International Committee on Mental Health in Cystic Fibrosis: Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus statements for screening and treating depression and anxiety

Studies measuring psychological distress in individuals with cystic fibrosis (CF) have found high rates of both depression and anxiety. Psychological symptoms in both individuals with CF and parent caregivers have been associated with decreased lung function, lower body mass index, worse adherence, worse health-related quality of life, more frequent hospitalisations and increased healthcare costs. To identify and treat depression and anxiety in CF, the CF Foundation and the European CF Society invited a panel of experts, including physicians, psychologists, psychiatrists, nurses, social workers, a pharmacist, parents and an individual with CF, to develop consensus recommendations for clinical care. Over 18 months, this 22-member committee was divided into four workgroups: Screening; Psychological Interventions; Pharmacological Treatments and Implementation and Future Research, and used the Population, Intervention, Comparison, Outcome methodology to develop questions for literature search and review. Searches were conducted in PubMed, PsychINFO, ScienceDirect, Google Scholar, Psychiatry online and ABDATA by a methodologist at Dartmouth. The committee reviewed 344 articles, drafted statements and set an 80% acceptance for each recommendation statement as a consensus threshold prior to an anonymous voting process. Fifteen guideline recommendation statements for screening and treatment of depression and anxiety in individuals with CF and parent caregivers were finalised by vote. As these recommendations are implemented in CF centres internationally, the process of dissemination, implementation and resource provision should be closely monitored to assess barriers and concerns, validity and use

Risk of thromboembolism in patients developing critical illness-associated atrial fibrillation

This is the author accepted manuscript. The final version is available from the Royal College of Physicians via the DOI in this record.Although common, the long-term significance of developing atrial fibrillation (AF) during a period of critical illness is unclear. We undertook a retrospective cohort analysis to assess the rate of thromboembolism (TE) in patients developing atrial fibrillation de novo during admission to our intensive care unit. 1955 patients were followed up (maximum follow-up 1276 days) for the occurrence of TE, of which 220 (11.3%) had developed AF or atrial flutter during their critical care admission. There were 11 TE events among the patients with new AF (0.053 events per patientyear), compared with 18 in the non-AF group (0.0059 events per patient-year). The unadjusted hazard ratio for TE in patients developing new AF compared with those not developing AF was 8.09 (95% CI 3.08 – 17.19, p<0.001). In patients admitted to critical care, the development of AF appears to be associated with a significantly increased risk of subsequent thromboembolism

Endothelin-1 mediates Aspergillus fumigatus induced airway inflammation and remodelling

BACKGROUND: Asthma is a chronic inflammatory condition of the airways and patients sensitised to airborne fungi such as Aspergillus fumigatus have more severe asthma. Thickening of the bronchial subepithelial layer is a contributing factor to asthma severity for which no current treatment exists. Airway epithelium acts as an initial defence barrier to inhaled spores, orchestrating an inflammatory response and contributing to subepithelial fibrosis. OBJECTIVE: We aimed to analyse the production of profibrogenic factors by airway epithelium in response to A. fumigatus, in order to propose novel anti-fibrotic strategies for fungal-induced asthma. METHODS: We assessed the induction of key profibrogenic factors, TGFβ1, TGFβ2, periostin and endothelin-1, by human airway epithelial cells and in mice exposed to A. fumigatus spores or secreted fungal factors. RESULTS: A. fumigatus specifically caused production of endothelin-1 by epithelial cells in vitro but not any of the other profibrogenic factors assessed. A. fumigatus also induced endothelin-1 in murine lungs, associated with extensive inflammation and airway wall remodelling. Using a selective endothelin-1 receptor antagonist, we demonstrated for the first time, that endothelin-1 drives many features of airway wall remodelling and inflammation elicited by A. fumigatus. CONCLUSION: Our findings are consistent with the hypothesis that elevated endothelin-1 levels contribute to subepithelial thickening and highlight this factor as a possible therapeutic target for difficult-to-treat fungal-induced asthma

LIGAND BASED PHARMACOPHORE MODELING, VIRTUAL SCREENING AND MOLECULAR DOCKING STUDIES TO DESIGN NOVEL PANCREATIC LIPASE INHIBITORS

Objective: To understand the essential structural features required for pancreatic lipase (PL) inhibitory activity and to design novel chemical entities, ligand-based pharmacophore modeling, virtual screening and docking studies were carried out.Methods: The pharmacophore model was generated based on 133 compounds with PL inhibitory activity using PHASE. An external test set and decoy dataset methods were applied to validate the hypothesis and to retrieve potential PL inhibitors. The generated hypothesis model was further subjected to virtual screening and molecular docking studies.Results: A five point pharmacophoric hypothesis model which consists of three hydrogen bond acceptor sites and two hydrophobic sites was developed. The generated pharmacophore gave significant 3D QSAR (three-dimensional Quantitative Structural Activity Relationship) model with r2 of 0.9389 and Q2 value of 0.4016. After database screening, five molecules were found to have better glide scores and binding interactions with the active site amino acid residues.Conclusion: As an outcome of this study, five hit molecules were suggested as potent PL inhibitors as they showed good glide scores as well as binding interactions with required active site amino acids. The five molecules obtained from this study may serve as potential leads for the development of promising anti-obesity agents.Â

Angle-dependence of quantum oscillations in YBa2Cu3O6.59 shows free spin behaviour of quasiparticles

Measurements of quantum oscillations in the cuprate superconductors afford a new opportunity to assess the extent to which the electronic properties of these materials yield to a description rooted in Fermi liquid theory. However, such an analysis is hampered by the small number of oscillatory periods observed. Here we employ a genetic algorithm to globally model the field, angular, and temperature dependence of the quantum oscillations observed in the resistivity of YBa2Cu3O6.59. This approach successfully fits an entire data set to a Fermi surface comprised of two small, quasi-2-dimensional cylinders. A key feature of the data is the first identification of the effect of Zeeman splitting, which separates spin-up and spin-down contributions, indicating that the quasiparticles in the cuprates behave as nearly free spins, constraining the source of the Fermi surface reconstruction to something other than a conventional spin density wave with moments parallel to the CuO2 planes.Comment: 8 pages, 4 figure

Current practice in methodology and reporting of the sample size calculation in randomised trials of hip and knee osteoarthritis: a protocol for a systematic review

Background A key aspect of the design of randomised controlled trials (RCTs) is determining the sample size. It is important that the trial sample size is appropriately calculated. The required sample size will differ by clinical area, for instance, due to the prevalence of the condition and the choice of primary outcome. Additionally, it will depend upon the choice of target difference assumed in the calculation. Focussing upon the hip and knee osteoarthritis population, this study aims to systematically review how the trial size was determined for trials of osteoarthritis, on what basis, and how well these aspects are reported. Methods Several electronic databases (Medline, Cochrane library, CINAHL, EMBASE, PsycINFO, PEDro and AMED) will be searched to identify articles on RCTs of hip and knee osteoarthritis published in 2016. Articles will be screened for eligibility and data extracted independently by two reviewers. Data will be extracted on study characteristics (design, population, intervention and control treatments), primary outcome, chosen sample size and justification, parameters used to calculate the sample size (including treatment effect in control arm, level of variability in primary outcome, loss to follow-up rates). Data will be summarised across the studies using appropriate summary statistics (e.g. n and %, median and interquartile range). The proportion of studies which report each key component of the sample size calculation will be presented. The reproducibility of the sample size calculation will be tested. Discussion The findings of this systematic review will summarise the current practice for sample size calculation in trials of hip and knee osteoarthritis. It will also provide evidence on the completeness of the reporting of the sample size calculation, reproducibility of the chosen sample size and the basis for the values used in the calculation. Trial registration As this review was not eligible to be registered on PROSPERO, the summary information was uploaded to Figshare to make it publicly accessible in order to avoid unnecessary duplication amongst other benefits (https://doi.org/10.6084/m9.figshare.5009027.v1); Registered January 17, 2017

Treatment compliance and effectiveness of a cognitive behavioural intervention for low back pain : a complier average causal effect approach to the BeST data set

Background: Group cognitive behavioural intervention (CBI) is effective in reducing low-back pain and disability in comparison to advice in primary care. The aim of this analysis was to investigate the impact of compliance on estimates of treatment effect and to identify factors associated with compliance. Methods: In this multicentre trial, 701 adults with troublesome sub-acute or chronic low-back pain were recruited from 56 general practices. Participants were randomised to advice (control n = 233) or advice plus CBI (n = 468). Compliance was specified a priori as attending a minimum of three group sessions and the individual assessment. We estimated the complier average causal effect (CACE) of treatment. Results: Comparison of the CACE estimate of the mean treatment difference to the intention-to-treat (ITT) estimate at 12 months showed a greater benefit of CBI amongst participants compliant with treatment on the Roland Morris Questionnaire (CACE: 1.6 points, 95% CI 0.51 to 2.74; ITT: 1.3 points, 95% CI 0.55 to 2.07), the Modified Von Korff disability score (CACE: 12.1 points, 95% CI 6.07 to 18.17; ITT: 8.6 points, 95% CI 4.58 to 12.64) and the Modified von Korff pain score (CACE: 10.4 points, 95% CI 4.64 to 16.10; ITT: 7.0 points, 95% CI 3.26 to 10.74). People who were non-compliant were younger and had higher pain scores at randomisation. Conclusions: Treatment compliance is important in the effectiveness of group CBI. Younger people and those with more pain are at greater risk of non-compliance

Saleability of Anti-malarials in Private Drug Shops in Muheza, Tanzania: A Baseline study in an era of assumed Artemisinin Ccombination Therapy (ACT).

Artemether-lumefantrine (ALu) replaced sulphadoxine-pymimethamine (SP) as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT) is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. All drug shops selling prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. All surveyed drug shops illicitly sold SP and quinine (QN), and legally amodiaquine (AQ). Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%), QN (11%) and ACT (2%). In community practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp strategy. Further studies are recommended to find out barriers for ACT utilization and preference for self-medication and to train private drug dispensers

A Spectral Line Survey from 138.3 to 150.7 GHZ toward Orion-KL

We present the results of a spectral line survey from 138.3 to 150.7 GHz toward Orion-KL. The observations were made using the 14 m radio telescope of Taeduk Radio Astronomy Observatory. Typical system temperatures were between 500 and 700 K, with the sensitivity between $0.02 - 0.06$ K in units of $\rm T_A^*$. A total of 149 line spectra are detected in this survey. Fifty lines have been previously reported, however we find 99 new detections. Among these new lines, 32 are `unidentified', while 67 are from molecular transitions with known identifications. There is no detection of H or He recombination lines. The identified spectra are from a total of 16 molecular species and their isotopic variants. In the range from 138.3 to 150.7 GHz, the strongest spectral line is the J=3-2 transition of CS molecule, followed by transitions of the $\rm H_2CO$, $\rm CH_3OH$, $\rm CH_3CN$, and $\rm SO_2$. Spectral lines from the large organic molecules such as $\rm CH_3OH$, $\rm CH_3OCH_3$, $\rm HCOOCH_3$, $\rm C_2H_5CN$ and $\rm CH_3CN$ are prominent; with 80 % of the identified lines arising from transitions of these molecules. The rotational temperatures and column densities are derived using the standard rotation diagram analysis for $\rm CH_3OH$ ($\rm ^{13}CH_3OH$), $\rm HCOOCH_3$, $\rm CH_3CN$ and $\rm SO_2$ with $\rm 10\sim 270 K$ and $\rm 0.2\sim 20\times 10^{15} cm^{-2}$. These estimates are fairly comparable to the values for the same molecule in other frequency regions by other studies.Comment: 10 figures, 2 tex files for a manuscript and tables, accepted to Ap

New strategies to measure intracellular sodium concentrations

Fluorescent ion indicators are widely used to measure ion concentrations in living cells. However, despite considerable efforts in synthesizing new compounds, no ratiometric sodium indicator is available that can be excited at visible wavelengths. Ratiometric indicators have an advantage in that measured fluorescence intensities can be corrected for fluctuations of the indicator concentration and the illumination intensity, which is not possible when non-ratiometric indicators are used. One way to circumvent this problem is to measure fluorescence lifetimes, which are independent of these factors. Another way to overcome the disadvantages of a non-ratiometric indicator dye is to embed it, together with a reference dye, into nanoparticles. By relating the indicator fluorescence to the fluorescence of the reference dye, inhomogeneities in the nanosensor concentration or the illumination intensity can be cancelled out reliably. In this study we compare the benefits and drawbacks of these approaches. © 2010 Copyright SPIE - The International Society for Optical Engineering