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Severe acute respiratory coronavirus 2 (SARS-CoV-2) has spread globally since its emergence in 2019. Most SARS-CoV-2 infections generate immune responses leading to rising levels of immunoglobulins (Ig) M, A and G which can be detected using diagnostic tests including enzyme-linked immunosorbent assays (ELISA). Whilst implying previous SARS-CoV-2 infection, the detection of Ig by ELISA does not guarantee the presence of neutralising antibodies (NAb) that can prevent the virus infecting cells. Plaque reduction neutralisation tests (PRNT) detect NAb, but are not amenable to mass testing as they take several days and require use of SARS-CoV-2 in high biocontainment laboratories. We evaluated the ability of IgG and IgM ELISAs targeting SARS-CoV-2 spike subunit 1 receptor binding domain (S1-RBD), and spike subunit 2 (S2) and nucleocapsid protein (NP), at predicting the presence and magnitude of NAb determined by PRNT. IgG S2 + NP ELISA was 96.8% [95% CI 83.8–99.9] sensitive and 88.9% [95% CI 51.8–99.7] specific at predicting the presence of NAbs (PRNT80 > 1:40). IgG and IgM S1-RBD ELISAs correlated with PRNT titre, with higher ELISA results increasing the likelihood of a robust neutralising response. The IgM S1-RBD assay can be used as a rapid, high throughput test to approximate the magnitude of NAb titre.

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 Early identification of patients unlikely to achieve good long‐term disease control with anti–tumor necrosis factor therapy in axial spondyloarthritis (SpA) and psoriatic arthritis (PsA) is important for physicians following treat‐to‐target recommendations. Here we assess associations between disease activity or clinical response during the first 12 weeks of treatment and attainment of treatment targets at week 48 in axial SpA and PsA patients receiving certolizumab pegol. Methods The relationship between disease activity or clinical response during the first 12 weeks of treatment and achievement of week‐48 targets (for axial SpA: inactive disease based on Ankylosing Spondylitis Disease Activity Score [ASDAS] using the C‐reactive protein [CRP] level, or Bath Ankylosing Spondylitis Disease Activity Index 5.1 at week 12, compared to 73% of patients (57 of 78) with DAS28‐CRP

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.

Adult zebrafish, in contrast to mammals, regenerate neurons in their brain, but the extent and variability of this capacity is unclear. Here we ask whether the loss of various dopaminergic neuron populations is sufficient to trigger their functional regeneration. Both sexes of zebrafish were analyzed. Genetic lineage tracing shows that specific diencephalic ependymo-radial glial (ERG) progenitor cells give rise to new dopaminergic [tyrosine hydroxylase-positive (TH(+))] neurons. Ablation elicits an immune response, increased proliferation of ERG progenitor cells, and increased addition of new TH(+) neurons in populations that constitutively add new neurons (e.g., diencephalic population 5/6). Inhibiting the immune response attenuates neurogenesis to control levels. Boosting the immune response enhances ERG proliferation, but not addition of TH(+) neurons. In contrast, in populations in which constitutive neurogenesis is undetectable (e.g., the posterior tuberculum and locus ceruleus), cell replacement and tissue integration are incomplete and transient. This is associated with a loss of spinal TH(+) axons, as well as permanent deficits in shoaling and reproductive behavior. Hence, dopaminergic neuron populations in the adult zebrafish brain show vast differences in regenerative capacity that correlate with constitutive addition of neurons and depend on immune system activation. SIGNIFICANCE STATEMENT Despite the fact that zebrafish show a high propensity to regenerate neurons in the brain, this study reveals that not all types of dopaminergic neurons are functionally regenerated after specific ablation. Hence, in the same adult vertebrate brain, mechanisms of successful and incomplete regeneration can be studied. We identify progenitor cells for dopaminergic neurons and show that activating the immune system promotes the proliferation of these cells. However, in some areas of the brain this only leads to insufficient replacement of functionally important dopaminergic neurons that later disappear. Understanding the mechanisms of regeneration in zebrafish may inform interventions targeting the regeneration of functionally important neurons, such as dopaminergic neurons, from endogenous progenitor cells in nonregenerating mammals.

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.

Background: The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap. Methods: This 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927. Findings: Between Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2·1 points (95% CI -3·0 to -1·3; p

To compare primary urethral realignment (PR) with suprapubic cystostomy (SPC) for the management of pelvic fracture-associated posterior urethral injuries with regards to rates of stricture, erectile dysfunction, and urinary incontinence.Two electronic databases (MEDLINE and EMBASE) were searched with the assistance of a librarian. Title, abstract, and full text screening was carried out by 2 independent reviewers, with discrepancies resolved by consensus. Narrative reviews, surveys, and historical articles were excluded. Only studies reporting a direct comparison of PR vs SPC for the management of posterior urethral injuries associated with blunt trauma in adults were included. Quality assessment of the included articles was performed in duplicate. Stricture incidence was evaluated for all included studies, as were erectile dysfunction and incontinence rates when reported. All outcomes were treated as dichotomous data with calculation of odds ratio and were pooled using a random effects model with Review Manager 5.1.Our comprehensive search yielded 161 unique articles. Nine articles were included in the final meta-analysis. Stricture rate was significantly lower in the PR group (odds ratio [OR] = 0.12, 95% confidence interval [CI] 0.04-0.41, P.001). There was no significant difference between the 2 interventions with regards to erectile dysfunction (OR = 1.19, 95% CI 0.73-1.92, P = .49) or incontinence (OR = 0.75, 95% CI 0.38-1.48, P = .41).PR appears to reduce the incidence of stricture formation after pelvic fracture-associated posterior urethral injuries as compared with SPC.

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.

Background: The optimal choice of chest tube size for the treatment of pleural infection is unknown, with only small cohort studies reported describing the efficacy and adverse events of different tube sizes. Methods: A total of 405 patients with pleural infection were prospectively enrolled into a multicenter study investigating the utility of fibrinolytic therapy. The combined frequency of death and surgery, and secondary outcomes (hospital stay, change in chest radiograph, and lung function at 3 months) were compared in patients receiving chest tubes of differing size (χ2, t test, and logistic regression analyses as appropriate). Pain was studied in detail in 128 patients. Results: There was no significant difference in the frequency with which patients either died or required thoracic surgery in patients receiving chest tubes of varying sizes ( 20F, 30/69 [44%]; χ2trend, 1 degrees of freedom [df ] = 1.21, P = .27), nor any difference in any secondary outcome. Pain scores were substantially higher in patients receiving (mainly blunt dissection inserted) larger tubes (20F, 6 [6-8]; χ2, 3 df = 10.80, P =.013, Kruskal-Wallis; χ2trend, 1 df = 6.3, P =.014). Conclusions: Smaller, guide-wire-inserted chest tubes cause substantially less pain than blunt-dissection-inserted larger tubes, without any impairment in clinical outcome in the treatment of pleural infection. These results suggest that smaller size tubes may be the initial treatment of choice for pleural infection, and randomized studies are now required. Trial registration: MIST1 trial ISRCTN number: 39138989. © 2010 American College of Chest Physicians.

Background - Standard treatment for pleural infection includes catheter drainage and antibiotics. Tube drainage often falls if the fluid is loculated by fibrinous adhesions when surgical drainage is needed. Streptokinase may aid the process of pleural drainage, but there have been no controlled trials to assess its efficacy. Methods - Twenty four patients with infected community acquired parapneumonic effusions were studied. All had either frankly purulent/culture or Gram stain positive pleural fluid (13 cases; 54%) or fluid which fulfilled the biochemical criteria for pleural infection. Fluid was drained with a 14F catheter. The antibiotics used were cefuroxime and metronidazole or were guided by culture. Subjects were randomly assigned to receive intrapleural streptokinase, 250 000 IU daily, or control saline flushes for three days. The primary end points related to the efficacy of pleural drainage - namely, the volume of pleural fluid drained and the chest radiographic response to treatment. Other end points were the number of pleural procedures needed and blood indices of inflammation. Results - The streptokinase group drained more pleural fluid both during the days of streptokinase/control treatment (mean (SD) 391 (200)ml versus 124 (44)ml; difference 267 ml, 95% confidence interval (CI) 144 to 390; p

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.

BACKGROUND: Patients with respiratory failure have early fatiguability which may be due to limitation of oxygen supply for oxidative (mitochondrial) ATP synthesis. Skeletal muscle in exercise and recovery was studied to examine the effect of chronic hypoxia on mitochondrial activity in vivo. METHODS: The skeletal muscle of five patients with respiratory failure (PaO2 < 9 kPa) was studied by phosphorus-31 magnetic resonance spectroscopy and compared with 10 age and sex matched controls. Patients lay in a 1.9 Tesla superconducting magnet with the gastrocnemius muscle overlying a six cm surface coil. Spectra were acquired at rest, during plantar flexion exercise, and during recovery from exercise. Relative concentrations of inorganic phosphate (Pi), phosphocreatine (PCr) and ATP were measured from peak areas, and pH and free ADP concentration were calculated. For the start of exercise, the rates of PCr depletion and estimated lactic acid production were calculated. For the post exercise recovery period, the initial rate of PCr recovery (a quantitative measure of mitochondrial ATP synthesis), the apparent Vmax for mitochondrial ATP synthesis (calculated from initial PCr resynthesis and the end exercise ADP concentration which drives this process), and the recovery half times of PCr, Pi, and ADP (also measures of mitochondrial function) were determined. RESULTS: Considerably greater and faster PCr depletion and intracellular acidosis were found during exercise. This is consistent with limitation of oxygen supply to the muscle and might explain the early fatiguability of these patients. There was no abnormality in recovery from exercise, however, suggesting that mitochondria function normally after exercise. CONCLUSIONS: These results are consistent with one or more of the following: (a) decreased level of activity of these patients; (b) changes in the fibre type of the muscle; (c) decreased oxygen supply to the muscle during exercise but not during recovery. They are not consistent with an intrinsic defect of mitochondrial ATP synthesis in skeletal muscle in respiratory failure.

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.

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) has been associated with cardiovascular disease in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on systemic inflammation involved in the atherosclerotic process remains unclear. METHODS: 100 men with moderate-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 49) CPAP treatment for 4 weeks to investigate the effects of active treatment on inflammatory markers such as highly sensitive C reactive protein (hsCRP), interleukin (IL)6, interferon gamma (IFNgamma) and anti-inflammatory adiponectin. RESULTS: 4 weeks of therapeutic CPAP did not significantly change blood levels of hsCRP compared with the subtherapeutic control group (difference between median changes -0.24 mg/l (95% CI -0.88 to +0.24); p = 0.30). Plasma levels of IL6 and IFNgamma did not change significantly following therapeutic compared with subtherapeutic CPAP (difference between median changes +0.52 and -0.07 pg/ml (95% CI -0.72 to +1.94 and -0.81 to +0.44); p = 0.45 and p = 0.82, respectively). Furthermore, 4 weeks of therapeutic CPAP did not significantly change levels of adiponectin in plasma compared with the subtherapeutic control group (difference between median changes +0.05 pg/ml (95% CI -0.36 to +0.47); p = 0.84). If patients with hsCRP values above 8 mg/l at baseline were excluded, differences between the changes in hsCRP, IL6, IFNgamma and adiponectin after 4 weeks of CPAP were smaller, and again not statistically different between groups. CONCLUSIONS: 4 weeks of CPAP treatment has no beneficial effect on blood markers of inflammation and adiponectin in patients with moderate-severe obstructive sleep apnoea.

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)

Summary Background Mesothelioma invades the tracts made by chest instrumentation. Prophylactic radiotherapy is effective at preventing malignant seeding at these sites. Methods We assessed the use and effectiveness of radiotherapy at our centre in 39 of the 40 patients identified with mesothelioma between January 2000 and September 2003. Results Thirty-seven (95%) patients received radiotherapy to their chest instrumentation site between 6 and 42 days (median 26 days) following the diagnosis of mesothelioma. The radiotherapy field size varied, from 4 cm square to 14×10.5 cm. The radiotherapy was given as 21 Gy in 3 fractions over 1 week. In 3 patients (8%), there was already tumour invasion of the skin at the time of radiotherapy. In 2 other patients (5%), there was tumour recurrence following radiotherapy; in both this was at the edge of the previous radiotherapy fields. Further treatment was administered to an adjacent field in both. One patient with an indwelling pleural catheter developed tumour growth at the catheter insertion site. This was treated successfully with radiotherapy, with no catheter damage. Conclusions Prompt radiotherapy referral and radiotherapy field selection is important to maximise the effect of radiotherapy given to prevent chest wall tumour growth. There was no tumour growth in areas that were treated with radiotherapy. Further chest interventions outside the radiotherapy field should be followed with further radiotherapy.

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.

AIM: To assess the role of contrast-enhanced computed tomography (CT) prospectively in patients with suspected malignant pleural effusions. MATERIALS AND METHODS: Forty consecutive patients referred for the investigation of a suspected malignant pleural effusion had contrast-enhanced thoracic CT, thoracoscopy, thoraco-centesis and pleural biopsy, either percutaneously or at thoracoscopy. Final diagnoses were based on histopathological or cytological analysis ( n =30), autopsy findings ( n =3) or clinical follow-up ( n =7). The pleural surfaces were classified at contrast-enhanced CT as normal or abnormal and, if abnormal, as benign or malignant in appearance using previously established CT criteria for malignant pleural thickening by two observers unaware of the pathological diagnosis. RESULTS: Pleural effusions were malignant in 32 patients and benign in eight patients. Pleural surfaces assessed at CT showed features of malignancy in 27 out of 32 patients with a malignant effusion (sensitivity 84%, specificity 100%). Overall, CT appearances indicated the presence of malignancy in 28 of 32 (87%) patients. All eight patients with benign pleural disease were correctly diagnosed by CT. CONCLUSION: Contrast-enhanced CT is of value in patients with suspected malignant pleural effusions. The previously established criteria for malignant pleural thickening of nodularity, irregularity and pleural thickness >1cm are reliable in the presence of a pleural effusion. Traill, Z. C. et al . (2001). Clinical Radiology , 56 , 193–196.

BackgroundThe therapeutic and economic benefits of continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnoea syndrome (OSAS) have been established in middle-aged people. In older people there is a lack of evidence.ObjectiveTo determine the clinical efficacy of CPAP in older people with OSAS and to establish its cost-effectiveness.DesignA randomised, parallel, investigator-blinded multicentre trial with within-trial and model-based cost-effectiveness analysis.MethodsTwo hundred and seventy-eight patients, aged ≥ 65 years with newly diagnosed OSAS [defined as oxygen desaturation index at ≥ 4% desaturation threshold level for > 7.5 events/hour and Epworth Sleepiness Scale (ESS) score of ≥ 9] recruited from 14 hospital-based sleep services across the UK.InterventionsCPAP with best supportive care (BSC) or BSC alone. Autotitrating CPAP was initiated using standard clinical practice. BSC was structured advice on minimising sleepiness.Coprimary outcomesSubjective sleepiness at 3 months, as measured by the ESS (ESS mean score: months 3 and 4) and cost-effectiveness over 12 months, as measured in quality-adjusted life-years (QALYs) calculated using the European Quality of Life-5 Dimensions (EQ-5D) and health-care resource use, information on which was collected monthly from patient diaries.Secondary outcomesSubjective sleepiness at 12 months (ESS mean score: months 10, 11 and 12) and objective sleepiness, disease-specific and generic quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, cardiovascular risk factors and events at 3 and 12 months.ResultsTwo hundred and seventy-eight patients were randomised to CPAP (n = 140) or BSC (n = 138) over 27 months and 231 (83%) patients completed the trial. Baseline ESS score was similar in both groups [mean (standard deviation; SD) CPAP 11.5 (3.3), BSC 11.4 (4.2)]; groups were well balanced for other characteristics. The mean (SD) in ESS score at 3 months was –3.8 (0.4) in the CPAP group and –1.6 (0.3) in the BSC group. The adjusted treatment effect of CPAP compared with BSC was –2.1 points [95% confidence interval (CI) –3.0 to –1.3 points;p p p = 0.02), increased mobility (p = 0.03) and reduced total and low-density lipoprotein cholesterol (p = 0.05,p = 0.04, respectively) at 3 months but not at 12 months. In the BSC group, there was a fall in systolic blood pressure of 3.7 mmHg at 12 months, which was not seen in the CPAP group (p = 0.04). Mood, functionality, nocturia, accidents, cognitive function and cardiovascular events were unchanged. There were no medically significant harms attributable to CPAP.ConclusionIn older people with OSAS, CPAP reduces sleepiness and is marginally more cost-effective than BSC over 12 months. Further work is required in the identification of potential biomarkers of sleepiness and those patients at increased risk of cognitive impairment. Early detection of which could be used to inform the clinician when in the disease cycle treatment is needed to avert central nervous system sequelae and to assist patients decision-making regarding treatment and compliance. Treatment adherence is also a challenge in clinical trials generally, and adherence to CPAP therapy in particular is a recognised concern in both research studies and clinical practice. Suggested research priorities would include a focus on optimisation of CPAP delivery or support and embracing the technological advances currently available. Finally, the improvements in quality of life in trials do not appear to reflect the dramatic changes noted in clinical practice. There should be a greater focus on patient centred outcomes which would better capture the symptomatic improvement with CPAP treatment and translate these improvements into outcomes which could be used in health economic analysis.Trial registrationCurrent Controlled Trials ISRCTN90464927.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 19, No. 40. See the NIHR Journals Library website for further project information.

Summary Background Over 200 000 pleural effusions are attributable to cancer in the UK and USA every year. Cytological examination of pleural fluid classifies about 60% of malignant effusions. Pleural biopsy needs to be done in the remaining cases. We aimed to assess whether CT-guided biopsy is an improvement over standard pleural biopsy in this setting. Methods 50 consecutive patients with cytologically negative suspected malignant pleural effusions were recruited. All had a contrast-enhanced thoracic CT scan to assess pleural thickening. Patients were randomly allocated, stratified by baseline pleural thickening, to either Abrams' pleural biopsy (standard care; n=25) or CT-guided cutting needle biopsy (n=25). Sensitivity for pleural malignancy from the biopsy specimen was the primary endpoint, with the patient's clinical outcome after 1 year being the diagnostic gold standard. Analysis was per protocol. Findings Three patients did not undergo biopsy. Abrams' biopsy correctly diagnosed malignancy in eight of 17 patients (sensitivity 47%, specificity 100%, negative predictive value 44%, positive predictive value 100%). CT-guided biopsy correctly diagnosed malignancy in 13 of 15 (sensitivity 87%, specificity 100%, negative predictive value 80%, positive predictive value 100%; difference in sensitivity between Abrams' and CT-guided 40%, 95% CI 10–69, p=0·02). Diagnostic advantage was similar in patients proving to have mesothelioma. Interpretation Primary use of CT-guided biopsy would avoid doing at least one Abrams' biopsy for every 2·5 CT-guided biopsies undertaken. In cytology-negative suspected malignant pleural effusions, CT-guided pleural biopsy is a better diagnostic test than Abrams' pleural biopsy.

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.

For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven.To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion.A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013.Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]).Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%).Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20).Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy.isrctn.org Identifier: ISRCTN33288337.

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.

BACKGROUND Thoracic ultrasound-guided pleural procedures are associated with fewer adverse events than 'blind' procedures for patients with pleural effusion. Ultrasound is increasingly practised by respiratory physicians but there has been no prospective assessment of its safety and diagnostic accuracy when delivered by respiratory physicians. METHODS The activity level, safety and diagnostic accuracy of thoracic ultrasound delivered by respiratory physicians were prospectively assessed. Diagnostic accuracy was assessed using a stepwise pragmatic approach (recording if pleural fluid was obtained or effusion was present on another radiological modality). In the absence of the above, ultrasound clips were reviewed by a blinded radiologist. The number of ultrasounds referred to radiologists and adverse events within 1 week were recorded. The complication rate was compared with the published literature. RESULTS 960 ultrasound scans occurred over a 3 year period. The activity of the service increased over time, as a result of increased use of interventional ultrasound. The referral rate to radiology remained constant over the study period (mean proportion 4.0%). Physician-delivered ultrasound correctly identified the presence/absence of pleural fluid in 951 of 955 evaluable scans (99.6% CI 98.9% to 99.9%). The major complication rate was 3/558=0.5% (95% CI 0.1% to 1.6%), which compared favourably with the identified published literature. CONCLUSION Respiratory physician-delivered thoracic ultrasound appears to be safe and effective in the diagnosis/intervention of pleural effusion, and is associated with a major complication rate comparable with that of published studies. Continued liaison with the radiology service has here been demonstrated as a requirement for a physician-based service.

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.

Introduction This 28-week, phase IIIb study assessed safety and maintenance of response to certolizumab pegol (CZP) in a diverse population of rheumatoid arthritis (RA) patients, stratified by prior anti-TNF exposure, concomitant methotrexate (MTX) use and disease duration. The ability to predict achievement of low disease activity (LDA) at week 28 from improvements in Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), swollen joint count (SJC) and Clinical Disease Activity Index (CDAI) up to week 12 was assessed. Methods The 28-week study population included all patients who completed the double-blind (DB) phase and entered the open-label (OL) phase, receiving 200 mg CZP every 2 weeks (Q2W) ≥16 weeks. In the 12-week DB period, patients with active RA and an inadequate response to ≥1 disease-modifying antirheumatic drug (DMARD) were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4 then 200 mg Q2W) or placebo (Q2W), stratified by prior anti-TNF use, concomitant use of MTX and disease duration (

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.

STUDY OBJECTIVES Two pontine reticular regions are implicated in cholinergic triggering of rapid eye movement (REM) sleep: the dorsomedial tegmental region and the ventral nucleus pontis oralis. We previously determined that, in urethane-anesthetized rats, microinjections of a cholinergic agonist, carbachol, into the dorsal region produce REM sleep-like effects comprising cortical activation, hippocampal theta rhythm, suppression of hypoglossal (XII) nerve activity, and silencing of pontine noradrenergic neurons. Our goal was to determine whether carbachol injections into the ventral nucleus pontis oralis elicits comparable effects. DESIGN Recording of cortical electroencephalogram, hippocampal activity, XII nerve activity, and discharge of noradrenergic cells of the locus coeruleus. SETTING Basic neurophysiologic research laboratory. PARTICIPANTS AND INTERVENTIONS Urethane-anesthetized, paralyzed, and artificially ventilated or nonparalyzed and spontaneously breathing rats with microinjections of carbachol (10 nL, 10 mM) into the ventral nucleus pontis oralis. MEASUREMENTS AND RESULTS In artificially ventilated rats, carbachol injections repeatedly elicited cortical activation and hippocampal theta rhythm. Concomitantly, the activity of locus coeruleus neurons increased from 2.0 per second +/- 0.4 (SE) to 2.6 per second +/- 0.4 (P < .05, n = 8), as did XII nerve activity (by 42.5% +/- 8.8%; P < .01). In spontaneously breathing animals, carbachol similarly activated the cortical electroencephalogram and hippocampal activity, whereas XII nerve activity was reduced by 6.7% +/- 2.5% (P < .05) together with increased ventilation, as indicated by reduced end-expiratory CO2. CONCLUSION Carbachol injections into the ventral nucleus pontis oralis activate, rather than silence, noradrenergic locus coeruleus neurons. This is not compatible with the state of REM sleep.

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.

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.

To examine the safety and efficacy of fluoxetine in child and adolescent obsessive-compulsive disorder (OCD).Between 1991 and 1998, 43 patients were randomly assigned to fluoxetine or placebo for 8 weeks. Dosing was fixed for the first 6 weeks (up to 60 mg/day) and then could be increased to 80 mg/day. Responders entered an 8-week maintenance phase. The primary outcome measures were the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinical Global Impression-Improvement (CGI-I) scale. Analyses were done on the intent-to-treat sample.Fluoxetine patients (n = 21) had significantly lower CY-BOCS scores than placebo patients (n = 22) after 16 (but not 8) weeks. Fluoxetine responders (n = 11) had significantly lower CY-BOCS scores than placebo responders (n = 7) after an additional 8 weeks of treatment. After 16 weeks, 57% of fluoxetine (versus 27% of placebo) patients were much or very much improved on the CGI-I scale (p.05). No patient terminated the study because of adverse medication effects.Fluoxetine was well tolerated and effective for the treatment of child and adolescent OCD, but fluoxetine's full effect took more than 8 weeks to develop.

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

Study objectives: Pleural fluid cytology and non–image-guided Abrams or Cope biopsies have sensitivities of approximately 30% for detecting malignant mesothelioma, and thoracoscopic biopsy has a sensitivity of approximately 90%. The difference between these two probably relates to obtaining adequate tissue. The use of immunohistochemical stains allows a firm diagnosis to be made from relatively small samples. This study explores whether percutaneous image-guided cutting needle biopsy (CNB) combined with immunohistochemistry is accurate in diagnosing pleural thickening due to mesothelioma. Design: Retrospective review of image-guided CNB of pleural thickening performed on consecutive patients over 7 years by a single radiologist. Setting: Teaching hospital chest radiology department. Patients: Twenty-one adult patients with a final diagnosis of malignant mesothelioma were identified from 53 consecutive patients who underwent percutaneous image-guided CNB. All 21 patients had pleural thickening identified on contrast-enhanced CT, and all had a final histologic diagnosis of mesothelioma confirmed by postmortem examination or thoracoscopy. Interventions: Fourteen-gauge and 18-gauge cutting needles were used. Biopsy guidance was by ultrasound in 6 patients and by CT in 15 patients. Measurements and results: A correct histologic diagnosis of malignant mesothelioma was made by CNB in 18 patients (86% sensitivity and 100% specificity). Complications included one chest wall hematoma and a small hemoptysis. Four patients with a pleural thickness of < 5 mm underwent biopsy, and all specimens were diagnostic for mesothelioma. Conclusions: Image-guided percutaneous CNB of pleural thickening is a safe procedure, with 86% sensitivity for detecting malignant mesothelioma. Pleural thickening of < 5 mm may be successfully sampled. (CHEST 2001; 120:1798 –1802)

The aim of this study was to identify the subtle influences of exposure and individual lifestyles on the risk of developing tuberculosis. A retrospective case-control study (with matching by sex, age, postcode and ethnicity) of all tuberculosis cases notified over a 7-yr period in Liverpool, UK, was carried out. Multiple logistic regression showed that, before diagnosis, cases were 7.4 times more likely to have had visitors from abroad; 4.0 times more likely to have been born abroad; and 3.8 times more likely to have lived with someone with tuberculosis. Subtle socioeconomic factors were also evident with cases 4.0 times less likely to have additional bathrooms. Lifestyle factors emerged with cases 2.3 times more likely to have smoked for at least 30 yrs, 3.8 times less likely to eat dairy products every week and 2.6 times less likely to have had high blood pressure. At interview, these factors were still evident, but cases, unlike controls, had reduced their smoking and alcohol consumption and were less likely to go out of the home or exercise than before their illness. Within individuals, lifestyle consequences of tuberculosis lead to a "healthier" lifestyle on the one hand (less smoking and alcohol consumption), but a reduced quality of life (social activity) on the other.

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.