Macrolide antibiotics for bronchiectasis

Background Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the smaller airways. Bacterial colonisation of the damaged airways leads to chronic cough and sputum production, often with breathlessness and further structural damage to the airways. Long-term macrolide antibiotic therapy may suppress bacterial infection and reduce inflammation, leading to fewer exacerbations, fewer symptoms, improved lung function, and improved quality of life. Further evidence is required on the efficacy of macrolides in terms of specific bacterial eradication and the extent of antibiotic resistance. Objectives To determine the impact of macrolide antibiotics in the treatment of adults and children with bronchiectasis. Search methods We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted all searches on 18 January 2018. Selection criteria We included randomised controlled trials (RCTs) of at least four weeks' duration that compared macrolide antibiotics with placebo or no intervention for the long-term management of stable bronchiectasis in adults or children with a diagnosis of bronchiectasis by bronchography, plain film chest radiograph, or high-resolution computed tomography. We excluded studies in which participants had received continuous or high-dose antibiotics immediately before enrolment or before a diagnosis of cystic fibrosis, sarcoidosis, or allergic bronchopulmonary aspergillosis. Our primary outcomes were exacerbation, hospitalisation, and serious adverse events. Data collection and analysis Two review authors independently screened the titles and abstracts of 103 records. We independently screened the full text of 40 study reports and included 15 trials from 30 reports. Two review authors independently extracted outcome data and assessed risk of bias for each study. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures as expected by Cochrane. Main results We included 14 parallel-group RCTs and one cross-over RCT with interventions lasting from 8 weeks to 24 months. Of 11 adult studies with 690 participants, six used azithromycin, four roxithromycin, and one erythromycin. Four studies with 190 children used either azithromycin, clarithromycin, erythromycin, or roxithromycin. We included nine adult studies in our comparison between macrolides and placebo and two in our comparison with no intervention. We included one study with children in our comparison between macrolides and placebo and one in our comparison with no intervention. In adults, macrolides reduced exacerbation frequency to a greater extent than placebo (OR 0.34, 95% confidence interval (CI) 0.22 to 0.54; 341 participants; three studies; I2 = 65%; moderate-quality evidence). This translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 8). Data show no differences in exacerbation frequency between use of macrolides (OR 0.31, 95% CI 0.08 to 1.15; 43 participants; one study; moderate-quality evidence) and no intervention. Macrolides were also associated with a significantly better quality of life compared with placebo (MD -8.90, 95% CI -13.13 to -4.67; 68 participants; one study; moderate-quality evidence). We found no evidence of a reduction in hospitalisations (OR 0.56, 95% CI 0.19 to 1.62; 151 participants; two studies; I2 = 0%; low-quality evidence), in the number of participants with serious adverse events, including pneumonia, respiratory and non-respiratory infections, haemoptysis, and gastroenteritis (OR 0.49, 95% CI 0.20 to 1.23; 326 participants; three studies; I2 = 0%; low-quality evidence), or in the number experiencing adverse events (OR 0.83, 95% CI 0.51 to 1.35; 435 participants; five studies; I2 = 28%) in adults with macrolides compared with placebo. In children, there were no differences in exacerbation frequency (OR 0.40, 95% CI 0.11 to 1.41; 89 children; one study; low-quality evidence); hospitalisations (OR 0.28, 95% CI 0.07 to 1.11; 89 children; one study; low-quality evidence), serious adverse events, defined within the study as exacerbations of bronchiectasis or investigations related to bronchiectasis (OR 0.43, 95% CI 0.17 to 1.05; 89 children; one study; low-quality evidence), or adverse events (OR 0.78, 95% CI 0.33 to 1.83; 89 children; one study), in those receiving macrolides compared to placebo. The same study reported an increase in macrolide-resistant bacteria (OR 7.13, 95% CI 2.13 to 23.79; 89 children; one study), an increase in resistance to Streptococcus pneumoniae (OR 13.20, 95% CI 1.61 to 108.19; 89 children; one study), and an increase in resistance to Staphylococcus aureus (OR 4.16, 95% CI 1.06 to 16.32; 89 children; one study) with macrolides compared with placebo. Quality of life was not reported in the studies with children. Authors' conclusions Long-term macrolide therapy may reduce the frequency of exacerbations and improve quality of life, although supporting evidence is derived mainly from studies of azithromycin, rather than other macrolides, and predominantly among adults rather than children. However, macrolides should be used with caution, as limited data indicate an associated increase in microbial resistance. Macrolides are associated with increased risk of cardiovascular death and other serious adverse events in other populations, and available data cannot exclude a similar risk among patients with bronchiectasis

Unitarity Meets Channel-Duality for Rolling / Decaying D-Branes

Investigations for decay of unstable D-brane and rolling of accelerated D-brane dynamics have revealed that various proposed prescriptions give different result for spectral amplitudes and observables. Here, we study them with particular attention to unitarity and open-closed channel duality. From "ab initio" derivation in the open string channel, both in Euclidean and Lorentzian worldsheet approaches, we find heretofore overlooked contribution to the spectral amplitudes and obervables. The contribution is fortuitously absent for decay of unstable D-brane, but is present for rolling of accelerated D-brane. We finally show that the contribution is imperative for ensuring unitarity and optical theorem at each order in string loop expansion.Comment: Latex, 28 pages, 2 figures (colored

HOPX functions as a tumour suppressor in head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is generalized term that encompasses a diverse group of cancers that includes tumours of the oral cavity (OSCC), oropharynx (OPSCC) and nasopharynx (NPC). Genetic alterations that are common to all HNSCC types are likely to be important for squamous carcinogenesis. In this study, we have investigated the role of the homeodomain-only homeobox gene, HOPX, in the pathogenesis of HNSCC. We show that HOPX mRNA levels are reduced in OSCC and NPC cell lines and tissues and there is a general reduction of HOPX protein expression in these tumours and OPSCCs. HOPX promoter methylation was observed in a subset of HNSCCs and was associated with a worse overall survival in HPV negative tumours. RNAseq analysis of OSCC cells transfected with HOPX revealed a widespread deregulation of the transcription of genes related to epithelial homeostasis and ectopic over-expression of HOPX in OSCC and NPC cells inhibited cell proliferation, plating efficiency and migration, and enhanced sensitivity to UVA-induced apoptosis. Our results demonstrate that HOPX functions as a tumour suppressor in HNSCC and suggest a central role for HOPX in suppressing epithelial carcinogenesis

D-Brane Propagation in Two-Dimensional Black Hole Geometries

We study propagation of D0-brane in two-dimensional Lorentzian black hole backgrounds by the method of boundary conformal field theory of SL(2,R)/U(1) supercoset at level k. Typically, such backgrounds arise as near-horizon geometries of k coincident non-extremal NS5-branes, where 1/k measures curvature of the backgrounds in string unit and hence size of string worldsheet effects. At classical level, string worldsheet effects are suppressed and D0-brane propagation in the Lorentzian black hole geometry is simply given by the Wick rotation of D1-brane contour in the Euclidean black hole geometry. Taking account of string worldsheet effects, boundary state of the Lorentzian D0-brane is formally constructible via Wick rotation from that of the Euclidean D1-brane. However, the construction is subject to ambiguities in boundary conditions. We propose exact boundary states describing the D0-brane, and clarify physical interpretations of various boundary states constructed from different boundary conditions. As it falls into the black hole, the D0-brane radiates off to the horizon and to the infinity. From the boundary states constructed, we compute physical observables of such radiative process. We find that part of the radiation to infinity is in effective thermal distribution at the Hawking temperature. We also find that part of the radiation to horizon is in the Hagedorn distribution, dominated by massive, highly non-relativistic closed string states, much like the tachyon matter. Remarkably, such distribution emerges only after string worldsheet effects are taken exactly into account. From these results, we observe that nature of the radiation distribution changes dramatically across the conifold geometry k=1 (k=3 for the bosonic case), exposing the `string - black hole transition' therein.Comment: 51 pages, 5 figures, v2: referece added, note added replying the comment made in hep-th/060206

Chemostratigraphy of Neoproterozoic carbonates: implications for 'blind dating'

The delta C-13(carb) and Sr-87/Sr-86 secular variations in Neoproteozoic seawater have been used for the purpose of 'isotope stratigraphy' but there are a number of problems that can preclude its routine use. In particular, it cannot be used with confidence for 'blind dating'. The compilation of isotopic data on carbonate rocks reveals a high level of inconsistency between various carbon isotope age curves constructed for Neoproteozoic seawater, caused by a relatively high frequency of both global and local delta C-13(carb) fluctuations combined with few reliable age determinations. Further complication is caused by the unresolved problem as to whether two or four glaciations, and associated negative delta C-13(carb) excursions, can be reliably documented. Carbon isotope stratigraphy cannot be used alone for geological correlation and 'blind dating'. Strontium isotope stratigraphy is a more reliable and precise tool for stratigraphic correlations and indirect age determinations. Combining strontium and carbon isotope stratigraphy, several discrete ages within the 590-544 Myr interval, and two age-groups at 660-610 and 740-690 Myr can be resolved

S-matrix elements and off-shell tachyon action with non-abelian gauge symmetry

We propose that there is a unique expansion for the string theory S-matrix elements of tachyons that corresponds to non-abelian tachyon action. For those S-matrix elements which, in their expansion, there are the Feynman amplitudes resulting from the non-abelian kinetic term, we give a prescription on how to find the expansion. The gauge invariant action is an $\alpha'$ expanded action, and the tachyon mass $m$ which appears as coefficient of many different couplings, is arbitrary. We then analyze in details the S-matrix element of four tachyons and the S-matrix element of two tachyons and two gauge fields, in both bosonic and superstring theories, in favor of this proposal. In the superstring theory, the leading terms of the non-abelian gauge invariant couplings are in agreement with the symmetrised trace of the direct non-abelian generalization of the tachyonic Born-Infeld action in which the tachyon potential is consistent with $V(T)=e^{\pi\alpha' m^2T^2}$. In the bosonic theory, on the other hand, the leading terms are those appear in superstring case as well as some other gauge invariant couplings which spoils the symmetrised trace prescription. These latter terms are zero in the abelian case.Comment: Latex, 27 pages, no figures,v4:change the introduction section, add some notes to clarify the idea, add reference

Conductance behavior of tetraphenyl-Aza-Bodipys

We studied the electrical conductance of single-molecule junctions formed from molecular wires with four anchor groups. Three tetraphenyl-aza-BODIPYs with four or two thiomethyl anchor groups were synthesized, and their single-molecule conductance was measured using break-junction-STM. Using DFT based calculations these compounds were shown to display a combination of a high and low conductance, depending on the molecule's connectivity in the junction. A scissor correction is employed to obtain the corrected HOMO-LUMO gaps and a tight binding model (TBM) is used to highlight the role of transport through the pi system of the tetraphenyl-aza-BODIPY central unit. The three higher-conductance geometries follow the sequence 3 > 4 > 2, which demonstrates that their conductances are correlated with the number of anchors

The effect of autonomy, training opportunities, age and salaries on job satisfaction in the South East Asian retail petroleum industry

South East Asian petroleum retailers are under considerable pressure to improve service quality by reducing turnover. An empirical methodology from this industry determined the extent to which job characteristics, training opportunities, age and salary influenced the level of job satisfaction, an indicator of turnover. Responses are reported on a random sample of 165 site employees (a 68% response rate) of a Singaporean retail petroleum firm. A restricted multivariate regression model of autonomy and training opportunities explained the majority (35.4%) of the variability of job satisfaction. Age did not moderate these relationships, except for employees >21 years of age, who reported enhanced job satisfaction with additional salary. Human Capital theory, Life Cycle theory and Job Enrichment theory are invoked and explored in the context of these findings in the South East Asian retail petroleum industry. In the South East Asian retail petroleum industry, jobs providing employees with the opportunity to undertake a variety of tasks that enhanced the experienced meaningfulness of work are likely to promote job satisfaction, reduce turnover and increase the quality of service

Data-driven definitions for active and structural MRI lesions in the sacroiliac joint in spondyloarthritis and their predictive utility

Objectives. To determine quantitative SI joint MRI lesion cut-offs that optimally define a positive MRI for inflammatory and structural lesions typical of axial SpA (axSpA) and that predict clinical diagnosis.Methods. The Assessment of SpondyloArthritis international Society (ASAS) MRI group assessed MRIs from the ASAS Classification Cohort in two reading exercises where (A) 169 cases and 7 central readers; (B) 107 cases and 8 central readers. We calculated sensitivity/specificity for the number of SI joint quadrants or slices with bone marrow oedema (BME), erosion, fat lesion, where a majority of central readers had high confidence there was a definite active or structural lesion. Cut-offs with >= 95% specificity were analysed for their predictive utility for follow-up rheumatologist diagnosis of axSpA by calculating positive/negative predictive values (PPVs/NPVs) and selecting cut-offs with PPV >= 95%.Results. Active or structural lesions typical of axSpA on MRI had PPVs >= 95% for clinical diagnosis of axSpA. Cut-offs that best reflected a definite active lesion typical of axSpA were either >= 4 SI joint quadrants with BME at any location or at the same location in >= 3 consecutive slices. For definite structural lesion, the optimal cut-offs were any one of >= 3 SI joint quadrants with erosion or >= 5 with fat lesions, erosion at the same location for >= 2 consecutive slices, fat lesions at the same location for >= 3 consecutive slices, or presence of a deep (i.e. >1 cm depth) fat lesion.Conclusion. We propose cut-offs for definite active and structural lesions typical of axSpA that have high PPVs for a long-term clinical diagnosis of axSpA for application in disease classification and clinical research.Pathophysiology and treatment of rheumatic disease