Non-invasive evaluation of pulmonary glutathione in the exhaled breath condensate of otherwise healthy alcoholics

SummaryBackgroundChronic alcoholism is associated with an elevated risk for pulmonary infection and a 3-fold chance for incidence and mortality of acute respiratory distress syndrome with critical injury. Limited sampling of the alveolar lining fluid has restricted clinical studies of the role of glutathione (GSH) redox balance in pulmonary function and diseased states. Non-invasive sampling in the exhaled breath condensate (EBC) to monitor alveolar GSH would facilitate research in pulmonary oxidative stress.MethodsEBC was collected from otherwise healthy subjects with and without a history of alcohol abuse. Reduced and oxidized EBC glutathione (GSH and GSSG, respectively), pH, and hydrogen peroxide were measured.ResultsGSH was statistically decreased in alcohol abusers only when normalized to protein (4.7nmol/mg protein [0.75, 11.4] vs. 13.4 [7.8, 26.4], p=0.03). In contrast, GSSG was significantly elevated in the EBC from alcohol abusers when compared to controls, 5.62 [0.45, 8.94] vs. 0.50nM [0.38, 0.80], p=0.03. Thus, a greater percentage was in the oxidized GSSG form when subjects abused alcohol (35.3% [11.8, 58.1] vs. 5.2 [3.6, 6.1], p<0.001). These concentrations represented a 40mV shift in GSH redox state towards a more oxidized state.ConclusionsProper sample preparation was essential to prevent GSH loss and artificial oxidation. The shift in redox potential or %GSSG, which were not affected by dilution, may serve as better markers of pulmonary oxidative stress. Furthermore, these data suggested that the oxidant stress observed in the lavage fluid of otherwise healthy alcoholics could be measured non-invasively in the EBC

Association of pregnancy complications/risk factors with the development of future long-term health conditions in women : overarching protocol for umbrella reviews

Acknowledgments Patient representatives and MuM-PreDiCT team. Funding This work was funded by the Strategic Priority Fund 'Tackling multimorbidity at scale' programme (grant number-MR/W014432/1) delivered by the Medical Research Council and the National Institute for Health and Care Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council.Peer reviewedPublisher PD

Uterine artery embolization or myomectomy for women with uterine fibroids: Four-year follow-up of a randomised controlled trial

Objective: To examine the quality of life experienced by women with symptomatic uterine fibroids who had been treated with UAE in comparison to myomectomy. We report the four-year follow-up of the FEMME randomised trial. Two-year follow-up data has been previously reported. Study Design: Premenopausal women who had symptomatic uterine fibroids amenable to myomectomy or uterine artery embolization were recruited from 29 UK hospitals. Women were excluded if they had significant adenomyosis, any malignancy, pelvic inflammatory disease or had had a previous open myomectomy or uterine artery embolization. Participants were randomised to myomectomy or embolization in a 1:1 ratio using a minimisation algorithm. Myomectomy could be open abdominal, laparoscopic or hysteroscopic, according to clinician preference. Embolization of the uterine arteries was performed according to local practice, under fluoroscopic guidance. The primary outcome measure was the Uterine Fibroid Symptom Quality of Life questionnaire, adjusted for baseline score and reported here at four years post-randomisation. Subsequent procedures for fibroids, pregnancy and outcome were amongst secondary outcomes. Trial registration ISRCTN70772394 https://doi.org/10.1186/ISRCTN70772394 Results: 254 women were randomized, 127 to myomectomy (105 underwent myomectomy) and 127 to uterine artery embolization (98 underwent embolization). At four years, 67 (53%) and 81 (64%) completed UFS-QoL quality of life scores. Mean difference in the UFS-QoL at 4 years was 5.0 points (95% CI −1.4 to 11.5; p = 0.13) in favour of myomectomy. There were 15 pregnancies in the UAE group and 7 in the myomectomy group, with a cumulative pregnancy rate to four years of 15% and 6% respectively (hazard ratio: 0.48; 95% CI 0.18–1.28). The cumulative repeat procedure rate to four years was 24% in the UAE group and 13% in the myomectomy group (hazard ratio: 0.53; 95% CI 0.27–1.05). Conclusions: Myomectomy resulted in greater improvement in quality of life compared with uterine artery embolization, although by four years, this difference was not statistically significant. Missing data may limit the generalisability of this result. The numbers of women becoming pregnant were too small draw a conclusion on the effect of the procedures on fertility

The development of a core outcome set for studies of pregnant women with multimorbidity

Acknowledgements We would like to thank the following individuals, organisations and many others for helping with the recruitment of the Delphi surveys: 4M Mentor Mothers, African and Caribbean Support Northern Ireland, Alopecia UK, Ammalife, Association of South Asian Midwives, Attention Deficit Hyperactivity Disorder UK, Autism Connected, Balachandran Kumarendran, Birthrights, Black Female Doctors UK, Black Mothers Matter, Bliss, Breast Cancer Now, Bristol, North Somerset and South Gloucestershire Maternity Voices Partnership, British Adult Congenital Cardiac Nurse Association, British Association of Perinatal Medicine, British Human Immunodeficiency Virus Association, British Intrapartum Care Society, British Maternal and Fetal Medicine Society, British Thyroid Foundation, Cardiff Lupus Support Group, Cardiomyopathy UK, Chelsea and Westminster Maternity Voices Partnership, Community of Cultures Sheffield Maternity Cooperation, Core Outcome Measures in Effectiveness Trials Initiative, Crohn's and Colitis Canada, Crohn's and Colitis UK, Dads Matter, Diabetes UK, Disability Maternity Care (Australia), Elly Charity, E69 MOTIVE Trial, Epilepsy Foundation of America, Epilepsy Society, Fair Treatment for the Women of Wales, Fibromyalgia Action UK, General Practitioners Championing Perinatal Care, Global Kidney Foundation, Graham Mcllroy, Haemophilia Foundation Australia, Hereditary Spastic Paraplegia Support Group, Institute of Health Visiting, International League Against Epilepsy (Africa), Irish Neonatal Health Alliance, Juvenile Diabetes Research Foundation, Katie's Team, Kidney Patient Involvement Network, Kidney Wales, LGBT Mummies, MacDonald Obstetric Medicine Society, Malaysian Obstetric Medicine, Maternity and Midwifery Forum, MIDIRS Midwifery Digest, Midlands Maternal Medicine Network, Milena Forte, MQ Mental Health Research, Multiple Sclerosis Australia, Mums Like Us, Mum's Pride, Mumsnet, Muslim Women's Network UK, National Childbirth Trust, National Human Immunodeficiency Virus Nurses Association, National Kidney Federation, National Rheumatoid Arthritis UK, Newport Yemeni Community Association, Niina Kolehmainen, Obsessive Compulsive Disorder Action, Obstetric Anaesthetists' Association, Organisation for Sickle Cell Anaemia Relief and Thalassaemia Support Birmingham, Parathyroid UK, Parent Voices in Wales, Parents 1st 83 , Positive East, Positive Life Northern Ireland, Postural Tachycardia Syndrome UK, Psoriasis Association, Raham Project, Royal College of Midwives, Royal Surrey County Hospital Maternity Voices Partnership, Scottish 86 Perinatal Network, Scottish Research Nurse, Midwife & Coordinators' Network, Section for Women's Mental Health Institute of Psychiatry, Psychology and Neuroscience (King's College London), Sjogern's India, Society of Obstetric Medicine of Australia and New Zealand, Society of Obstetric Medicine (India), Somerville Heart Foundation, Sophia Forum, South African Nephrology Society, South Asian Health Foundation, South London Applied Research Collaboration Maternal and Perinatal Mental Health Research Patient and Public Involvement, Stockport Foundation Trust, Taraki, The Black Wellbeing Collective, The International Marcé Society for Perinatal Mental Health, The Pituitary Foundation, Thyroid Patients Canada, Tommy's, Turner Syndrome Support Society UK, UK Audit and Research Collaborative in Obstetrics and Gynaecology, UK Preconception Early-and Mid-Career Researchers Network, UK Teratology Information Service, University of Bristol Centre for Academic Primary Care and Patient and Public Involvement Panel, Vasculitis Ireland Awareness, Verity Polycystic Ovarian Syndrome UK, Wales Perinatal Mental Health Network. We would also like to thank Clare Evans for her input in reviewing this manuscript Funding This work was funded by the Strategic Priority Fund “Tackling multimorbidity at scale” programme (grant number MR/W014432/1) delivered by the Medical Research Council and the National Institute for Health Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council. BT was funded by the National Institute for Health Research (NIHR) West Midlands Applied Research Collaboration. The views expressed are those of the author and not necessarily those of the funders, the NIHR or the UK Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis

We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air-liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and 'benchmarked' against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90-100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F/HN-pseudotyped lentiviral vector into a first-in-man CF trial in 2017

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit