protocol for a hospital-based registry study

Introduction Obstructive sleep apnoea (OSA), the most common type of sleep- disordered breathing, is associated with significant immediate and long-term morbidity, including fragmented sleep and impaired daytime functioning, as well as more severe consequences, such as hypertension, impaired cognitive function and reduced quality of life. Perioperatively, OSA occurs frequently as a consequence of pre-existing vulnerability, surgery and drug effects. The impact of OSA on postoperative respiratory complications (PRCs) needs to be better characterised. As OSA is associated with significant comorbidities, such as obesity, pulmonary hypertension, myocardial infarction and stroke, it is unclear whether OSA or its comorbidities are the mechanism of PRCs. This project aims to (1) develop a novel prediction score identifying surgical patients at high risk of OSA, (2) evaluate the association of OSA risk on PRCs and (3) evaluate if pharmacological agents used during surgery modify this association. Methods Retrospective cohort study using hospital-based electronic patient data and perioperative data on medications administered and vital signs. We will use data from Partners Healthcare clinical databases, Boston, Massachusetts. First, a prediction model for OSA will be developed using OSA diagnostic codes and polysomnography procedural codes as the reference standard, and will be validated by medical record review. Results of the prediction model will be used to classify patients in the database as high, medium or low risk of OSA, and we will investigate the effect of OSA on risk of PRCs. Finally, we will test whether the effect of OSA on PRCs is modified by the use of intraoperative pharmacological agents known to increase upper airway instability, including neuromuscular blockade, neostigmine, opioids, anaesthetics and sedatives. Ethics and dissemination The Partners Human Research Committee approved this study (protocol number: 2014P000218). Study results will be made available in the form of manuscripts for publication and presentations at national and international meetings

Developing gender-equitable ecological restoration initiatives: A synthesis of guidance to improve restoration practice

Ecological restoration has the potential to contribute to all Sustainable Development Goals (SDGs). Yet, social issues, including gender relations, often remain unaddressed in ecological restoration initiatives. As the UN Decade on Ecosystem Restoration begins, it is critical to learn from existing knowledge and experiences to restore degraded lands in ways that enhance the equity of restoration, and ensure that restoration initiatives and agendas leave no one behind. This 'guide to guides' places existing resources and guidance materials (frameworks, tools, guidelines, and manuals) designed to enhance equity in restoration initiatives in a common 'Reach, Benefit, Empower, Transform' framework, and highlights the strengths that different resource materials bring to understanding and planning for gender-equitable restoration. As per the framework, the guide provides actionable strategies and recommendations for the design, implementation, and monitoring, evaluation, learning and impact assessment (MELIA) of gender-equitable restoration initiatives. The ultimate goal is to enhance the equity and sustainability of restoration initiatives and allow restoration to achieve its full potential to advance all the SDGs

Effects of obstructive sleep apnoea risk on postoperative respiratory complications: protocol for a hospital-based registry study

Introduction: Obstructive sleep apnoea (OSA), the most common type of sleep-disordered breathing, is associated with significant immediate and long-term morbidity, including fragmented sleep and impaired daytime functioning, as well as more severe consequences, such as hypertension, impaired cognitive function and reduced quality of life. Perioperatively, OSA occurs frequently as a consequence of pre-existing vulnerability, surgery and drug effects. The impact of OSA on postoperative respiratory complications (PRCs) needs to be better characterised. As OSA is associated with significant comorbidities, such as obesity, pulmonary hypertension, myocardial infarction and stroke, it is unclear whether OSA or its comorbidities are the mechanism of PRCs. This project aims to (1) develop a novel prediction score identifying surgical patients at high risk of OSA, (2) evaluate the association of OSA risk on PRCs and (3) evaluate if pharmacological agents used during surgery modify this association. Methods: Retrospective cohort study using hospital-based electronic patient data and perioperative data on medications administered and vital signs. We will use data from Partners Healthcare clinical databases, Boston, Massachusetts. First, a prediction model for OSA will be developed using OSA diagnostic codes and polysomnography procedural codes as the reference standard, and will be validated by medical record review. Results of the prediction model will be used to classify patients in the database as high, medium or low risk of OSA, and we will investigate the effect of OSA on risk of PRCs. Finally, we will test whether the effect of OSA on PRCs is modified by the use of intraoperative pharmacological agents known to increase upper airway instability, including neuromuscular blockade, neostigmine, opioids, anaesthetics and sedatives. Ethics and dissemination The Partners Human Research Committee approved this study (protocol number: 2014P000218). Study results will be made available in the form of manuscripts for publication and presentations at national and international meetings

Differential Effects of Isoflurane and Propofol on Upper Airway Dilator Muscle Activity and Breathing

Background: Anesthesia impairs upper airway integrity, but recent data suggest that low doses of some anesthetics increase upper airway dilator muscle activity, an apparent paradox. The authors sought to understand which anesthetics increase or decrease upper airway dilator muscle activity and to study the mechanisms mediating the effect. Methods: The authors recorded genioglossus electromyogram, breathing, arterial blood pressure, and expiratory carbon dioxide in 58 spontaneously breathing rats at an estimated ED 50 (median effective dose) of isoflurane or propofol. The authors further evaluated the dose-response relations of isoflurane under different study conditions: (1) normalization of mean arterial pressure, or end-expiratory carbon dioxide; (2) bilateral lesion of the Kölliker-Fuse nucleus; and (3) vagotomy. To evaluate whether the markedly lower inspiratory genioglossus activity during propofol could be recovered by increasing flow rate, a measure of respiratory drive, the authors performed an additional set of experiments during hypoxia or hypercapnia. Results: In vagally intact rats, tonic and phasic genioglossus activity were markedly higher with isoflurane compared with propofol. Both anesthetics abolished the genioglossus negative pressure reflex. Inspiratory flow rate and anesthetic agent predicted independently phasic genioglossus activity. Isoflurane dose-dependently decreased tonic and increased phasic genioglossus activity, and increased flow rate, and its increasin

MAPKinase inhibition after failure of immune checkpoint blockade in patients with advanced melanoma – an evaluation of the multicenter prospective skin cancer registry ADOREG

Objectives: Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30-40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. Methods: Patients with advanced (non- resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. Results: We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy- three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival ( PFS) on ICI was 2.6 (95% CI 2.2-2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4 -7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2-20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. Conclusions: BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1- based immunotherapy. Rates of long- term benefit and survival in our study were similar to those reported for treatment-naive patients receiving first-line MAPKi

Protein tyrosine phosphatases expression during development of mouse superior colliculus

Protein tyrosine phosphatases (PTPs) are key regulators of different processes during development of the central nervous system. However, expression patterns and potential roles of PTPs in the developing superior colliculus remain poorly investigated. In this study, a degenerate primer-based reverse transcription-polymerase chain reaction (RT-PCR) approach was used to isolate seven different intracellular PTPs and nine different receptor-type PTPs (RPTPs) from embryonic E15 mouse superior colliculus. Subsequently, the expression patterns of 11 PTPs (TC-PTP, PTP1C, PTP1D, PTP-MEG2, PTP-PEST, RPTPJ, RPTPε, RPTPRR, RPTPσ, RPTPκ and RPTPγ) were further analyzed in detail in superior colliculus from embryonic E13 to postnatal P20 stages by quantitative real-time RT-PCR, Western blotting and immunohistochemistry. Each of the 11 PTPs exhibits distinct spatiotemporal regulation of mRNAs and proteins in the developing superior colliculus suggesting their versatile roles in genesis of neuronal and glial cells and retinocollicular topographic mapping. At E13, additional double-immunohistochemical analysis revealed the expression of PTPs in collicular nestin-positive neural progenitor cells and RC-2-immunoreactive radial glia cells, indicating the potential functional importance of PTPs in neurogenesis and gliogenesis

Lymphoepithelioma-like carcinoma of the vulva, an underrecognized entity? Case report with a single inguinal micrometastasis detected by sentinel node technique

This report describes an unusual EBV-negative lymphoepithelioma-like carcinoma of the vulva in a 73-year-old patient. The lesion was localised at the right minor labium and was resected by partial vulvectomy. A synchronous sentinel lymph node biopsy revealed a single micrometastasis in the right inguinal region, which prompted local radiotherapy. Follow-up nine months later showed only slight vulvar atrophy, without signs of local recurrence or distant metastases

Collins and Sivers asymmetries in muonproduction of pions and kaons off transversely polarised protons

Measurements of the Collins and Sivers asymmetries for charged pions and charged and neutral kaons produced in semi-inclusive deep-inelastic scattering of high energy muons off transversely polarised protons are presented. The results were obtained using all the available COMPASS proton data, which were taken in the years 2007 and 2010. The Collins asymmetries exhibit in the valence region a non-zero signal for pions and there are hints of non-zero signal also for kaons. The Sivers asymmetries are found to be positive for positive pions and kaons and compatible with zero otherwise. © 2015