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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.

To reduce reliance on fossil fuels there has been a global push to minimise fuel consumption, and incorporate the use of bio-derived fuels. In practical combustion systems that use liquid fuels, observing the spray behaviour of these biofuels is key in understanding fuel performance; in particular, droplet size distribution is known to have a strong influence on the fuel energy release and pollutant formation processes. This paper is aimed at the use of the TSI Global Sizing Velocimetry (GSV) interferometric technique as a method to gain detailed understanding of droplet number and size distribution, with a particular focus on ethanol-gasoline fuel blends. The imaging system for the GSV technique consisted of a Nd:YAG laser and a 4 MP (million pixel) camera, and the spray was generated using a generic automotive port fuel injector. The results showed that the GSV technique was able to effectively measure droplet concentration and diameters for all the fuel blends tested in this study. Ethanol was observed to have larger droplet diameters (both D10 and D32) as compared to fossil gasoline, with droplet diameters generally increasing as the proportion of ethanol in the gasoline was increased. The droplet concentration reduced with increasing radial distance from the spray centreline, but no appreciable change was observed with axial displacement from the nozzle tip. Degradation in the image quality was observed for fuel blends with less than 40% ethanol content. The GSV drop sizing measurements were validated using a mono-disperse droplet generator, and an excellent agreement (within 2%) was observed.

Genitourinary (GU) injury is present in approximately 10% of cases of abdominal trauma.1 Of those GU injuries, up to 67% involve the external genitalia.2,3 GU trauma is more common in males, especially in the instance of genital injury. This increased incidence in males is secondary to both anatomical considerations and increased participation in activities such as contact sports, violent interaction, and war activities.2 The lower urinary tract is susceptible to traumatic injury by way of various mechanisms. These injuries, and their sequelae, can affect patients of any age or background. Though lower urinary tract trauma rarely results in life-threating pathology, appropriate management of these injuries is pivotal in decreasing long-term morbidity.4 Although the external genitalia in males are at high risk of injury in trauma because of their extracorporeal location, the scrotum and testes are relatively well-protected from severe damage for the following reasons: 1) the testes are inherently mobile within the scrotum; 2) the scrotal skin provides reasonable elasticity allowing for internal structures to slip away from the point of contact in blunt trauma; 3) the cremasteric reflex offers a protective reflex mechanism; and 4) the tunica albuginea serves as a tough fibrous physical defense with its tensile strength.4–6 Resultantly, the incidence of scrotal or testicular injury in a trauma activation is generally considered to be less than one percent. However, the associated morbidity to the patient (including psychological effects of testicular injury or loss) and health system costs associated with these injuries warrant special attention.5,7–9 In general, there are two broad domains to consider when evaluating scrotal trauma: blunt vs. penetrating injury. Historically, blunt injury has been thought to comprise the significant majority (i.e., 75–80%) of genital trauma.2,4 A recent analysis of the National Trauma Data Bank in the U.S. described a more balanced distribution of penetrating vs. blunt scrotal trauma, with both representing nearly half of all injuries.5 However, this significant difference in reported mechanism may be attributable to input biases and geopolitical determinants (e.g., increased incidence of gunshot wound [penetrating] injuries in the U.S. compared to other nations). The importance of categorizing these these types of injuries into broad classes lies in the special diagnostic and management considerations for each type of injury (Fig. 2). For example, while just 1.5% of blunt testicular injury involves the gonads bilaterally, approximately 30% of penetrating scrotal injury will involve both testes. Additionally, penetrating injury occurs with associated injuries in approximately 70% of patients, decreasing the threshold of suspicion of damage to neighboring structures, such as the penis, bladder, urethra, and femoral vessels.2,4 However, workup for associated injury should not be neglected in the setting of blunt trauma either, and nearby structures should be appropriately investigated when clinical suspicion is present (e.g., blood at the urethral meatus suggesting urethral injury).4 Other domains of scrotal trauma, including thermal and degloving/scrotal wall avulsion injuries, are described in the literature as well and will be discussed here briefly. Open in a separate window Fig. 2 Simplified diagnostic and management pathway in blunt and penetrating scrotal trauma.

A classical inventory problem is studied from the perspective of embedded options, reducing inventory-management to the design of optimal contracts for forward delivery of stock (commodity). Financial option techniques a la Black-Scholes are invoked to value the additional ‘option to expand stock’. A simplified approach which ignores distant time effects identifies an optimal ‘time to deliver’ and an optimal ‘amount to deliver’ for a production process run in continuous time modelled by a Cobb-Douglas revenue function. Commodity prices, quoted in initial value terms, are assumed to evolve as a geometric Brownian process with positive (inflationary) drift. Expected revenue maximization identifies an optimal ‘strike price’ for the expansion option to be exercised and reveals the underlying martingale in a truncated (censored) commodity price. The paper establishes comparative statics of the censor, using sensitivity analysis on the related censor functional equation; key here is that the censor, as a function of the drift and volatility of price, is the solution of a functional equation. Asymptotic approximation allows a tractable analysis of the optimal timing.

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.

Background:Several disease activity measures and thresholds have been recommended as psoriatic arthritis (PsA) treatment targets, although consensus on the most appropriate assessment tool is lacking.1Reports suggest low disease activity (LDA) and remission may be associated with minimal structural progression in PsA.2Objectives:To report the relationship between PsA disease activity and structural progression over 216 weeks’ (wks) treatment with certolizumab pegol (CZP), an Fc-free, PEGylated, tumour necrosis factor inhibitor (TNFi) that has shown long-term efficacy and safety in PsA.3Methods:Patients (pts) enrolled in RAPID-PsA (NCT01087788) with active PsA (≥3 tender joints; ≥3 swollen joints; ESR ≥28 mm/hour and/or CRP >upper limit of normal) who had failed treatment with ≥1 csDMARD were randomised 1:1:1 to CZP 200 mg every 2 wks (Q2W), CZP 400 mg every 4 wks (Q4W), or placebo (PBO). All CZP pts received CZP 400 mg at Wks 0/2/4. PBO pts were re-randomised to CZP 200 mg Q2W or 400 mg Q4W at Wk 16 or 24.3Pts were heterogenous for structural damage and disease duration at baseline. Disease activity was assessed using minimal disease activity (MDA) criteria (MDA: 5–6/7 criteria; very LDA [VLDA]: 7/7 criteria), Psoriatic Arthritis Disease Activity Score (PASDAS) (LDA: >1.9–≤3.2; remission: ≤1.9), or Disease Activity Index for Psoriatic Arthritis (DAPSA) (LDA: >4–≤14; remission: ≤4). Radiographs were read in four reading campaigns using the van der Heijde modified Total Sharp Score (mTSS) for PsA. A risk of structural progression (RSP) subgroup (baseline mTSS >median for all pts) was also assessed. Mean change from baseline (CFB) in mTSS and associations with disease activity states were estimated using a hierarchical linear mixed effects model (fixed effects: reading campaign/interactions of concurrent disease activity levels with time; random effects: pt/reading campaign nested within pt) which allowed mean mTSS trajectory, and impact of disease activity levels on this, to differ over time.Results:407/409 randomised pts were assessed for mTSS at least once. At Wk 0, mean (standard deviation) DAPSA=44.5 (22.7), PASDAS=6.0 (1.1). 3/409 (0.7%) pts reported MDA. The proportion of pts achieving remission/VLDA states increased to Wk 216, as did estimated mean mTSS. Estimated mean mTSS CFB remained low overall (0.46 at Wk 216; standard error 0.16;Figure). Across disease activity measures, remission/VLDA states were associated with mTSS estimated mean CFB ≤0 in both the overall group and RSP subgroup (Table).Conclusion:These data indicate that achievement of remission in PsA is important to prevent further structural damage, particularly in pts with pre-existing structural changes. This supports the rationale for strict disease activity targets.References:[1]Coates L. Arthritis Rheumatol 2018;70:345–55;2.Tucker LJ. Curr Rheumatol Rep 2018;20:71;3.van der Heijde D. RMD Open 2018;4:e000582.Table.Estimated mTSS (mixed effects model)mTSS estimated mean CFB (standard error)All patients(N=407)RSP(n=202)PASDASRemission-0.20 (0.25)-0.55 (0.49)LDA0.01 (0.23)-0.07 (0.47)>LDA1.31 (0.22)2.54 (0.43)DAPSARemission-0.34 (0.23)-0.67 (0.46)LDA0.40 (0.22)0.81 (0.44)>LDA1.37 (0.24)2.46 (0.48)MDAVLDA-0.40 (0.28)-0.84 (0.55)MDA0.39 (0.24)0.55 (0.48)>MDA0.89 (0.20)1.73 (0.39)mTSS estimated mean CFB: ≤0; ≤0.5; >0.5. Data to Wk 216 pooled for all pts randomised.Acknowledgments:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Laura C Coates: None declared, Joseph F. Merola Consultant of: Merck, AbbVie, Dermavant, Eli Lilly, Novartis, Janssen, UCB Pharma, Celgene, Sanofi, Regeneron, Arena, Sun Pharma, Biogen, Pfizer, EMD Sorono, Avotres and LEO Pharma, Arthur Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB – grant/research support, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Owen Davies Employee of: UCB Pharma, Oscar Irvin-Sellers Employee of: UCB Pharma, Tommi Nurminen Employee of: UCB Pharma, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV

Part 1 Scene setting: is health care a business? an analysis of health care, and its considerations as a business, John L. Deffenbaugh managing the design of health care services, Moira Fischbacher and Arthur Francis. Part 2 Quality in health care: towards critical quality, Mike Walsh whose quality? different interest groups' perspectives on health care quality, Juan I. Baeza and Michael Calnan the quantification of patient satisfaction, Mike Hart managing clinical audit - diagnozing the problems and designing solutions, Gail Johnston et al improving child dental health in Scotland - an audit in primary care, Chris Southwick et al human resource management audits - contributions to quality, Sandra Nutley. Part 3 Using performance indicators: what are we counting with hospital episode statistics (HES)?, Richard Wilson clinical outcomes indicators in Scotland - lessons and prospects, Steve Kendrick et al what do managers and physicians prefer as indicators of clinical outcome?, Regis Blais et al performance indicators - a patient-centred approach, Anne Ludbrook and Colin Gordon is indicator use for quality improvement and performance measurement compatible?, Joanne Lally and Richard Thomson published health outcomes - guiding lights or wreckers' lanterns?, Huw T.O. Davies et al.

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.

[Ti(OR)4] (R = Pri or But) and their heteroleptic derivatives [Ti(OR)2(L)2] [L = bidentate donor-functionalized alkoxide: mmp (1-methoxy-2-methylpropan-2-olate) dmae (2-(dimethylamino)ethanoxide), dmop (2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propan-2-olate) or dmom ((4,4-dimethyl-4,5-dihydrooxazol-2-yl)methoxide)] are investigated as single source precursors for liquid injection MOCVD of TiO2 on F-doped SnO2 substrates. The influence of the ligands on the phase and morphology of the deposited films is investigated, and [Ti(OPri)2(dmae)2] is found to be the most effective precursor for growth of nanostructured anatase. The identity of the monodentate alkoxide is found to have the greatest influence on the phase of the thin film: OPri-containing precursors deposit anatase under all conditions whereas OBut-containing precursors have a greater tendency to deposit rutile or mixed phases. The effect of film morphology on the photoinduced hydrophilic state is demonstrated. [Ti(OR)2(dmop)2] (R = Pri or But) have been characterised by single crystal X-ray diffraction.

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.

Diflunisal is a new salicylic acid derivative identified after a search for a compound with improved potency, enhanced gastrointestinal tolerance relative to its antiinflammatory activity, and a longer duration of action than that of aspirin. Animal and clinical studies have confirmed these properties. As an inhibitor of cyclooxygenase tested in vitro in a sheep seminal vesicle preparation, diflunisal was less potent than indomethacin but 10 to 20 times more active than aspirin. In addition, it was shown biochemically to act as a moderate free radical scavenger. Diflunisal is well absorbed from the gastrointestinal tract, is subject to dose-dependent pharmacokinetics (like aspirin), and reaches steady-state levels in a predictable fashion in most persons. The drug is excreted by the kidneys, and its apparent half-life is lengthened in the presence of renal failure. A number of drug interactions have been described. Diflunisal produces reversible effects on platelet aggregation when given in high doses, whereas aspirin produces irreversible aggregation at low doses. Measurements of fecal blood loss and endoscopic examinations have confirmed the improved gastrointestinal tolerance of diflunisal compared to aspirin.

Part 1 Involvement and partnership arrangements: primary care groups - what are they and why are they here? setting up local health groups in Wales - challenges and opportunites developing an organization made up of people who thrive on changes. Part 2 Two teams and interdisciplinary working: introducing self-directed primary care teams in the NHS - an overview of initial strategic issues interprofessional education - one aspect of archiving quality health and social care getting the message across - mental health matters in older age. Part 3 Leadership: primary care groups - a study into the development of appropriate managerial skills the role of middle managers in realizing human resource strategy - evidence from the NHS effective and ineffective leadership within the NHS in Wales strategic leadership in health care in challenging times emperor's clothes? does training pay off? evaluating health management training in the developing world. Part 4 Future trends in development: the future of the European health sector - a scenarios approach institutional change and trust in the National Health Service - examining the impact of reform on the NHS value structure explaining variation in grant funding of health voluntary organizaions by Scottish health boards power as a concept in the evaluation of telehealth.

Background RAPID-axSpA (NCT01087762) was a long-term study in patients (pts) with axial spondyloarthritis (axSpA) treated with certolizumab pegol (CZP). This is the first report of 4-year imaging results in CZP-treated axSpA pts, including ankylosing spondylitis (AS) and non-radiographic (nr-)axSpA. Objectives To report 4-year X-ray and MRI data in CZP-treated axSpA pts. Methods RAPID-axSpA 1 was double-blind and placebo (PBO)-controlled to Wk24, dose-blind to Wk48, and open-label to Wk204. Pts fulfilling ASAS axSpA criteria were stratified using a local read according to presence/absence of radiographic sacroiliitis (AS/nr-axSpA) at randomization and had active disease. Wk0 CZP-randomized pts (200mg Q2W/400mg Q4W) continued assigned dose; PBO pts received CZP after Wk16/24. Centrally-read lateral X-rays of cervical/lumbar spine at baseline (BL), Wk96, and Wk204 were assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Sacroiliac (SI) joint X-rays were scored for sacroiliitis at BL and Wk204. MRI scans performed at BL, Wks12, 48, 96, and 204 were assessed using Spondyloarthritis Research Consortium of Canada (SPARCC) score for SI joints and Berlin score for spine. Data are shown for CZP-treated pts including those starting on PBO. SI joint X-rays (recorded at BL and Wk204) and magnetic resonance imaging (MRI) observed data are presented for pts with valid assessments. mSASSS data were estimated for all pts using observed data and by mixed model for repeated measures (MMRM) analysis. Results Of 315 CZP-treated pts, 196 had available spinal X-rays and were included in MMRM analyses (BL mean mSASSS: 9.47). 158 pts had MRI assessments (BL mean SPARCC: 8.17 [n=151]; Berlin score: 6.10 [n=153]) and 137 pts had SI joint X-rays at BL and Wk204 (BL: 67.9% radiographic sacroiliitis). In AS pts, mean mSASSS change between BL and Wk204 was 0.98; 0.67 from BL to Wk96, and 0.31 from Wk96 to Wk204 (0.06, -0.01, and 0.07 respectively for nr-axSpA) (Table A). MMRM estimates were similar to observed values (0.62 and 0.70, respectively [axSpA Wk204 mean change]). Limited changes in SI joint X-ray grading were observed to Wk204: only 4.5% of pts progressed to AS, whilst 4.3% moved from an AS classification to nr-axSpA. MRI assessments showed sustained improvement (Table B). Conclusions This is the first trial to report imaging data in both AS and nr-axSpA pts over 4 years. Limited spinal radiographic progression was observed in CZP-treated pts with lower progression between Wks96 and 204 compared with the first 96 wks. Limited change in radiographic sacroiliitis was observed. Early reductions in MRI inflammation were maintained to Wk204. References Landewe R. Ann Rheum Dis 2014;73:39–47. Acknowledgements This study was funded by UCB Pharma. We thank the patients and their caregivers in addition to the investigators and their teams who contributed to this study. Editorial services were provided by Costello Medical Consulting. Disclosure of Interest D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, UCB Pharma, Employee of: Director of Imaging Rheumatology BV, X. Baraliakos Grant/research support from: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Janssen, MSD, Novartis, Pfizer, UCB Pharma, Consultant for: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Janssen, MSD, Novartis, Pfizer, UCB Pharma, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Janssen, MSD, Novartis, Pfizer, UCB Pharma, K. G. Hermann Speakers bureau: AbbVie, MSD, Pfizer, UCB Pharma, R. Landewe Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth, Consultant for: Abbott, Ablynx, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Centocor, GlaxoSmithKline, Novartis, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth, Speakers bureau: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth, P. Machado Consultant for: AbbVie, Centocor, Janssen, MSD, Novartis, Pfizer, Speakers bureau: AbbVie, Centocor, Janssen, MSD, Novartis, Pfizer, W. Maksymowych Grant/research support from: AbbVie, Amgen, Eli-Lilly, Janssen, Merck, Pfizer, Synarc, Sanofi, UCB Pharma, Consultant for: AbbVie, Amgen, Eli-Lilly, Janssen, Merck, Pfizer, Synarc, Sanofi, UCB Pharma, Speakers bureau: AbbVie, Amgen, Eli-Lilly, Janssen, Merck, Pfizer, Synarc, Sanofi, UCB Pharma, O. Davies Shareholder of: UCB Pharma, Employee of: UCB Pharma, N. de Peyrecave Employee of: UCB Pharma, B. Hoepken Employee of: UCB Pharma, L. Bauer Shareholder of: UCB Pharma, Employee of: UCB Pharma, T. Nurminen Employee of: UCB Pharma, J. Braun Grant/research support from: Abbott, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Johnson & Johnson, MSD, Novartis, Pfizer, Roche, UCB Pharma, Consultant for: Abbott, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Johnson & Johnson, MSD, Novartis, Pfizer, Roche, UCB Pharma

Change is inevitable. All organizations need to change to maintain relevance and to successfully adapt to varying external forces. Change is a challenge for those involved in it. It is the antithesis of consistency and at its core requires a shift in behaviour that is reflexic and instinctual. The authors of this paper would suggest that given the nature of healthcare, its evolving research, its social value/importance, and its cost, that no other profession is more subject to change than medicine. Change is necessary, inevitable, and difficult. A solid understanding of change and its management process is a prerequisite for professional survival. Preparation, conviction, purpose, and clarity are the core values of change. Physicians, more than any other profession, have been driven to and exposed to change. Physicians are in a position to distill its process to a level of understanding that would serve as a model for others to follow. The goals of this paper are to outline the rationale of change, as well as to review change management options and strategies to increase successful change.

Introduction: The management of pelvic fracture-associated urethral injuries (PFUI) is not standardized and optimal management is controversial. We surveyed Canadian urologists about their experiences and opinions regarding optimal management of PFUI.Methods: Canadian urologists were surveyed via an anonymous, bilingual, web-based, 12-item questionnaire. A total of 735 Canadian urologists were invited to participate via email distributed by the Canadian Urological Association.Results: Of the 146 urologists who participated (19.9% response rate), the majority practice at a trauma centre (53.2%), but manage only 1‒5 PFUI/year (71.5%). Most participants (82.6%) favour primary realignment compared to suprapubic (SP) tube with delayed repair (15.3%) and immediate reconstruction (2.1%). Compared to SP diversion and delayed repair, the majority of participants believe primary realignment is associated with equivocal incontinence (61.2%) and erectile dysfunction rates (75.8%), but has lower stricture rates (73.0%). Among respondents who perform primary realignment, 45.4% concurrently place a SP tube, while 54.6% do not. While 91% believe SP tubes do not increase the risk of pelvic hardware infections, 31.6% report that orthopedic surgeons alter their management of pelvic fractures in the presence of a SP tube.Conclusions: Most Canadian urologist respondents — even those practicing at trauma centres — manage very few PFUIs/year. There is reasonable consensus among respondents that primary realignment is favourable to delayed or immediate reconstruction, but discordance on whether or not to place concurrent SP tubes. The urological and orthopedic consequences of SP tubes in the management of traumatic urological injuries warrant further investigation.

Excessive reactive oxygen species (ROS) can damage proteins, lipids, and DNA, which result in cell damage and death. The outcomes can be acute, as seen in stroke, or more chronic as observed in age-related diseases such as Parkinson’s disease. Here we investigate the antioxidant ability of a novel synthetic flavonoid, Proxison (7-decyl-3-hydroxy-2-(3,4,5-trihydroxyphenyl)-4-chromenone), using a range ofin vitroandin vivoapproaches. We show that, while it has radical scavenging ability on par with other flavonoids in a cell-free system, Proxison is orders of magnitude more potent than natural flavonoids at protecting neural cells against oxidative stress and is capable of rescuing damaged cells. The unique combination of a lipophilic hydrocarbon tail with a modified polyphenolic head group promotes efficient cellular uptake and mitochondrial localisation of Proxison. Importantly,in vivoadministration of Proxison demonstrated effective and well tolerated neuroprotection against oxidative stress in a zebrafish model of dopaminergic neuronal loss.

Objective To report MRI outcomes and explore the relationship between clinical remission and MRI inflammation in patients with axial spondyloarthritis (axSpA) from the RAPID-axSpA trial, including radiographic (r-)axSpA and non-radiographic (nr-)axSpA. Methods RAPID-axSpA (NCT01087762) was double-blind and placebo-controlled to week 24, dose-blind to week 48 and open-label to week 204. Patients were randomised to certolizumab pegol (CZP) or placebo. Placebo patients entering dose-blind were rerandomised to CZP. MRIs performed at baseline, weeks 12, 48 and 96 were scored by 2 reviewers independently: Spondyloarthritis Research Consortium of Canada (SPARCC) for sacroiliac (SI) joints; Berlin modification of the Ankylosing Spondylitis spine MRI scoring system for disease activity (Berlin) for spine. Inflammation thresholds: SPARCC≥2; Berlin>2. Remission thresholds: SPARCC

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

This article explores the private trade networks of English East India Company merchants on the west coast of India during the first half of the eighteenth century. Existing studies of English private trade in the Indian Ocean have almost exclusively focused on India's eastern seaboard, the Coromandel Coast and the Bay of Bengal regions. This article argues that looking at private trade from the perspective of the western Indian Ocean provides a different picture of this important branch of European trade. It uses EIC records and merchants' private papers to argue against recent metropolitan-centred approaches to English private trade, instead emphasising the importance of more localised political and economic contexts, within the Indian Ocean world, for shaping the conduct and success of this commerce.

The Belvoir Park Forest landslip is situated in Northern Ireland. It was monitored for more than five years with inclinometers, standpipe piezometers, and slip indicators providing detailed information on the long term behaviour and rate of movement of a large low angle failure in Glacial Till. A detailed geological model was constructed on the basis of the geomorphology and geology of the area and ground investigation data. A detailed geotechnical model was prepared with estimates of stiffness, permeability, shear strength and unit weight data. The geometry of the failure plane, residual strengths, movement rates, pore pressure fluctuations and rainfall data was used to complete a model of the failure with limit equilibrium methods. This model was able to demonstrate that pore water pressure was the most influential factor when considering the stability of the slope, but could not determine the effect of rainfall fluctuations on the observed rate of movement of the slip. A more sophisticated coupled hydro-mechanical model based on Shetran and Flac-tp flow was used to determine the effect of fluctuations of pore pressures, rainfall and mechanical strains on slip movement. This paper illustrates some of the advantages of using more sophisticated slope modelling approaches alongside more ‘traditional’ modelling of residual slope failures to understand their future evolution.

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.

Many small- and medium-sized mammals dig for their food. This activity potentially affects soil condition and fertility. Digging is well developed especially in Australian mammals, many of which have recently become rare or extinct. We measured the effects of digging by mammals on soil in a Tasmanian temperate dry sclerophyll forest with an intact mammal community. The density of diggings was 5812 ha −1 , affecting 11% of the forest floor. Diggings were created at a rate of around 3113 diggings ha −1 yr −1 , disturbing 6.5% of the forest floor and displacing 7.1 m 3 ha −1 of soil annually. Most diggings were made by eastern bettongs ( Bettongia gaimardi) and short-beaked echidnas ( Tachyglossus aculeatus ). Many (approx. 30%) fresh diggings consisted of re-excavations of old diggings. Novel diggings displaced 5 m 3 ha yr −1 of soil. Diggings acted as traps for organic matter and sites for the formation of new soil, which had higher fertility and moisture content and lower hardness than undisturbed topsoil. These effects on soil fertility and structure were strongest in habitats with dry and poor soil. Creation of fine-scaled heterogeneity by mammals, and amelioration of dry and infertile soil, is a valuable ecosystem service that could be restored by reintroduction of digging mammals to habitats from which they have declined or gone extinct.

Excessive reactive oxygen species (ROS) can damage proteins, lipids, and DNA, which result in cell damage and death. The outcomes can be acute, as seen in stroke, or more chronic as observed in age-related diseases such as Parkinson’s disease. Here we investigate the antioxidant ability of a novel synthetic flavonoid, Proxison (7-decyl-3-hydroxy-2-(3,4,5-trihydroxyphenyl)-4-chromenone), using a range of in vitro and in vivo approaches. We show that, while it has radical scavenging ability on par with other flavonoids in a cell-free system, Proxison is orders of magnitude more potent than natural flavonoids at protecting neural cells against oxidative stress and is capable of rescuing damaged cells. The unique combination of a lipophilic hydrocarbon tail with a modified polyphenolic head group promotes efficient cellular uptake and moderate mitochondrial enrichment of Proxison. Importantly, in vivo administration of Proxison demonstrated effective and well tolerated neuroprotection against cell loss in a zebrafish model of dopaminergic neurodegeneration.

Simulation is an effective and valuable asset to medical education. Skills unique to surgery such as procedural steps and communication in theatre are benefiting from improved surgical models and expertise in utilising them to produce high fidelity educational scenarios. We delivered a simulation based Emergency Neurosurgery course for Foundation Year 2 doctors, junior Neurosurgical trainees and trainee theatre staff in fully functioning operating theatre, supported by the Trust. The aim was to provide delegates with the knowledge and practical skills, including decision making and effective communication that are required for safe working in a Neurosurgical theatre, within a controlled but realistic environment to maximise the learning potential. Delegates were brought to a patient (SimMan®) in a resuscitation scenario to make their initial assessment with the patient demonstrating real time vitals, pupil sizes and verbal responses. After completing the initial assessment delegates were required to interpret CT scans and consent the patient’s relatives before taking the patient to theatre. Once there, delegates carried out the emergency Neurosurgical operation, using image guidance on surgical model heads (Rowena®) and surgical drills, assisted by trainee scrub nurses and theatre HCAs . As the scenario unfolded, complications arose to highlight the importance of human factors and multi-disciplinary working. This tested delegates’ clinical acumen, decision making and communication skills in a pressured environment. Delegates were supervised by senior trainees who were able to give personalised feedback. The course received global positive feedback from delegates, with particular focus on learning alongside other healthcare professionals to improve inter-professional working and theatre safety. It is possible to deliver teaching to a multidisciplinary group using simulation to mimic the normal working environment as closely as possible. Future plans are to repeat the course with anaesthetic colleagues involved to help design increasingly challenging scenarios for senior trainees and scrub team members.

Background Simulation is an increasingly important aspect of surgical training as it can provide opportunity for skill acquisition in a safe and controlled environment. This is particularly important in skull base surgery where the margins for error are small and their consequences grave. Skull base surgery often involves neurosurgery and ENT working closely together, combining their varied skills and experience. For the neurosurgical trainee, experience at anterior and lateral skull base approaches may not be obtained until the latter years of training, whereas for ENT trainees, the techniques and skills required for transnasal and transtemporal approaches are core competencies developed from earlier stages of training. The purpose of this collaborative was to assess the viability and utility of integrated skull base simulation training. Methodology Each ENT trainee was paired with a neurosurgery trainee for cadaver-based simulated lateral and anterior approaches to skull base and sinuses. Peer-to-peer instruction with consultant supervision was utilised to exchange expertise between specialties. Qualitative feedback was obtained from participants. Results Participants (n = 12) rated their confidence on a scale of 1 to 10, in performing 4 operative approaches prior to and after simulation training. On average, confidence improved by 2.3 points in each approach (paired t-tests p Conclusions Cadaveric simulation training for approaches to the skull base provides a positive training experience. Collaborative and integrated training amongst related surgical specialties offers additional benefits from the sharing of knowledge and experience, as well as maximising limited resources and reducing costs.

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

Pleural infection is responsible for significant morbidity and mortality worldwide, and its clinical management is challenging. The diagnosis of empyema and tuberculous pleurisy may be difficult, and these conditions may be confused with other causes of exudative pleural effusions. Complicated parapneumonic effusion or empyema may present with 'atypical' clinical features; delays in diagnosis are common and may contribute to the high mortality of these infections. Pleural aspiration is the key diagnostic step; pleural fluid that is purulent or that has a pH < 7.2, or organisms on Gram stain or culture, is an indication for formal intercostal drainage. In order to achieve a definitive diagnosis of tuberculous pleurisy, Mycobacterium tuberculosis must be isolated in the culture of pleural fluid, pleural tissue or sputum; demonstration of granulomas in pleural tissue is also suggestive of tuberculosis. The use of pleural fluid biochemical markers, such as adenosine deaminase, in the diagnosis of tuberculous pleurisy varies among clinicians; the diagnostic value of such markers is affected by the background prevalence of tuberculosis and the likelihood of an alternative diagnosis. Uncertainties also remain regarding the treatment of pleural infection. Treatment of complicated parapneumonic effusion and empyema involves prolonged courses of antibiotics and attention to the patient's nutritional state. The role of intrapleural fibrinolytics and the optimal timing of surgical intervention are unknown. The lack of clear predictors of clinical outcome in empyema contributes to the difficulty in treating this condition. The pharmacological treatment of tuberculous pleurisy is the same as for pulmonary tuberculosis; the precise role of steroids in the treatment of tuberculous pleurisy remains uncertain.

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.

PURPOSE OF REVIEW: Complicated parapneumonic effusion and empyema continue to account for significant morbidity and mortality, and uncertainties remain regarding their optimal management. This review describes recent advances in this field, as well as areas for future research. RECENT FINDINGS: Recent advances have addressed the pathogenesis, bacteriology, and treatment of pleural infection. Key areas for research in the development of empyema include the interplay between inflammatory and coagulation cascades and development of fibrosis within the pleural space. The varied bacteriology of empyema has been more clearly defined, and in particular the differences between community- and hospital-acquired infection highlighted. Studies of treatment have focused particularly on the roles of intrapleural fibrinolytics and surgery. SUMMARY: Increased understanding of the pathogenesis of empyema may ultimately yield novel therapeutic targets. Comprehensive descriptions of the bacteriology of empyema aids antibiotic choice, and the use of intrapleural DNase shows promise in facilitating drainage of infected pleural fluid. Uncertainties remain, such as the role of intrapleural fibrinolytics and the optimal timing of surgical intervention.

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)