of PPCs in the multivariable analysis (hazard ratio=1.06; P=0.69). Peak inspiratory pressure of Conclusions Both intraoperative peak inspiratory pressure and FiO2 are independent factors significantly associated with development of a postoperative pulmonary complication in emergency laparotomy patients. Further studies are required to identify causality and to demonstrate if their manipulation could lead to better clinical outcomes.

ObjectivesTo report 4-year imaging outcomes in the RAPID-axSpA (NCT01087762) study of patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA), treated with certolizumab pegol (CZP).MethodsThis phase III, randomised trial was placebo-controlled and double-blind to week 24, dose-blind to week 48 and open-label to week 204. Patients fulfilling the Assessment of Spondyloarthritis International Society (ASAS) axSpA criteria with active disease were stratified (AS/nr-axSpA) according to the modified New York (mNY) criteria at randomisation. Spinal radiographs were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). MRI inflammation used the Spondyloarthritis Research Consortium of Canada (SPARCC) score for sacroiliac joints (SIJ) and the Berlin spinal score (remission defined as SPARCC ResultsMRI improvements from baseline (BL) to week 12 were maintained to week 204 (SPARCC BL: AS=8.5, nr-axSpA=7.5; SPARCC week 204: AS=1.3, nr-axSpA=2.4; Berlin BL: AS=7.4, nr-axSpA=4.4; Berlin week 204: AS=2.6, nr-axSpA=1.9). 66.7% of patients with AS and 69.6% of patients with nr-axSpA with BL SPARCC scores ≥2, and 65.4% of patients with AS and 57.3% of patients with nr-axSpA with BL Berlin score >2, achieved remission at week 204. Mean mSASSS change in AS from BL to week 204 was 0.98 (95% CI 0.34, 1.63); 0.67 (95% CI 0.21,1.13) from BL to week 96; and 0.31 (95% CI 0.02,0.60) from week 96 to week 204. Corresponding nr-axSpA changes were 0.06 (95% CI −0.17,0.28), –0.01 (95% CI −0.19,0.17) and 0.07 (95% CI −0.07,0.20). 4.5% of patients with nr-axSpA fulfilled the mNY criteria at week 204, while 4.3% of patients with AS no longer did so.ConclusionsIn patients with CZP-treated axSpA, rapid decreases in spinal and SIJ MRI inflammation were maintained to week 204. Overall, 4-year spinal progression was low, with less progression during years 2–4 than 0–2. Radiographic SIJ grading changes demonstrated limited progression.Trial registration numberNCT01087762; Post-results.

Objective The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA. Methods RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further patient-reported outcomes, peripheral arthritis, enthesitis, uveitis and quality-of-life measures are also reported. Results Two hundred and eighteen of 325 patients randomized (AS: 121; nr-axSpA: 97) received certolizumab pegol from week 0. Of these, 65% remained in the study at week 204 (AS: 67%; nr-axSpA: 63%). Across all outcomes, for AS and nr-axSpA, sustained improvements were observed to week 204 [week 204 overall axSpA: ASAS20: 54.1% (non-responder imputation); 83.7% (observed case, OC); ASAS40: 44.0% (non-responder imputation); 68.1% (OC); ASDAS inactive disease: 32.1% (last observation carried forward); 31.4% (OC)]. In the safety set (n = 315), there were 292.8 adverse events and 10.4 serious adverse events per 100 patient-years. No deaths were reported. Conclusion In the first study to evaluate the efficacy of an anti-TNF across both axSpA subpopulations, improvements in clinical and patient-reported outcomes at 24 and 96 weeks were sustained through 4 years of treatment, with no new safety signals. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01087762.

Contains fulltext : 177598.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Excessive fluid therapy in patients with sepsis may be associated with risks that outweigh any benefit. We investigated the possible influence of early fluid balance on outcome in a large international database of ICU patients with sepsis. DESIGN: Observational cohort study. SETTING: Seven hundred and thirty ICUs in 84 countries. PATIENTS: All adult patients admitted between May 8 and May 18, 2012, except admissions for routine postoperative surveillance. For this analysis, we included only the 1,808 patients with an admission diagnosis of sepsis. Patients were stratified according to quartiles of cumulative fluid balance 24 hours and 3 days after ICU admission. MEASUREMENTS AND MAIN RESULTS: ICU and hospital mortality rates were 27.6% and 37.3%, respectively. The cumulative fluid balance increased from 1,217 mL (-90 to 2,783 mL) in the first 24 hours after ICU admission to 1,794 mL (-951 to 5,108 mL) on day 3 and decreased thereafter. The cumulative fluid intake was similar in survivors and nonsurvivors, but fluid balance was less positive in survivors because of higher fluid output in these patients. Fluid balances became negative after the third ICU day in survivors but remained positive in nonsurvivors. After adjustment for possible confounders in multivariable analysis, the 24-hour cumulative fluid balance was not associated with an increased hazard of 28-day in-hospital death. However, there was a stepwise increase in the hazard of death with higher quartiles of 3-day cumulative fluid balance in the whole population and after stratification according to the presence of septic shock. CONCLUSIONS: In this large cohort of patients with sepsis, higher cumulative fluid balance at day 3 but not in the first 24 hours after ICU admission was independently associated with an increase in the hazard of death.

Objective To investigate clinical efficacy and safety of 2 certolizumab pegol (CZP) maintenance dosing regimens plus methotrexate (MTX) in active rheumatoid arthritis (RA) patients achieving the American College of Rheumatology 20% improvement criteria (ACR20) after the CZP 200 mg every 2 weeks open-label run-in period. Methods DOSEFLEX (dosing flexibility) was a double-blind, placebo-controlled randomized study with an open-label run-in phase. During the run-in phase, all patients received CZP 400 mg (weeks 0, 2, and 4) and 200 mg every 2 weeks to week 16. Week 16 ACR20 responders were randomized 1:1:1 at week 18 to CZP 200 mg every 2 weeks, 400 mg every 4 weeks, or placebo. Results A total of 209 (of 333) patients were randomized at week 18 (CZP: 200 mg, n = 70; 400 mg, n = 70; placebo, n = 69). Groups had similar baseline characteristics (week 0). Week 34 ACR20 response rates were comparable between the CZP 200 mg every 2 weeks and the 400 mg every 4 weeks groups (67.1% versus 65.2%), which was significantly higher than placebo (44.9%; P = 0.009 and P = 0.017). ACR50/70 and remission criteria were met more frequently in CZP groups than placebo at week 34, with similar responses between anti–tumor necrosis factor–experienced and naive patients. Improvements from baseline Disease Activity Score in 28 joints using the erythrocyte sedimentation rate and Health Assessment Questionnaire disability index scores were maintained in CZP groups from week 16 to 34 while worsening on placebo. Adverse event (AE) rates in the double-blind phase were 62.9% versus 60.9% versus 62.3%; serious AE rates were 7.1% versus 2.9% versus 0.0% (CZP 200 mg, 400 mg, and placebo groups). Conclusion In active RA patients with an incomplete MTX response, CZP 200 mg every 2 weeks and 400 mg every 4 weeks were comparable and better than placebo for maintaining clinical response to week 4 following a 16-week, open-label run-in phase.

Summary Background Bacterial infection of the pleural space often causes adherence of the pleural membranes by fibrous tissue, probably mediated by inflammation initiated by bacterial cell-wall motifs, including lipoteichoic acid-T (LTA-T). We postulated that therapeutically administered LTA-T might produce a similar effect, achieving control of malignant pleural effusion (pleurodesis). Methods Patients with histocytologically proven symptomatic malignant pleural effusions were included in this phase I toxicity and dose-escalation study, An indwelling pleural catheter was placed in the pleural effusion to drain the fluid fully. A control dose of intrapleural saline was administered after complete drainage (day 1) and pleural-fluid production was recorded for 7 days. On day 7 a single dose of intrapleural LTA-T (increasing in each patient) was administered and pleural-fluid production was monitored for a further 7 days. Long-term fluid control was recorded. This study is registered as an International Standard Randomised Controlled Trial, ISRCTN44367564. Findings Between November, 2004, and November, 2005, 14 patients were enrolled on the trial at the Oxford Centre for Respiratory Medicine (Oxford, UK). 13 of 14 patients received escalated doses of LTA-T. A dose-limiting toxic effect (ie, systemic inflammation) occurred at 3000 μg, and a therapeutic dose of 750–1500 μg was established. Toxic effects were mild and had no consistent pattern at the therapeutic dose. Pleural-fluid production decreased significantly after a dose of at least 750 μg LTA-T, compared with saline control (mean fluid production after saline control 1244 mL [SD 933], mean fluid production after LTA-T 394 mL [SD 375], mean difference −850 mL [SD 699], p=0·028), and six of seven (86%) patients achieved pleural-fluid control at 1 month with no further intervention. Interpretation The toxic effects of intrapleural LTA-T seem to be mild and favourable when compared with the toxicity profiles of standard pleurodesis agents. There is early evidence of LTA-T-induced pleurodesis efficacy, suggesting that this might be a viable therapeutic strategy for the control of malignant pleural effusion. Funding Lunamed, Chur, Switzerland.

Recurrent, chronic pleural infection creates difficult management issues. Surgical drainage is currently recommended for patients who have failed initial "medical treatment" (ie, tube thoracostomy and antibiotic therapy), but the options for patients not fit for surgery are limited. Prolonged closed tube drainage may be an option in this group, although concerns exist regarding the efficacy and risk of catheter blockage. Long-term indwelling pleural catheters are increasingly used for the treatment of recurrent malignant pleural effusion. Pleural infection is recognized as a complication and is cited as a contraindication to insertion of an indwelling pleural drain within the product literature. We report two patients with empyema in a fixed pleural space in whom the insertion of an ambulatory catheter produced successful drainage. Long-term indwelling pleural catheters may have a role in maintaining the drainage of a chronically infected pleural space that is not readily treated in other ways.

In pleural infection, medical treatment failure (chest-tube drainage and antibiotics) requires surgery and increases mortality. It would be helpful to predict which patients will fail this approach. We examined clinical predictors in 85 consecutive patients with pleural infection receiving chest drainage and intrapleural fibrinolytics, and recorded age, length of history, antibiotic delay and choice, time to drainage, blood/pleural fluid (PF) bacteriology, PF pH, lactate dehydrogenase (LDH), glucose and appearance, effusion size, pleural thickness on computed tomographic (CT) scan, and survival from time of drainage. Failures (surgery/death) were compared with successes. There were 13 (15%) medical failures. PF purulence was more frequent in medical failures (10 of 13 versus 29 of 72 successes, p < 0.02 chi-square). Absence of purulence was a useful predictor of success (positive predictive value [PPV] 93%). Purulence was not useful in predicting medical failure (PPV 26%). There was a trend for positive blood culture to predict failure (5 of 13 failures versus 11 of 72 successes, p = 0.05 chi-square), but no significant differences in other endpoints. Twelve (14%) patients died in follow-up, all with comorbidity within 400 d after drainage. Probability of survival at 4 yr was 86%. Of endpoints considered in this study, PF purulence was the only useful predictor of outcome with medical therapy in pleural infection. There is good long-term survival from pleural infection.

Objective: Pleural effusions are a frequent complication of malignancy and cause considerable morbidity from dyspnea. The drainage and control of malignant effusions relieve symptoms and maintain quality of life but these are difficult in patients with multiloculated effusions in whom drainage usually fails. This observational series reports the use of intrapleural streptokinase (IPSK) in the management of malignant multiloculated pleural effusions resistant to standard chest tube drainage. Methods: Ten consecutive patients with malignant multiloculated pleural effusions, aged 39 to 89 years, were given 250,000-IU doses of IPSK twice daily after failure to drain the effusions with a standard chest tube because of multiloculation and multiseptation, as demonstrated by CT or ultrasound scanning. Outcome was assessed by radiographic improvement and symptom control. Results: All 10 patients responded to between 500,000 and 1,500,000 IU of streptokinase. There was an increase in pleural fluid drained (mean volume 6 SD; pre-IPSK, 843 6 690 mL; post-IPSK, 2,368 6 1,051 mL; p < 0.001, paired t test), and radiographic improvement was seen in all 10 patients. All subjects tolerated the instillation of streptokinase well. One subject required opiate analgesia for transient chest pain, and there were no hemorrhagic or allergic complications. One patient died of unrelated septicemia. Conclusions: This series suggests that IPSK may be useful in the drainage of malignant multiloculated pleural effusions in patients who fail to drain adequately with a standard chest tube. Malignant pleural effusions should not be considered a contraindication to IPSK. (CHEST 1999; 115:729 ‐733)

Background: Obstructive sleep apnoea syndrome (OSAS) has been suggested to be an independent risk factor for non-alcoholic fatty liver disease (NAFLD), possibly via intermittent hypoxia that influences blood pressure, lipid levels and insulin resistance, factors themselves known to cause NAFLD. In observational studies, OSAS has been associated with elevated levels of liver enzymes. Continuous positive airway pressure (CPAP) is the treatment for OSAS, but the effects of CPAP on liver enzymes have not been studied in a randomized controlled trial. Objective: To determine if 4 weeks of CPAP influence alanine-aminotransferase (ALT) and aspartate-aminotranferase (AST) levels. Methods: 94 patients with moderate-to-severe OSAS were randomized to therapeutic or sub-therapeutic CPAP treatment. Plasma ALT and AST were measured before and after 4 weeks of CPAP. Results: Results are means ± SD. ALT levels decreased from 39.1 ± 26.3 to 30.3 ± 16.4 IU/l in patients treated with therapeutic CPAP, but also decreased from 36.9 ± 20.7 to 31.5 ± 16.5 IU/l in patients treated with sub-therapeutic CPAP (difference between mean changes –3.4, 95% CI –7.8 to 1.0 IU/l, p = 0.13 between groups). AST levels did not change significantly with therapeutic CPAP (from 29.1 ± 14.7 to 30.2 ± 13.6 IU/l), nor with sub-therapeutic CPAP (from 28.2 ± 16.2 to 29.5 ± 12.6 IU/l; difference between mean changes –0.2, 95% CI –3.0 to 2.6 IU/l, p = 0.87 between groups). Conclusions: Four weeks of active CPAP has no beneficial effect on aminotransferase levels when compared to sub-therapeutic CPAP in patients with OSAS. Therefore, CPAP does not seem to improve biochemical markers of potential NAFLD in OSAS patients.

The pharyngeal airway narrows when pharyngeal muscle tone decreases. During sleep, partial collapse at this level leads to snoring, and complete collapse to obstructive sleep apnoea [25], Such upper airway incompetence is relatively common: 17% of randomly selected normal British men snore [60]; one in 300 have severe obstructive sleep apnoea and cannot maintain a patent airway in any sleeping posture [60]. In hospital inpatient cohorts the prevalence is greater still. In one middle-aged group with ischaemic heart disease, significant obstructive sleep apnoea affected 14% of the sample [30]. Obstructive sleep apnoea has a range of undesirable acute effects which may be avoided by appropriate management. This review considers the causes of upper airway collapse, its consequences and treatment for the patient in hospital. Aetiology of upper airway collapse during sleep The patency of the muscular pharynx depends on the balance of forces acting across the pharyngeal wall. Muscle tone widens the airway, while external pressure from the peripharyngeal tissues, combined with intraluminal negative inspiratory pressures, narrow it. Any factor which adversely affects this balance tends to provoke airway collapse. Increased peripharyngeal soft tissue reduces sleeping airway calibre, probably through a simple mass effect [38]. In adults, neck fat deposition is the commonest factor predisposing to obstructive sleep apnoea; the circumference of the neck is a simple predictor of those at risk [13]. Internal airway narrowing as a result of retrognathia [49], adenotonsillar hypertrophy [61], craniofacial abnormalities [5, 33], nasal obstruction [29] and pharyngeal masses [66] also has a role. In children, large tonsils and adenoids are the usual reason for sleep apnoea, and among children awaiting tonsillectomy more than 50% have some respiratory disturbance during sleep [61]. Finally, a reduction in upper airway muscle tone caused by neuromuscular blocking drugs, sedatives [19,44] and some antihypertensive drugs [41] exacerbates airway incompetence. This reduction in tone also underlies the widely recognized association between alcohol intake, snoring and obstructive sleep apnoea [31, 54, 63]. Similar effects have been shown for

AIM: Imaging of pleural empyema by ultrasound (US) or computed tomography (CT) is used to confirm the diagnosis and facilitate drainage. However, the information gained from US and CT may also have prognostic significance. The aim of the present study was to determine if CT and US appearances correlated with the severity of infection as determined by established microbiological and biochemical indicators, and to establish whether either technique could predict those patients who will fail drainage and require surgery. MATERIALS AND METHODS: Fifty patients with parapneumonic effusions were assessed. All had thoracic CT and the results of thoracic US were available in 36 patients. Imaging features were compared to the stage of the effusion and clinical outcome. RESULTS: At US, 7/36 (19%) pleural collections were anechoic, 5/36 (14%) were hyperechoic without septae and 24/36 (67%) were hyperechoic with septae. There was no relationship between US appearances and the presence of pus, the effusion stage or the need for surgical treatment. On CT pleural enhancement was seen in all patients. There was evidence of pleural thickening in 46/50 (92%) and thickening of extrapleural fat in 38/50 (76%). There was a trend for mean pleural thickness to increase with an increasing stage of pleural infection. However, a wide range of appearances were seen and overall the thickness of pleural/extrapleural tissues was not significantly related to the stage of effusion or to the requirement for surgery. CONCLUSIONS: Although US and CT have established roles in the investigation of parapneumonic effusions, neither technique reliably identifies the stage of pleural infection or predicts those patients who subsequently require surgical intervention after failed management by chest tube drainage and intrapleural fibrinolytics.Kearney, S. E. (2000). Clinical Radiology 55 , 542–547.

Objective Axial spondyloarthritis (axial SpA) is characterized by inflammation of the spine and sacroiliac joints and can also affect extraarticular sites, with the most common manifestation being uveitis. Here we report the incidence of uveitis flares in axial SpA patients from the RAPID-axSpA trial, including ankylosing spondylitis (AS) and nonradiographic (nr) axial SpA. Methods The RAPID-axSpA (NCT01087762) trial is double-blind and placebo-controlled to week 24, dose-blind to week 48, and open-label to week 204. Patients were randomized to certolizumab pegol (CZP) or placebo. Placebo patients entering the dose-blind phase were re-randomized to CZP. Uveitis events were recorded on extraarticular manifestation or adverse event forms. Events were analyzed in patients with/without history of uveitis, and rates reported per 100 patient-years. Results At baseline, 38 of 218 CZP-randomized patients (17.4%) and 31 of 107 placebo-randomized patients (29.0%) had past uveitis history. During the 24-week double-blind phase, the rate of uveitis flares was lower in CZP (3.0 [95% confidence interval (95% CI) 0.6–8.8] per 100 patient-years) than in placebo (10.3 [95% CI 2.8–26.3] per 100 patient-years). All cases observed during the 24-week double-blind phase were in patients with a history of uveitis; in these patients, rates were similarly lower for CZP (17.1 [95% CI 3.5–50.1] per 100 patient-years) than placebo (38.5 [95% CI 10.5–98.5] per 100 patient-years). Rates of uveitis flares remained low up to week 96 (4.9 [95% CI 3.2–7.4] per 100 patient-years) and were similar between AS (4.4 [95% CI 2.3–7.7] per 100 patient-years) and nr-axial SpA (5.6 [95% CI 2.9–9.8] per 100 patient-years). Conclusion The rate of uveitis flares was lower for axial SpA patients treated with CZP than placebo during the randomized controlled phase. Incidence of uveitis flares remained low to week 96 and was comparable to rates reported for AS patients receiving other anti–tumor necrosis factor antibodies.

Multidrug-resistant tuberculosis (MDR-TB, defined as resistance to at least both rifampicin and isoniazid) has become a serious problem in the United Kingdom. As it is uncommon, no one clinician has sufficient experience of it to be confident in providing the best management for the patient. The model of a centralised system of management, such as is used in the Baltic countries, would seem a suitable method to adapt to the United Kingdom. With the agreement of the relevant professional organisations, a virtual electronic expert panel, the UK Multidrug-Resistant Tuberculosis Service, has been developed. This body gives advice via a secure website on MDR-TB patients referred by e-mail by clinicians across the country managing MDR-TB cases. In the first 2 years of operation, advice was sought on 60 patients with culture-proven MDR-TB (54% of the UK total). The number of clinicians accessing the advisory service increased from 27 in 2008 to 33 in 2009. Patients of non-UK origin accounted for 90% of all cases, including all four extensively drug-resistant tuberculosis cases. A central electronic virtual committee providing advice via a secure website has proved to be practical, economical and efficient. It could provide a model for MDR-TB management in other countries and for the management of other uncommon diseases.

Objective. Certolizumab pegol (CZP) is known to be effective as monotherapy at a dosage of 400 mg every 4 weeks in patients with active RA who have failed DMARDs. The aim of this study was to investigate every 4-week CZP in addition to continued MTX therapy in patients with an inadequate response to MTX alone. Methods. Patients with active RA with inadequate response to MTX, on background MTX, were randomized to double-blind treatment with CZP 400 mg or placebo every 4 weeks for 24 weeks (NCT00544154). The primary efficacy end-point was the ACR 20% improvement criteria (ACR20) response rate at Week 24. Other end-points included ACR50 and ACR70 response rates, ACR core components, 28-joint DAS (ESR) with three variables (DAS28-3) and health-related quality-of-life outcomes in addition to safety. Results. Of 247 randomized patients, 126 received CZP and 121 received placebo, in addition to MTX. ACR20 response rates were 45.9 vs 22.9%, respectively [P < 0.001 analysed by the Cochran MantelHaenszel (CMH) method], with improvements being apparent from Week 1. Statistically significant improvements over placebo were seen with CZP for ACR50, ACR core components, DAS28-3 and physical functioning. Rates of treatment-related adverse events were similar between groups (25.0 vs 27.7%), and there were no deaths or serious opportunistic infections. Conclusion. CZP 400 mg every 4 weeks plus MTX demonstrated a favourable riskbenefit profile with rapid onset of action in RA patients with an inadequate response to an earlier MTX therapy.

Copyright © 2009 by the American Thoracic Society. Rationale: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care. Objectives: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI. Methods: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNγ and IL-2 ELISpot assays and FACS. Measurements and Main Results: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-γ and IL-2 response that was durable for 52 weeks. The magnitude of IFN-γ response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin–vaccinated individuals. Antigen 85A–specific polyfunctional CD4+ T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination. Conclusions: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas. Oxford Biomedical Research Centre, Wellcome Trust, and AFTBVAC.

OBSTRUCTIVE SLEEP APNEA (OSA) IS CHARACTERIZED BY REPETITIVE APNEAS AND HYPOPNEAS DURING SLEEP ASSOCIATED WITH OXYGEN DESATURATION, leading to sleep disruption and excessive daytime sleepiness. It has been estimated that OSA is present in 9% to 24%1 of adults, being clinically significant in 2% to 4%,1 and becoming more prevalent as the average population body weight rises.2 Excessive daytime sleepiness related to increased sleep fragmentation and impaired sleep quality clearly has an adverse impact on quality of life and health status.3 Nasal continuous positive airways pressure (CPAP) is considered to be the treatment of choice for OSA. Excessive daytime sleepiness remains the main indication for CPAP treatment in OSA,4 although cardiovascular benefits are thought to result as well. Results from previous studies, including a randomized double-blind controlled parallel trial of therapeutic versus subtherapeutic CPAP showed that CPAP has beneficial effects on excessive daytime sleepiness and on self-reported functioning and well-being, affecting quality of life of OSA patients.4–8 The cost-effectiveness of this treatment has also been demonstrated.9 Despite an increasing amount of information on the efficacy of CPAP treatment in OSA patients, data from randomized double-blind controlled trials on treatment outcome measures that included quality of life assessment have been reported in only 2 previous studies.4,7 Particularly, it remains unclear which aspects of symptomatic improvement are the most sensitive to CPAP treatment and carry independent information in predicting response to CPAP. To address this uncertainty we investigated, using data from a randomized double-blind controlled trial, which outcome measures best identify the effect of real CPAP compared to nonspecific placebo effects. The overall aim of this study is to improve the current knowledge about the efficacy of CPAP treatment on symptoms and health status. This issue may be relevant in clinical practice and for future treatment trials.

Background In 2003, residents of the District of Columbia (DC) experienced an abrupt rise in lead levels in drinking water, which followed a change in water-disinfection treatment in 2001 and which was attributed to consequent changes in water chemistry and corrosivity. Objectives To evaluate the public health implications of the exceedance, the DC Department of Health expanded the scope of its monitoring programs for blood lead levels in children. Methods From 3 February 2004 to 31 July 2004, 6,834 DC residents were screened to determine their blood lead levels. Results Children from 6 months to 6 years of age constituted 2,342 of those tested; 65 had blood lead levels > 10 μg/dL (the “level of concern” defined by the Centers for Disease Control and Prevention), the highest with a level of 68 μg/dL. Investigation of their homes identified environmental sources of lead exposure other than tap water as the source, when the source was identified. Most of the children with elevated blood lead levels (n = 46; 70.8%) lived in homes without lead drinking-water service lines, which is the principal source of lead in drinking water in older cities. Although residents of houses with lead service lines had higher blood lead levels on average than those in houses that did not, this relationship is confounded. Older houses that retain lead service lines usually have not been rehabilitated and are more likely to be associated with other sources of exposure, particularly lead paint. None of 96 pregnant women tested showed blood lead levels > 10 μg/dL, but two nursing mothers had blood lead levels > 10 μg/dL. Among two data sets of 107 and 71 children for whom paired blood and water lead levels could be obtained, there was no correlation (r2 = –0.03142 for the 107). Conclusions The expanded screening program developed in response to increased lead levels in water uncovered the true dimensions of a continuing problem with sources of lead in homes, specifically lead paint. This study cannot be used to correlate lead in drinking water with blood lead levels directly because it is based on an ecologic rather than individualized exposure assessment; the protocol for measuring lead was based on regulatory requirements rather than estimating individual intake; numerous interventions were introduced to mitigate the effect; exposure from drinking water is confounded with other sources of lead in older houses; and the period of potential exposure was limited and variable.

Background This study assessed the psychological and behavioral responses of residents of the Washington DC metropolitan area to the October 2002 sniper shootings, as well as the association between measures of exposure to the shootings and elevated traumatic stress symptoms. Methods Random-digit-dial telephone survey of 1205 adults living in Washington DC and two surrounding counties during the shootings, conducted May 2003. Main outcome measures included self-reports regarding traumatic stress symptoms, perceptions of safety, behavioral responses, and exposures to incidents. Results Forty-five percent of residents reported going to public spaces such as parks and shopping centers less than usual, and 5.5% reported missing at least 1 day of work because of the sniper attacks. Women who reported living within 5 miles of any shooting incident were significantly more likely to report elevated traumatic stress symptoms—consistent with a probable diagnosis of post-traumatic stress disorder—than women who reported living farther from incidents (odds ratio=4.2, 95% confidence interval=1.9–9.3). Among men, there was no significant association between reported residential proximity and elevated traumatic stress symptoms. Conclusions These results suggest the substantial behavioral and psychological impact that traumatic events such as these sniper shootings can have on communities. They support the importance of clinicians and community leaders addressing psychological functioning in the setting of such events that threaten a population. The results further suggest that women who report residing closest to such incidents are at greatest risk for experiencing elevated symptoms of traumatic stress, and perhaps warrant special attention.

Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality. Several randomised controlled trials have shown that continuous positive airway pressure (CPAP) treatment of OSA reduces blood pressure (BP). This randomised, sham-placebo controlled crossover trial assesses whether CPAP produces a similar clinically significant fall in BP in hypertensive OSA patients, but without hypersomnolence. Thirty-five, nonsleepy, hypertensive patients with OSA were treated with CPAP for 1 month, randomised first to either therapeutic or sham-placebo (subtherapeutic CPAP, about 1 cmH(2)O pressure). The second months' alternative treatment followed a 2-week washout period. BP was measured over 24 h, before and at the end of the two treatment periods: mean 24-h BP was the primary outcome variable. There was no overall significant difference in mean 24-h BP: the change in mean 24-h BP on therapeutic CPAP was -2.1 mmHg (sd 8.1), and -1.1 mmHg (sd 8.1) on subtherapeutic CPAP, with a difference of 0.7 mmHg (95% confidence interval (CI) +2.9- -4.4). There was a small significant fall in Epworth Sleepiness Score, therapeutic (-1.4) versus sham (-0.3), and difference -1.2 (95% CI -2.0- -0.4), but no change in objective sleepiness. In nonhypersomnolent hypertensive patients with obstructive sleep apnoea, there is no significant fall in mean 24-h blood pressure with continuous positive airway pressure, in contrast to the fall seen in hypersomnolent patients with obstructive sleep apnoea.

There is increasing evidence of a link between tuberculosis and smoking. This paper reviews the epidemiological evidence from the UK, China, India and the USA, summarizing some of the main papers which indicate an association. Where an association has been found there seems to be an increase in tuberculosis case rates of between two- and four-fold for those smoking in excess of 20 cigarettes a day, but it may be difficult to control for other factors, particularly alcohol consumption. The final part of the paper reviews possible mechanisms. A likely possibility is that nicotine turns off the production of TNF-alpha by the macrophages in the lungs, rendering the patient more susceptible to the development of progressive disease from latent Mycobacterium tuberculosis infection.

Despite the growing popularity of online game playing, there has been no primary survey of its players. Therefore, an online questionnaire survey was used to examine basic demographic factors of online computer game players who played the popular online game Everquest (i.e., gender, age, marital status, nationality, education level, occupation). The survey also examined playing frequency (i.e., amount of time spent playing the game a week), playing history (i.e., how long they had been playing the game, who they played the game with, whether they had ever gender swapped their game character), the favorite and least favorite aspects of playing the game, and what they sacrifice (if anything) to play the game. Results showed that 81% of online game players were male, and that the mean age of players was 27.9 years of age. For many players, the social aspects of the game were the most important factor in playing. A small minority of players appear to play excessively (over 80 h a week), and results suggest that a small minority sacrifice important activities in order to play (e.g., sleep, time with family and/or partner, work, or schooling).

There is little doubt that video game playing is a psychological and social phenomenon. This paper outlines the main structural characteristics of video game playing (i.e., those characteristics that either induce gaming in the first place or are inducements to continue gaming irrespective of the individual's psychological, physiological, or socio-economic status). This online study is the first ever to assess what structural characteristics (if any) are important to a group of self-selected video game players (n = 382). The main variables examined were sound, graphics, background and setting, duration of game, rate of play, advancement rate, use of humor, control options, game dynamics, winning and losing features, character development, brand assurance, and multi-player features. Although there were many major gender differences, one of the main overall findings was the importance of a high degree of realism (i.e., realistic sound, graphics, and setting). Other important characteristics included a rapid absorption rate, character development, the ability to customize the game, and multiplayer features. Suggestions for future research are outlined.

Despite the growing popularity of online game playing, there have been no surveys comparing adolescent and adult players. Therefore, an online questionnaire survey was used to examine various factors of online computer game players (n = 540) who played the most popular online game Everquest. The survey examined basic demographic information, playing frequency (i.e. amount of time spent playing the game a week), playing history (i.e. how long they had been playing the game, who they played the game with, whether they had ever gender swapped their game character, the favourite and least favourite aspects of playing the game, and what they sacrifice (if anything) to play the game. Results showed that adolescent gamers were significantly more likely to be male, significantly less likely to gender swap their characters, and significantly more likely to sacrifice their education or work. In relation to favourite aspects of game play, the biggest difference between the groups was that significantly more adolescents than adults claimed their favourite aspect of playing was violence. Results also showed that in general, the younger the player, the longer they spent each week playing.

These guidelines have been replaced by BTS Pleural Disease Guideline 2010 Superseded By BTS Pleural Disease Guideline 2010: BTS Guidelines for the Management of Pleural Disease. Thorax 2003 May; 58(Suppl 2): 1–59.

Despite the rise of computer games as a leisure phenomenon, there has been relatively little research into this area. Furthermore, almost all of the research to date has concentrated on arcade or console games. More recently, the Internet has become a new medium in which players can play videogames. Since there is no published research in this area, some “benchmark” data on which future research can build was collected from two online gaming fan sites. Sociodemographics showed that the majority of players were male (approximately 85%). Over 60% of players were older than 19 years. The data provide clear evidence that the game clientele is very much an adult profile and suggest a different picture to the stereotypical image of an adolescent online gamer. The stereotype of the typical online player being a socially withdrawn young male with limited sex role identity appears to be misplaced.

Objectives This 52-week, randomised, double-blind phase IIIb study assessed efficacy and safety of certolizumab pegol (CZP) as add-on therapy to non-biologic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with low to moderate disease activity, and stopping therapy in patients in sustained remission. Methods Patients were randomised 1:1 to CZP (400 mg at weeks 0, 2 and 4, then 200 mg every 2 weeks) or placebo (every 2 weeks) plus current non-biologic DMARDs. At week 24, patients who achieved the primary endpoint of Clinical Disease Activity Index (CDAI) remission at both weeks 20 and 24 stopped study treatment and continued in the study until week 52. Results Of 194 patients (CZP=96; placebo=98), >90% had moderate disease activity at baseline. Significantly more CZP patients met the primary endpoint than placebo patients (week 20 and 24 CDAI remission rates: 18.8% vs 6.1%; p≤0.05). At week 24, 63.0% vs 29.7% of CZP versus placebo patients (p

Patients with obstructive sleep apnoea (OSA) are reported to have an increased risk of road traffic accidents. This study examines the nature of the impairment during simulated steering in patients with OSA, compared to normal subjects following either sleep deprivation or alcohol ingestion. Twenty-six patients with OSA and 12 normal subjects, either deprived of one night's sleep or following alcohol ingestion [mean (SD) alcohol blood level 71.6 mg dl(-1) (19.6)], performed a simulated steering task for a total of 90 min. Performance was measured using the tendency to wander (SD), deterioration across the task, number of 'off-road' events and the reaction time to peripheral events. Control data for OSA, sleep deprivation and alcohol were obtained following treatment with nasal continuous positive airway pressure (nCPAP), after a normal night of sleep, and following no alcohol, respectively. Patients with untreated OSA, and sleep-deprived or alcohol-intoxicated normal subjects performed significantly less well, compared to their respective controls (P

Objective: Ataque de nervios is a common, self-labeled Hispanic folk diagnosis. It typically describes episodic, dramatic outbursts of negative emotion in response to a stressor, sometimes involving destructive behavior. Dissociation and affective dysregulation during such episodes suggested a link to childhood trauma. We therefore assessed psychiatric diagnoses, history of ataque, and childhood trauma in treatment-seeking Hispanic outpatients (N = 70). Significantly more subjects with an anxiety or affective disorder plus ataque reported a history of physical abuse, sexual abuse, and/or or a substance-abusing caretaker than those with psychiatric disorder but no ataque. In some Hispanic individuals, ataque may represent a culturally sanctioned expression of extreme affect dysregulation associated with childhood trauma. Patients with ataque de nervios should receive a thorough traumatic history assessment.

Eleven mild atopic asthmatic patients were exposed for 6 h, in randomized order, to air, 100 ppb O3, 200 ppb NO2, and 100 ppb O3 + 200 ppb NO2, followed immediately by bronchial allergen challenge. Subsequently 10 of these patients were exposed for 3 h to air, 200 ppb O3, 400 ppb NO2, and 200 ppb O3 + 400 ppb NO2, followed immediately by bronchial allergen challenge. All exposures were carried out in an environmental chamber, with intermittent moderate exercise, and a minimal interval of 2 wk. Exposure for 6 h to 100 ppb O3, 200 ppb NO2, and 100 ppb O3 + 200 ppb NO2 did not lead to any significant increase in the airway response of these individuals to inhaled allergen, when compared with exposure for 6 h to air. In contrast, exposure for 3 h to 200 ppb O3, 400 ppb NO2, and 200 ppb O3 + 400 ppb NO2 significantly decreased the dose of allergen (in log cumulative breath units [CBU]) required to decrease FEV1 by 20% (allergen PD20FEV1), compared with exposure to air (geometric mean CBU: 3.0 for air versus 2.66 for O3 [p = 0.002]; 2.78 for NO2 [p = 0. 018]; 2.65 for O3 + NO2 [p = 0.002]). These results suggest that the pollutant-induced changes in airway response of mild atopic asthmatics to allergen may be dependent on a threshold concentration rather than the total amount of pollutant inhaled over a period of time.

Although studies have suggested that exposure to cigarette smoke (CS) may be associated with the development of atopy, the mechanisms underlying this are not clearly understood. It has been suggested that CS impairs the barrier function of the airway epithelium, leading to increased access of allergens such as those of the house dust mite (HDM) Dermatophagoides pteronyssinus (Der p) to antigen-presenting cells, with subsequent allergic sensitization. In order to test this hypothesis, we established primary explant cultures of human bronchial epithelial cells (HBEC) in cell culture inserts, and exposed these for 20 min, 1 h, 3 h, and 6 h to CS or air in the absence or presence of 300 ng/ml Der p, and then further incubated the cultures over a period of 24 h. The HBEC cultures were assessed for changes in permeability as measured by changes in: (1) electrical resistance (ER); and (2) passage of 14C-labeled bovine serum albumin (14C-BSA) and Der p allergens across the HBEC cultures. We also assessed the effects of protease inhibitors and the antioxidant glutathione (GSH) in this experimental system. Damage to HBEC cultures was assessed by the release of [51Cr]sodium chromate from prelabeled cells, and by release of lactate dehydrogenase (LDH). Twenty minutes of exposure to CS as compared with exposure to air did not significantly alter either the ER or passage of 14C-BSA across the HBEC cultures. In contrast, incubation with Der p led to a significant increase in the permeability of HBEC cultures, an effect that was enhanced by exposure to CS but was abrogated by the specific protease inhibitors and GSH. Passage of Der p was also increased by exposure to CS. Exposure of HBEC cultures to CS led to a significant release of 51Cr and LDH from these cells as compared with cells exposed to air. This effect was augmented further when HBEC cultures were incubated with Der p. Exposure of HBEC cultures for 1 h, 3 h, and 6 h to CS led to a markedly significant dose- and time-dependent increase in the permeability of these cells. These results suggest that exposure to CS significantly enhances Der p-induced decreases in electrical resistance and the increased passage across HBEC cultures of 14C-BSA and of the Der p allergen itself.

Summary Objective: To study the relative bioavailabilities of two generic rifampicin preparations with Rimactane. Method: Each of nineteen healthy volunteers received a single oral dose of 600 mg of rifampicin in an open cross-over randomised three-way single-dose design with a washout period of 7 days between each doses. Plasma concentrations of rifampicin were determined by HPLC. In vitro dissolution profiles of the same drugs were determined and compared with human bioavailability study results. Results:No statistically significant difference was found in main bioavailability parameters between Rimactane and generic preparations studied. Both generic preparations also fulfilled the bioequivalence criteria based on the 90% confidence intervals. There was a good correlation between in vivo and in vitro results: faster dissolution time corresponded to the lower Tmax value; lower percentage of released compound to the lower AUC value. Significant intersubject variations were found in main bioavailability parameters; significant negative correlation was found between average AUC values and body weight of the volunteer. Conclusion: All three products were bioequivalent. Our results also suggest the suitability of one-compartmental model with lag time, first order input and first order output to describe the kinetics of rifampicin.

Background: Recent studies have suggested that asthmatic patients may be more susceptible to the adverse effects of air pollutants, including diesel exhaust particles (DEP). The underlying mechanisms, however, are not clear. Methods: We cultured bronchial epithelial cells from bronchial biopsy specimens of well-characterized groups of nonatopic, nonasthmatic individuals and atopic patients with mild asthma and compared the ciliary beat frequency (CBF) and release of IL-8, GM-CSF, regulated on activation, normal T-cell expressed and secreted (RANTES), and soluble intercellular adhesion molecule-1 (sICAM-1) from these cells both before and after exposure for 24 hours to 10 to 100 μg/mL DEP in vitro. Results: The baseline CBF was not found to be significantly different in the bronchial epithelial cell cultures of nonasthmatic and asthmatic individuals. Incubation with DEP significantly attenuated the CBF of both the nonasthmatic and asthmatic bronchial epithelial cell cultures at all concentrations of DEP investigated and were maximal (55.5% and 45.2%, respectively) after incubation with 100 μg/mL DEP. The bronchial epithelial cell cultures of asthmatic patients constitutively released significantly greater amounts of IL-8, GM-CSF, and sICAM-1 than bronchial epithelial cell cultures of nonasthmatic subjects. The cultures of only asthmatic patients additionally released RANTES. Incubation of the asthmatic cultures with 10 μg/mL DEP significantly increased the release of IL-8 (from 102.0 to 167.8 pg/μg cellular protein; P < .01), GM-CSF (from 0.43 to 1.87 pg/μg cellular protein; P < .01), and sICAM-1 (from 14.7 to 38.1 pg/μg cellular protein; P < .02) after 24 hours. Incubation with 50 to 100 μg/mL DEP, however, significantly decreased the release of IL-8 and RANTES from these cultures. In contrast, only the higher concentrations of 50 to 100 μg/mL DEP significantly increased release of IL-8 (from 37.9 to 71.5 pg/μg cellular protein; P < .05) and GM-CSF (from 0.06 to 0.34 pg/μg cellular protein; P < .05) from the bronchial epithelial cells of nonasthmatic individuals. Conclusions: These results suggest that bronchial epithelial cells of asthmatic subjects are different from bronchial epithelial cells of nonasthmatic subjects with regard to the amounts and types of proinflammatory mediators they can release and that the increased sensitivity of bronchial epithelial cells of asthmatic subjects to DEP may possibly result in exacerbation of their disease symptoms. (J Allergy Clin Immunol 1998;102:771-82.)

Sleep fragmentation and respiratory disturbance measures are used in the assessment of obstructive sleep apnea (OSA) but have proved to be disappointingly poor correlates of daytime sleepiness. This study investigates the ability of electroencephalograph (EEG) and non-EEG sleep fragmentation indices to predict both presenting sleepiness and the improvement in sleepiness with subsequent nasal continuous positive airway pressure (nCPAP) therapy (nCPAP responsive sleepiness). Forty-one patients (36 men, 5 women), ranging from nonsnorers to severe OSA (> 4% O2 dip rate, median 11.1, range 0.4 to 76.5), had polysomnography with microarousal scoring, computerized EEG analysis, autonomic arousal detection, and body movement analysis. All patients received a trial of nCPAP regardless of sleep study outcome. Spearman's correlation analysis showed significant and similar associations between all sleep fragmentation indices with both pretreatment and nCPAP responsive sleepiness. There was no deterioration in sleepiness on nCPAP in the nonsnorers. Using stepwise multiple regression analysis, the best predictor of nCPAP responsive subjective and objective sleepiness was body movement index, explaining 38% and 43% of the variance, respectively. Variability in EEG sleep depth, quantified from computerized EEG analysis, was the only other index to contribute to these models. Together these indices explained 44% and 51% of the subjective and objective response to nCPAP, respectively. These results suggest that sleep fragmentation indices are useful for identifying OSA patients with sleepiness likely to respond to nCPAP.

We report the results of an 8-week open trial of imipramine in 15 patients with social phobia. Nine patients completed the trial; six dropped out early because of adverse effects. The mean reduction in the Liebowitz Social Anxiety Scale was 15% and 18% for the intent-to-treat and completer groups, respectively; the overall response rate (based on the Clinical Global Impression Scale of 1 or 2, very much or much improved) was 20% (3/15) and 22% (2/9), respectively. The results from this open trial do not support the efficacy of imipramine as a treatment for social phobia.

Background: Recent studies have suggested that airway epithelial cells of atopic and nonatopic individuals may differ in their ability to produce proinflammatory cytokines. Methods : We have cultured human nasal epithelial cells (NECs) as confluent explant cultures from nasal biopsy specimens of well-characterized nonatopic normal volunteers without rhinitis ( n =8), atopic volunteers without rhinitis ( n =9), and atopic patient volunteers with rhinitis ( n =10) and measured the amounts of IL-1β, IL-8, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and RANTES released spontaneously into the culture medium by these cells in vitro. NECs from patients with allergic rhinitis were cultured from biopsy specimens obtained on two different occasions, during and after the pollen season. Results : In general, NECs from atopic individuals released significantly greater amounts ofIL-1β, IL-8, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and RANTES than NECs from nonatopic individuals. IL-8 was released in greatest quantity and IL-1β in lowest quantity, regardless of whether the NECs were derived from atopic or nonatopic volunteers. Of the atopic individuals, NECs of atopic patients with rhinitis naturally exposed to pollen released greater quantities of all these cytokines, compared with NECs of atopic patients with rhinitis and atopic patients without rhinitis who were not exposed to allergen. Conclusions : These results suggest that NECs of atopic individuals, who are geneticallypredisposed to upper airway disease, release increased amounts of proinflammatory cytokines and that natural exposure to allergen enhances the release of these cytokines, exacerbating the symptoms of allergic disease.

The aim of this study was to determine the cause of death of those patients who died on general hospital wards after discharge from an intensive care unit. Of 1700 patients admitted over a 5-year period, 341 (20%) died in intensive care but a further 153 (9%) died on general wards. From data recorded at discharge from intensive care, 54.2% of those who died on the wards were considered at risk of death, 25.5% were expected to die but 20.3% were expected to survive. The main causes of death were pneumonia, hypoxic or structural brain damage, cerebrovascular accident, malignancy, myocardial infarction, renal or multi-organ failure and sepsis. Some of these may have been preventable with further intensive care or improved care on the wards.

Objectives Tissue interposition is an important part of vesicovaginal fistula (VVF) repair that has been shown to improve success rates. The most common interpositional flap used during a transabdominal VVF repair is the omental flap; however, in some cases, it cannot be used. The urachus is a well-vascularized tissue that is easily mobilized for interposition. We describe our experience using a urachal flap in VVF repair. Methods Patients undergoing VVF repair at our center were identified, and a retrospective chart review was performed. Patients who underwent a transabdominal repair with interposition of a urachal flap were included. Results Thirteen patients were identified between 2005 and 2009. All were evaluated with a history, physical, upper and lower tract imaging, and cystoscopy. Median patient age was 49 years (range, 31-88 years). Fistula etiology was hysterectomy in 11 and prolapse repair in 2. Five patients presented with recurrent fistulas having failed previous repair. Of 13 patients, 12 had successful repairs with our described technique, including 4 patients who failed previous repairs. There was no recurrence of fistula after median follow-up of 6 months (range, 2 weeks to 4 years). Two patients had preoperative and postoperative complaints of stress urinary incontinence that was mild and did not require surgery. Conclusions Vesicovaginal fistulas can be a difficult challenge for the reconstructive surgeon. The urachal flap is a well-vascularized tissue flap that can be easily mobilized and interposed for VVF repair. Of 13 patients in this series, 12 were successfully repaired using this technique. We feel that further evaluation and usage of this tissue flap are indicated.

The psychological and physiological effects of acute low-potency benzodiazepine administration on lactate-induced panic were examined in 10 patients with panic disorder (PD). The patients, who had panicked during a standard sodium-lactate infusion, underwent a repeat infusion modified by pretreatment with intravenous diazepam (5 mg). Acute Panic Inventory (API) scores preceding the second lactate infusion, which were associated with diazepam pretreatment, were significantly reduced in compared with those measured before the first lactate infusion. However, the second visit “fear of doom” item of the API was significantly reduced relative to the same time point of the first visit 35 min before lactate infusion, when diazepam had not yet been administered. Thus, the reduction of prelactate anxiety preceding the second infusion appeared to reflect both pharmacological and nonpharmacological contributions. The diazepam pretreatment condition was associated with a significantly increased infusion duration and a significant attenuation of rate of API symptom increase in response to lactate. Despite significant attenuation of lactate infusion effects associated with the diazepam pretreatment condition, 7 of 10 patients experienced a second panic attack. This pilot study suggests that diazepam pretreatment is associated with a marked reduction of symptomatic response during a second lactate infusion, although the magnitude of attenuation observed was insufficient to block lactate-induced panic in a majority of lactate-vulnerable PD patients.

BACKGROUND--The Hayek oscillator is a negative pressure cuirass that can operate at a range of frequencies to provide ventilation, and is a technique which could potentially be used on a general ward. This study examined the effect of different frequencies and different ranges of inspiratory and expiratory pressures on gas exchange, respiratory rate, and blood pressure in normal subjects. METHODS--Eight normal subjects received five minute periods of ventilation using the Hayek oscillator at five different frequencies, and a combination of two spans of inspiratory and expiratory pressures and two mean chamber pressures. A "sham" or control period was also performed at each frequency. Measurements were made of changes in gas exchange, spontaneous respiratory rate, and blood pressure before and after ventilation. RESULTS--There was significant intersubject variation in all results, independent of their height and weight. "Sham" settings acted as true controls in terms of gas exchange, but produced a fall in respiratory rate at 30 oscillations/min. The lower oscillatory frequencies of 30 and 60 oscillations/min produced the greatest increase in oxygenation, decrease in end tidal carbon dioxide pressure, and decrease in spontaneous respiratory rate. These effects were most significant at higher spans of pressure and were different from "sham" settings. No adverse effects were observed on blood pressure. CONCLUSIONS--The Hayek oscillator can provide assisted ventilation for short periods in normal conscious subjects with no adverse side effects on blood pressure. Maximal changes in gas exchange and a significant reduction in the spontaneous respiratory rate are seen when a combination of lower frequencies (30 and 60 oscillations/min) and higher spans of pressure are used.

Objective.To determine the relationship between timing and magnitude of Disease Activity Score [DAS28(ESR)] nonresponse (DAS28 improvement thresholds not reached) during the first 12 weeks of treatment with certolizumab pegol (CZP) plus methotrexate, and the likelihood of achieving low disease activity (LDA) at 1 year in patients with rheumatoid arthritis.Methods.In a post-hoc analysis of the RAPID 1 study, patients achieving LDA [DAS28(ESR) ≤ 3.2] at Year 1 were assessed according to DAS28 nonresponse at various timepoints within the first 12 weeks.Results.Seven-hundred eighty-three patients were included (CZP 200 mg, n = 393; CZP 400 mg, n = 390). A total of 86.9% of patients in the CZP 200 mg group had a DAS28 improvement of ≥ 1.2 by Week 12. Of the 13.1% of patients with DAS28 improvement < 1.2 by Week 12, only 2.0% had LDA at Year 1. Failure to achieve LDA at Year 1 depended on timing of nonresponse — 22.3%, 8.4%, and 2.0% of patients with DAS28 improvement < 1.2 by Weeks 1, 6, and 12, respectively, had LDA at Year 1 — and magnitude of initial lack of DAS28 improvement; for example, compared with the patients with DAS28 < 1.2 improvement, fewer patients with DAS28 < 0.6 had LDA at Year 1 (17.4%, 2.4%, and 0.0% at Weeks 1, 6, and 12, respectively).Conclusion.Failure to achieve improvement in DAS28 within the first 12 weeks of therapy was predictive of a low probability of achieving LDA at Year 1. Moreover, the accuracy of the prediction was found to be strongly dependent on the magnitude and timing of the lack of the response. (Clinical Trial Registration Nos. NCT00152386 and NCT00175877).

Increasing evidence suggests that cytokines play a role in airway inflammation by attracting and activating inflammatory cells. This may lead to epithelial cell damage and airway hyperresponsiveness. Bronchial provocative concentration of histamine causing a 20% fall in forced expiratory volume in 1 second was measured in patients with mild asthma, and bronchial biopsy specimens were stained for granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-8, and activated eosinophils (EG2) in the bronchial epithelium. The effect of inhaled beclomethasone dipropionate was also assessed in a placebo-controlled double-blind manner. There was a correlation between GM-CSF expression and EG2-staining cells (r = 0.484 p < 0.05) in the epithelium. Provocative concentration of histamine causing a 20% fall in forced expiratory volume in 1 second was correlated with GM-CSF expression (r = -0.462, p < 0.05). Treatment with inhaled beclomethasone dipropionate 500 micrograms twice a day led to a significant decrease in both the expression of GM-CSF (p < 0.01) and IL-8 (p < 0.02) and the number of EG2-staining cells (p < 0.01) in the epithelium. The changes in GM-CSF (r = 0.798, p < 0.01) and IL-8 (r = 0.653, p < 0.02) expression were correlated with the changes in EG2-staining cells after treatment. These results suggest that GM-CSF may influence eosinophil activation in the epithelium in vivo and participate in the etiology of bronchial hyperresponsiveness in mild asthma. Also, beclomethasone dipropionate may inhibit eosinophil activation partly by downregulating the expression of GM-CSF and IL-8 in the bronchial epithelium.

Expression of intercellular adhesion molecule-1 (ICAM-1) appears to be important to the development of bronchial hyperresponsiveness and eosinophilia in Ascaris sensitized monkeys. Beta 1-integrins are expressed on epithelial cells, and may contribute to adherence of epithelial cells to the basement membrane. The aim of this study was to determine whether adhesion receptor expression was altered in human asthmatic bronchial epithelium. Using monoclonal antibody staining, we have examined the expression of ICAM-1 and the alpha 1-alpha 6-subunits of the beta 1-integrin family in bronchial mucosal biopsies from 33 asthmatic and 13 nonasthmatic subjects. The epithelium was positive for ICAM-1 in 26 out of 33 asthmatics, although negative in all 13 nonasthmatics. ICAM-1 expression was not associated with bronchial responsiveness or with medication requirements. Beta 1-integrin staining showed that alpha 2-, alpha 3- and alpha 6-subunits stained the epithelium in all cases. Alpha 4 staining was weakly positive in the epithelium in five asthmatics. Alpha 5 staining was weak in asthmatics and normals. Alpha 4 and alpha 6-subunits also stained inflammatory cells. Epithelial upregulation of ICAM-1 is present in asthma. Beta 1-integrins with alpha 2-, alpha 3- and alpha 6-subunits appear to be constitutively expressed in bronchial epithelium.

Objective: Ataque de nervios ("attack of nerves") is an illness category used frequently by Hispanic individuals to describe one or more particular symptom complexes. A review of the literature on ataque suggested some overlap with panic disorder. This study investigated the overlap with panic disorder as well as other DSM-III-R axis I disorders. Method: Hispanic subjects seeking treatment at an anxiety disorders clinic (N = 156) were assessed with a specially designed questionnaire for self-report of ataque de nervios and panic symptoms and with structured or semistructured psychiatric interviews for axis I disorders. Results: Seventy percent of the subjects reported at least one ataque de nervios; 80% of these were female, whereas 57% of the group without these attacks were female. There were no differences in DSM-III-R diagnoses between the groups with and without ataque de nervios. Ataque was frequently associated with one or more anxiety and affective disorders, including panic disorder, generalized anxiety disorder, recurrent major depression, and anxiety not otherwise specified. Of the 45 subjects with both ataque de nervios and primary panic disorder, 80% appeared to have labeled panic disorder as ataque. Ataque de nervios was associated with panic symptoms even in subjects without panic disorder, but the self-reporting of ataque conveyed additional clinical information about the subjects with panic disorder. Ataque de nervios was similar in frequency and symptoms among subjects of Dominican and Puerto Rican origin. Conclusions: Ataque de nervios overlaps with panic disorder but is a more inclusive construct. Further study of its interrelation with axis I disorders is needed.

Expanded abstract Citation Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CW, Ali N, Kinnear W, Bentley A, Kahan BC, Wrightson JM, Davies HE, Hooper CE, Lee YC, Hedley EL, Crosthwaite N, Choo L, Helm EJ, Gleeson FV, Nunn AJ, Davies RJ: N Engl J Med 2011, 365:518-26. PMID: 21830966, available on www.pubmed. gov Background More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is the key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial therapy (Multicenter Intrapleural Sepsis Trial [MIST1]). Methods Objective: To evaluate the efficacy and safety of intrapleural DNase alone, alteplase alone, or the combination of both, to improve pleural drainage. Design: Multicenter, double-blind, double-dummy, 2 × 2 factorial randomized trial. Setting: Eleven centers in the United Kingdom (UK). Subjects: Adult patients (mean age 59 years, 72% men), who had clinical evidence of infection, and pleural fluid that had macroscopic purulence, a positive culture or Gram stain for bacteria, or a pH < 7.2. Intervention: Patients were assigned to 1 of the 4 study interventions for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. Outcomes: The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events. Results The mean (± SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (-29.5 ± 23.3% vs. -17.2 ± 19.6%; difference, -7.9%; 95% confidence interval [CI], -13.4 to -2.4; P = 0.005). The change observed with t-PA alone and with DNase alone (-17.2 ± 24.3 and -14.7 ± 16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P = 0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P = 0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P = 0.006). Hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups. Conclusions Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of hospital stay. Treatment with DNase alone or t-PA alone was ineffective.

To determine the levels of resistance to first-line tuberculosis drugs in three cities in three geopolitical zones in Nigeria.A total of 527 smear-positive sputum samples from Abuja, Ibadan and Nnewi were cultured on BACTEC- MGIT 960. Drug susceptibility tests (DST) for streptomycin, isoniazid, rifampicin and ethambutol were performed on 428 culture-positive samples on BACTEC-MGIT960.Eight per cent of the specimens cultured were multi-drug-resistant Mycobacterium tuberculosis (MDR-TB) with varying levels of resistance to individual and multiple first-line drugs. MDR was strongly associated with previous treatment: 5% of new and 19% of previously treated patients had MDR-TB (OR 4.1 (95% CI 1.9-8.8), P = 0.001) and with young adult age: 63% of patients with and 38% without MDR-TB were 25-34 years old (P = 0.01). HIV status was documented in 71%. There was no association between MDR-TB and HIV coinfection (P = 0.9) and gender (P0.2 for both).MDR-TB is an emerging problem in Nigeria. Developing good quality drug susceptibility test facilities, routine monitoring of drug susceptibility and improved health systems for the delivery of and adherence to first- and second-line treatment are imperative to solve this problem.