ERS technical standards for using type III devices (limited channel studies) in the diagnosis of sleep disordered breathing in adults and children.

For more than three decades, type III devices have been used in the diagnosis of sleep disordered breathing in supervised as well as unsupervised settings. They have satisfactory positive and negative predictive values for detecting obstructive and central sleep apnoea in populations with moderately high pre-test probability of symptoms associated with these events. However, standardisation of commercially available type III devices has never been undertaken and the technical specifications can vary widely. None have been subjected to the same rigorous processes as most other diagnostic modalities in the medical field. Although type III devices do not include acquisition of electroencephalographic signals overnight, the minimum number of physical sensors required to allow for respiratory event scoring using standards outlined by the American Academy of Sleep Medicine remains debatable. This technical standard summarises data on type III studies published since 2007 from multiple perspectives in both adult and paediatric sleep practice. Most importantly, it aims to provide a framework for considering current type III device limitations in the diagnosis of sleep disordered breathing while raising research- and practice-related questions aimed at improving our use of these devices in the present and future.

Lead optimisation of selective non-zinc binding inhibitors of MMP13. Part 2.

Directed screening has identified a novel series of non-zinc binding MMP13 inhibitors that possess good levels of activity whilst demonstrating excellent selectivity over related MMPs. A lead optimisation campaign has delivered compounds with enhanced MMP13 potency, good selectivity and acceptable bioavailability profiles leading to a predicted twice-a-day dosing regimen in man.

Lead optimisation of pyrazoles as novel FPR1 antagonists.

Optimisation of a series of pyrazole inhibitors of the human FPR1 receptor has been achieved. The use of an in vitro media loss assay was utilised to identify sub-series with more robust DMPK profiles. These were subsequently improved to generate analogues with attractive overall profiles.

Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin K inhibitors free from hERG channel inhibition.

The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.

Effect of lipophilicity modulation on inhibition of human rhinovirus capsid binders.

To try and generate broad spectrum human rhinovirus VP1 inhibitors with more attractive physicochemical, DMPK and safety profiles, we explored the current SAR of known VP1 compounds. This lead to the identification of specific structural regions where reduction in polarity can be achieved, so guiding chemistry to analogues with significantly superior profiles to previously reported inhibitors.

Discovery of small molecule human FPR1 receptor antagonists.

The identification of two novel series of formyl peptide receptor 1 (FPR1) antagonists are reported, represented by methionine benzimidazole 6 and diamide 7. Both series specifically inhibited the binding of labelled fMLF to hrFPR1 and selectively antagonized FPR1 function in human neutrophils, making them useful in vitro validation tools for the target.

Discovery of pyrazoles as novel FPR1 antagonists.

A series of pyrazole inhibitors of the human FPR1 receptor have been identified from high throughput screening. The compounds demonstrate potent inhibition in human neutrophils and attractive physicochemical and in vitro DMPK profiles to be of further interest.

Selective non zinc binding inhibitors of MMP13.

Directed screening has identified a novel series of MMP13 inhibitors that possess good levels of activity whilst possessing excellent selectivity over related MMPs. The binding mode of the series has been solved by co-crystallisation and demonstrates an interesting mode of inhibition without interaction with the catalytic zinc atom.

The influence of duration of fluid abstinence on hypotension during propofol induction.

BACKGROUND: Prolonged preoperative fasting might be expected to exacerbate hypotension during the induction of general anesthesia. We aimed to establish whether the duration of preoperative abstinence from fluids independently contributed to arterial blood pressure changes and dosage requirements during propofol induction. METHODS: We prospectively recruited 130 ASA I or II nonhypertensive patients, ages 18 to 65 years scheduled for surgery under general anesthesia. Standard physiological and electroencephalographic bispectral index (BIS) monitoring was applied to each patient. Intravenous propofol infusion was commenced at 40 mg · kg(-1) · h(-1) and reduced to 8 mg · kg(-1) · h(-1) when the BIS decreased to 50. Frequent cardiovascular data were collected for 15 minutes. The primary endpoint was maximal percentage decrease from baseline mean arterial blood pressure (max%ΔMAP). The secondary endpoint was the propofol dose at which BIS decreased to 50 (PDBIS50). Univariate linear regression and then multivariate linear regression was used to analyze the associations between potential predictors, including fasting time, and these 2 endpoints. RESULTS: Mean fluid abstinence time was 694 minutes (range: 115 to 1263 minutes). Unstandardized regression coefficients (95% confidence intervals [CIs]) for fluid abstinence (minutes) versus max%ΔMAP (%) and PDBIS50 (mg) were, respectively, 0.003% (-0.002% to + 0.009%) and 0.021 mg (-0.017 mg to + 0.059 mg). On adjusting for other, significant predictors in a multivariate model and applying type II sum of squares tests, the corresponding values were -0.0001% (-0.004% to + 0.004%, P = 0.94) and -0.006 mg (-0.039 mg to + 0.026 mg, P = 0.70). The effect of a 1-hour increase in fluid abstinence on max%ΔMAP was therefore -0.01% (-0.26% to + 0.24%) and on PDBIS50, -0.38 mg (-2.34 mg to + 1.58 mg). CONCLUSION: When propofol is infused rapidly for induction of anesthesia in healthy adults younger than 65 years, the duration of preoperative fluid abstinence does not appear to affect MAP or propofol dose requirements.

Introduction of bispectral index monitoring in a district general hospital operating suite: a prospective audit of clinical and economic effects.

BACKGROUND AND OBJECTIVE: Randomized controlled trials have shown several beneficial effects of intraoperative bispectral index monitoring. We conducted a prospective audit to determine whether these could be replicated in everyday clinical practice. METHODS: Recovery characteristics and drug costs from two 4-week periods were compared, immediately before (phase 1, n = 427 patients) and after (phase 2, n = 299 patients) the introduction of bispectral index monitoring in the main operating theatres of a district general hospital. RESULTS: Demographic and intraoperative variables for the two patient groups were similar. Nausea (P = 0.002), vomiting (P = 0.008) and antiemetic use (P = 0.001) in the postanaesthesia care unit all decreased in phase 2, though unrelated changes in antiemetic policy may have been partly responsible. Recovery time was unaffected. Drug costs decreased in phase 2 by an average of 0.86 pounds per patient. The cost of each semi-reusable sensor was 6.60 pounds. CONCLUSION: In a prospective audit, benefits of intraoperative bispectral index monitoring in our district general hospital were not seen to the same degree as in randomized controlled trials elsewhere.

A simple in vitro assay for assessing the reactivity of nitrile containing compounds.

A quantitative assay involving the reaction of nitriles with glutathione and cysteine has been used as a simple in vitro screen to assess potential toxicity risk of candidate compounds in drug discovery. Studies have indicated that, when benchmarked with selected compounds, the reaction of the nitriles with glutathione can provide a useful tool for deciding whether or not to progress compounds in the absence of radiolabelling studies.

5-Aminopyrimidin-2-ylnitriles as cathepsin K inhibitors.

A series of pyrimidine nitrile inhibitors of Cathepsin K with reduced glutathione reactivity has been identified and Molecular Core Matching (MoCoM) has been used to quantify the effect of an amino substituent at C5.

Design of selective Cathepsin inhibitors.

A number of molecular recognition features have been exploited in structure-based design of selective Cathepsin inhibitors.

Novel inhibitors of the alphavbeta3 integrin--lead identification strategy.

A novel approach to inhibition of the alphavbeta3 integrin is described, which uses compounds designed to generate nM potency without using the arginine binding site.

Dipeptidyl nitrile inhibitors of Cathepsin L.

A series of potent Cathepsin L inhibitors with good selectivity with respect to other cysteine Cathepsins is described and SAR is discussed with reference to the crystal structure of a protein-ligand complex.

Phosphorus retention and internal loading in the Bay of Quinte, Lake Ontario, using diagenetic modelling.

Internal phosphorus (P) loading significantly contributes to hysteresis in ecosystem response to nutrient remediation, but the dynamics of sediment P transformations are often poorly characterized. Here, we applied a reaction-transport diagenetic model to investigate sediment P dynamics in the Bay of Quinte, a polymictic, spatially complex embayment of Lake Ontario, (Canada). We quantified spatial and temporal variability of sediment P binding forms and estimated P diffusive fluxes and sediment P retention in different parts of the bay. Our model supports the notion that diagenetic recycling of redox sensitive and organic bound P forms drive sediment P release. In the recent years, summer sediment P diffusive fluxes varied in the range of 3.2-3.6 mg P m-2 d-1 in the upper bay compared to 1.5 mg P m-2 d-1 in the middle-lower bay. Meanwhile sediment P retention ranged between 71% and 75% in the upper and middle-lower bay, respectively. The reconstruction of temporal trends of internal P loading in the past century, suggests that against the backdrop of reduced external P inputs, sediment P exerts growing control over the lake nutrient budget. Higher sediment P diffusive fluxes since mid-20th century with particular increase in the past 20 years in the shallower upper basins, emphasize limited sediment P retention potential and suggest prolonged ecosystem recovery, highlighting the importance of ongoing P control measures.

Cerebral palsy and sleep disordered breathing.

Despite the known correlation between neurodisability and sleep disordered breathing, cases are still missed http://ow.ly/2pNS305Kll3.

Delineation of the role of nutrient variability and dreissenids (Mollusca, Bivalvia) on phytoplankton dynamics in the Bay of Quinte, Ontario, Canada.

The Bay of Quinte, a Z-shaped embayment at the northeastern end of Lake Ontario, has a long history of eutrophication problems primarily manifested as spatially extensive algal blooms and predominance of toxic cyanobacteria. The purpose of this study was to identify the structural changes of the phytoplankton community induced by two environmental alterations: point-source phosphorus (P) loading reduction in the late 1970s and establishment of dreissenid mussels in the mid-1990s. A combination of statistical techniques was used to draw inference about compositional shifts of the phytoplankton assemblage, the consistency of the seasonal succession patterns along with the mechanisms underlying the algal biovolume variability in the Bay of Quinte over the past three decades. Based on a number of diversity and similarity indices, the algal assemblages in the upper and middle segments of the Bay are distinctly different from those typically residing in the outer segments. Our analysis also identified significant differences among the phytoplankton communities, representing the pre- and post-P control as well as the pre- and post-dreissenid invasion periods. Recent shifts in phytoplankton community composition were mainly associated with increased frequency of occurrence of toxin-producing Microcystis outbreaks and reduced biovolume of N2 fixers, such as Aphanizomenon and Anabaena. Bayesian hierarchical models were developed to elucidate the importance of different abiotic factors (light attenuation, water temperature, phosphorus, and ammonium) on total cyanobacteria, Microcystis, Aphanizomenon, and Anabaena relative biovolume. Our modelling exercise suggests that there is significant spatial heterogeneity with respect to the role of the factors examined, and thus total phosphorus alone cannot always explain the year-to-year variability of cyanobacteria succession patterns in the system. The lessons learned from the present analysis will be helpful to the water quality criteria setting process and could influence the management decisions in order to delist the system as an Area of Concern.