Structural Insights from Recent CB1 X-Ray Crystal Structures

Over the past 2 years, X-ray crystal structures of the antagonist- and agonist-bound CB1 receptor have been reported. Such structures are expected to accelerate progress in the understanding of CB1 and should provide an exceptional starting point for structure-based drug discovery. This chapter examines the consistency of these X-ray structures with the CB1 experimental literature, including mutation, NMR and covalent labeling studies. These comparisons reveal discrepancies between this literature and the TMH1-2-3 region of each CB1 crystal structure. The chapter also examines crystal packing issues with each X-ray structure and shows that the discrepancies with the experimental literature can be attributed to crystal packing problems that force the N-terminus deep in the binding pocket of the two inactive state structures and force TMH2 to bend at G2.53/S2.54 and invade the binding pocket in the activated state structure. Revision is advisable before these structures are used for structure-based drug discovery

Application of oxygen saturation variability analysis for the detection of exacerbation in individuals with COPD: A proof-of-concept study

BACKGROUND: Individuals with chronic obstructive pulmonary disease (COPD) commonly experience exacerbations, which may require hospital admission. Early detection of exacerbations, and therefore early treatment, could be crucial in preventing admission and improving outcomes. Our previous research has demonstrated that the pattern analysis of peripheral oxygen saturation (Sp O2 ) fluctuations provides novel insights into the engagement of the respiratory control system in response to physiological stress (hypoxia). Therefore, this pilot study tested the hypothesis that the pattern of Sp O2 variations in overnight recordings of individuals with COPD would distinguish between stable and exacerbation phases of the disease. METHODS: Overnight pulse oximetry data from 11 individuals with COPD, who exhibited exacerbation after a period of stable disease, were examined. Stable phase recordings were conducted overnight and one night prior to exacerbation recordings were also analyzed. Pattern analysis of Sp O2 variations was carried examined using sample entropy (for assessment of irregularity), the multiscale entropy (complexity), and detrended fluctuation analysis (self-similarity). RESULTS: Sp O2 variations displayed a complex pattern in both stable and exacerbation phases of COPD. During an exacerbation, Sp O2 entropy increased (p = 0.029) and long-term fractal-like exponent (α2) decreased (p = 0.002) while the mean and standard deviation of Sp O2 time series remained unchanged. Through ROC analyses, Sp O2 entropy and α2 were both able to classify the COPD phases into either stable or exacerbation phase. With the best positive predictor value (PPV) for sample entropy (PPV = 70%) and a cut-off value of 0.454. While the best negative predictor value (NPV) was α2 (NPV = 78%) with a cut-off value of 1.00. CONCLUSION: Alterations in Sp O2 entropy and the fractal-like exponent have the potential to detect exacerbations in COPD. Further research is warranted to examine if Sp O2 variability analysis could be used as a novel objective method of detecting exacerbations

The clinical utility of forced oscillation technique during hospitalisation in patients with exacerbation of COPD

Background: Forced Oscillation Technique (FOT) is an innovative tool to measure within-breath reactance at 5 Hz (ΔXrs5Hz) but its feasibility and utility in acute exacerbations of COPD (AECOPD) is understudied. Methods: A prospective observational study was conducted in 82 COPD patients admitted due to AECOPD. FOT indices were measured and the association between these indices and spirometry, peak inspiratory flow rate, blood inflammatory biomarkers and patient-reported outcomes including assessment of dyspnoea, quality of life, anxiety and depression and frailty at admission and discharge were explored. Results: All patients were able to perform FOT in both sitting and supine position. The prevalence of expiratory flow limitation (EFL) in the upright position was 39% (32 out of 82) and increased to 50% (41 out of 82) in the supine position. EFL (measured by ΔXrs5Hz) and resistance at 5 Hz (Rrs5Hz) negatively correlated with forced expiratory volume in 1 s (FEV1); those with EFL had lower FEV1 (0.74±0.30 versus 0.94±0.36 L, p = 0.01) and forced vital capacity (1.7±0.55 versus 2.1±0.63 L, p = 0.009) and higher body mass index (27 (21-36) versus 23 (19-26) kg·m-2, p = 0.03) compared to those without EFL. During recovery from AECOPD, changes in EFL were observed in association with improvement in breathlessness. Conclusion: FOT was easily used to detect EFL during hospitalisation due to AECOPD. The prevalence of EFL increased when patients moved from a seated to a supine position and EFL was negatively correlated with airflow limitation. Improvements in EFL were associated with a reduction in breathlessness. FOT is of potential clinical value by providing a noninvasive, objective and effort-independent technique to measure lung function parameters during AECOPD requiring hospital admission

Nurse staffing levels revisited: a consideration of key issues in nurse staffing levels and skill mix research.

AIM: This paper revisits the published evidence relating to how nurse staffing levels impact on patient, nurse and service outcomes and considers the implications of this body of research for nurse managers in their quest to determine optimum nursing numbers. BACKGROUND: Within the context of the recognized global nursing shortage and particular local pressures within international health services, questions of appropriate nurse staffing levels and skill mix are once again becoming increasingly important. It would seem that the determination of optimum nurse staffing levels and skill mix is a central issue in relation to health service governance, service user involvement, as well as in the recruitment, retention and well-being of nursing staff across the service sectors. METHODS: A review of published evidence was carried out, applying key principles of the systematic method, in order to facilitate the identification of current factors and issues in nurse staffing levels research. The review did not seek to address a specific research question. The search covered 10 years from 1998 to 2008 and identified more than 500 relevant papers, giving a wide international perspective. KEY ISSUES: The majority of research in the field relates to the acute service sector and there are considerable similarities in issues that transcend international boundaries. Much of the research focuses on the impact on patients and nurses of 'poor' nurse staffing levels. More recent studies have explored the impact of nurse staffing levels on the service organization itself. However, while there may be an association between models of nurse staffing and outcomes, there is insufficient evidence to establish a causal relationship between these factors. In this context it is perhaps time to reconsider how nursing outcomes are defined and measured. IMPLICATIONS FOR NURSING MANAGEMENT AND CONCLUSION: Nurse managers, commissioners of services and workforce planners need to be cognisant of key issues and analyses in the consideration of nurse staffing levels. Not least of these is the need for a healthy degree of caution regarding the supposed objectivity, scientific basis, or evidence base, for rational calculation of optimum nurse staffing levels

Intersession repeatability of acoustic rhinometry measurements in healthy volunteers

Acoustic rhinometry is a rapid, reliable and non-invasive technique for the evaluation of conditions associated with impaired nasal patency. This study aimed to examine the intersession repeatability of acoustic rhinometry measurements of unilateral and combined nasal parameters in a group of healthy volunteers

Test-retest reliability of capability measurement in the UK general population

Although philosophically attractive, it may be difficult, in practice, to measure individuals' capabilities (what they are able to do in their lives) as opposed to their functionings (what they actually do). To examine whether capability information could be reliably self-reported, we administered a measure of self-reported capability (the Investigating Choice Experiments Capability Measure for Adults, ICECAP-A) on two occasions, 2 weeks apart, alongside a self-reported health measure (the EuroQol Five Dimensional Questionnaire with 3 levels, EQ-5D-3L). We found that respondents were able to report capabilities with a moderate level of consistency, although somewhat less reliably than their health status. The more socially orientated nature of some of the capability questions may account for the difference. © 2014 The Authors Health Economics Published by John Wiley & Sons Ltd

Genome sequence of the entomopathogenic Serratia entomophila isolate 626 and characterisation of the species specific itaconate degradation pathway

Background: Isolates of Serratia entomophila and S. proteamaculans (Yersiniaceae) cause disease specifc to the endemic New Zealand pasture pest, Costelytra giveni (Coleoptera: Scarabaeidae). Previous genomic profling has shown that S. entomophila isolates appear to have conserved genomes and, where present, conserved plasmids. In the absence of C. giveni larvae, S. entomophila prevalence reduces in the soil over time, suggesting that S. entomophila has formed a host-specifc relationship with C. giveni. To help define potential genetic mechanisms driving retention of the chronic disease of S. entomophila, the genome of the isolate 626 was sequenced, enabling the identifcation of unique chromosomal properties, and defining the gain/loss of accessory virulence factors relevant to pathogenicity to C. giveni larvae. Results: We report the complete sequence of S. entomophila isolate 626, a causal agent of amber disease in C. giveni larvae. The genome of S. entomophila 626 is 5,046,461 bp, with 59.1% G+C content and encoding 4,695 predicted CDS. Comparative analysis with five previously sequenced Serratia species, S. proteamaculans 336X, S. marcescens Db11, S. nematodiphila DH-S01, S. grimesii BXF1, and S. ficaria NBRC 102596, revealed a core of 1,165 genes shared. Further comparisons between S. entomophila 626 and S. proteamaculans 336X revealed fewer predicted phage-like regions and genomic islands in 626, suggesting less horizontally acquired genetic material. Genomic analyses revealed the presence of a four-gene itaconate operon, sharing a similar gene order as the Yersinia pestis ripABC complex. Assessment of a constructed 626::RipC mutant revealed that the operon confer a possible metabolic advantage to S. entomophila in the initial stages of C. giveni infection. Conclusions: Evidence is presented where, relative to S. proteamaculans 336X, S. entomophila 626 encodes fewer genomic islands and phages, alluding to limited horizontal gene transfer in S. entomophila. Bioassay assessments of a S. entomophila-mutant with a targeted mutation of the itaconate degradation region unique to this species, found the mutant to have a reduced capacity to replicate post challenge of the C. giveni larval host, implicating the itaconate operon in establishment within the host

Once Daily Versus Overnight and Symptom Versus Physiological Monitoring to Detect Exacerbations of Chronic Obstructive Pulmonary Disease: Pilot Randomized Controlled Trial

Background: Earlier detection of chronic obstructive pulmonary disease (COPD) exacerbations may facilitate more rapid treatment with reduced risk of hospitalization. Changes in pulse oximetry may permit early detection of exacerbations. We hypothesized that overnight pulse oximetry would be superior to once-daily monitoring for the early detection of exacerbations. / Objective: This study aims to evaluate whether measuring changes in heart rate and oxygen saturation overnight is superior to once-daily monitoring of both parameters and to assess symptom changes in facilitating earlier detection of COPD exacerbations. / Methods: A total of 83 patients with COPD were randomized to once-daily or overnight pulse oximetry. Both groups completed the COPD assessment test questionnaire daily. The baseline mean and SD for each pulse oximetry variable were calculated from 14 days of stable monitoring. Changes in exacerbation were expressed as Z scores from this baseline. / Results: The mean age of the patients was 70.6 (SD 8.1) years, 52% (43/83) were female, and the mean FEV1 was 53.0% (SD 18.5%) predicted. Of the 83 patients, 27 experienced an exacerbation. Symptoms were significantly elevated above baseline from 5 days before to 12 days after treatment initiation. Day-to-day variation in pulse oximetry during the stable state was significantly less in the overnight group than in the once-daily group. There were greater relative changes at exacerbation in heart rate than oxygen saturation. An overnight composite score of change in heart rate and oxygen saturation changed significantly from 7 days before initiation of treatment for exacerbation and had a positive predictive value for exacerbation of 91.2%. However, this was not statistically better than examining changes in symptoms alone. / Conclusions: Overnight pulse oximetry permits earlier detection of COPD exacerbations compared with once-daily monitoring. Monitoring physiological variables was not superior to monitoring symptoms, and the latter would be a simpler approach, except where there is a need for objective verification of exacerbations. / Trial Registration: ClinicalTrials.gov NCT03003702; https://clinicaltrials.gov/ct2/show/NCT0300370

Disease Progression Modelling in Chronic Obstructive Pulmonary Disease (COPD)

RATIONALE: The decades-long progression of Chronic Obstructive Pulmonary Disease (COPD) renders identifying different trajectories of disease progression challenging. OBJECTIVES: To identify subtypes of COPD patients with distinct longitudinal progression patterns using a novel machine-learning tool called "Subtype and Stage Inference (SuStaIn)", and to evaluate the utility of SuStaIn for patient stratification in COPD. METHODS: We applied SuStaIn to cross-sectional CT imaging markers in 3698 GOLD1-4 patients and 3479 controls from the COPDGene study to identify COPD patient subtypes. We confirmed the identified subtypes and progression patterns using ECLIPSE data. We assessed the utility of SuStaIn for patient stratification by comparing SuStaIn subtypes and stages at baseline with longitudinal follow-up data. MEASUREMENTS AND MAIN RESULTS: We identified two trajectories of disease progression in COPD: a "Tissue→Airway" subtype (n=2354, 70.4%) in which small airway dysfunction and emphysema precede large-airway wall abnormalities, and an "Airway→Tissue" subtype (n=988, 29.6%) in which large-airway wall abnormalities precede emphysema and small airway dysfunction. Subtypes were reproducible in ECLIPSE. Baseline stage in both subtypes correlated with future FEV1/FVC decline (r=-0.16 (p<0.001) in the Tissue→Airway group; r=-0.14 (p=0.011) in the Airway→Tissue group). SuStaIn placed 30% of smokers with normal lung function at non-baseline stages suggesting imaging changes consistent with early COPD. Individuals with early changes were 2.5 times more likely to meet COPD diagnostic criteria at follow-up. CONCLUSIONS: We demonstrate two distinct patterns of disease progression in COPD using SuStaIn, likely representing different endotypes. One-third of healthy smokers have detectable imaging changes, suggesting a new biomarker of 'early COPD'