Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND Use of maintenance antibiotic therapy with the macrolide azithromycin is increasing in a number of chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD. METHODS The Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) trial was a multicentre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial done at 6 European PCD clinics (tertiary paediatric care centres and university hospitals in Denmark, Germany, Netherlands, Switzerland, and UK). Patients with a confirmed diagnosis of PCD, aged 7-50 years old, and predicted FEV1 greater than 40% were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 mg or 500 mg as tablets according to bodyweight (</≥ 40 kg) or identical placebo, three times a week for 6 months. The random allocation sequence was a permuted block randomisation, with a block size of four, generated by an external consultancy. Participants, investigators, and care providers were masked to treatment allocation. The primary endpoint was the number of respiratory exacerbations over 6 months. Analysis was by intention to treat. This study is registered in the EU Clinical Trials Register, EudraCT number 2013-004664-58. FINDINGS Between June 24, 2014, and Aug 23, 2016, 102 patients were screened, of whom 90 were randomly assigned to either azithromycin (n=49) or placebo (n=41). The study was ended without having included the planned number of participants due to recruitment difficulties. The mean number of respiratory exacerbations over 6 months was 0·75 (SD 1·12) in the azithromycin group compared with 1·62 (1·64) in the placebo group, and participants receiving azithromycin had significantly lower rate of exacerbations during the individual treatment periods (rate ratio 0·45 [95% CI 0·26-0·78]; p=0·004). Four serious adverse events were reported, occurring in one (2%) of 47 participants in the azithromycin group and in three (7%) of 41 participants in the placebo group. Loose stools or diarrhoea were more common in the azithromycin group than in the placebo group (11 [23%] vs two [5%]). INTERPRETATION This first multinational randomised controlled trial on pharmacotherapy in PCD showed that azithromycin maintenance therapy for 6 months was well tolerated and halved the rate of respiratory exacerbations. Azithromycin maintenance therapy is an option for patients with PCD with frequent exacerbations potentially leading to reduced need for additional antibiotic treatments and preventing irreversible lung damage. FUNDING European Commission Seventh Framework Programme and Children's Lung Foundation (Denmark)

Surgical treatment of patients with infective endocarditis:changes in temporal use, patient characteristics, and mortality—a nationwide study

BACKGROUND: Valve surgery guidelines for infective endocarditis (IE) are unchanged over decades and nationwide data about the use of valve surgery do not exist. METHODS: We included patients with first-time IE (1999–2018) using Danish nationwide registries. Proportions of valve surgery were reported for calendar periods (1999–2003, 2004–2008, 2009–2013, 2014–2018). Comparing calendar periods in multivariable analyses, we computed likelihoods of valve surgery with logistic regression and rates of 30 day postoperative mortality with Cox regression. RESULTS: We included 8804 patients with first-time IE; 1981 (22.5%) underwent surgery during admission, decreasing by calendar periods (N = 360 [24.4%], N = 483 [24.0%], N = 553 [23.5%], N = 585 [19.7%], P = < 0.001 for trend). For patients undergoing valve surgery, median age increased from 59.7 to 66.9 years (P ≤ 0.001) and the proportion of males increased from 67.8% to 72.6% (P = 0.008) from 1999–2003 to 2014–2018. Compared with 1999–2003, associated likelihoods of valve surgery were: Odds ratio (OR) = 1.14 (95% CI: 0.96–1.35), OR = 1.20 (95% CI: 1.02–1.42), and OR = 1.10 (95% CI: 0.93–1.29) in 2004–2008, 2009–2013, and 2014–2018, respectively. 30 day postoperative mortalities were: 12.7%, 12.8%, 6.9%, and 9.7% by calendar periods. Compared with 1999–2003, associated mortality rates were: Hazard ratio (HR) = 0.96 (95% CI: 0.65–1.41), HR = 0.43 (95% CI: 0.28–0.67), and HR = 0.55 (95% CI 0.37–0.83) in 2004–2008, 2009–2013, and 2014–2018, respectively. CONCLUSIONS: On a nationwide scale, 22.5% of patients with IE underwent valve surgery. Patient characteristics changed considerably and use of valve surgery decreased over time. The adjusted likelihood of valve surgery was similar between calendar periods with a trend towards an increase while rates of 30 day postoperative mortality decreased. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12872-022-02761-z

Infrastructure for Detector Research and Development towards the International Linear Collider

The EUDET-project was launched to create an infrastructure for developing and testing new and advanced detector technologies to be used at a future linear collider. The aim was to make possible experimentation and analysis of data for institutes, which otherwise could not be realized due to lack of resources. The infrastructure comprised an analysis and software network, and instrumentation infrastructures for tracking detectors as well as for calorimetry.Comment: 54 pages, 48 picture

Search for CP Violation in the Decay Z -> b (b bar) g

About three million hadronic decays of the Z collected by ALEPH in the years 1991-1994 are used to search for anomalous CP violation beyond the Standard Model in the decay Z -> b \bar{b} g. The study is performed by analyzing angular correlations between the two quarks and the gluon in three-jet events and by measuring the differential two-jet rate. No signal of CP violation is found. For the combinations of anomalous CP violating couplings, ${\hat{h}}_b = {\hat{h}}_{Ab}g_{Vb}-{\hat{h}}_{Vb}g_{Ab}$ and $h^{\ast}_b = \sqrt{\hat{h}_{Vb}^{2}+\hat{h}_{Ab}^{2}}$, limits of \hat{h}_b < 0.59$and$h^{\ast}_{b} < 3.02$ are given at 95\% CL.Comment: 8 pages, 1 postscript figure, uses here.sty, epsfig.st

Use of cultivation-dependent and -independent techniques to assess contamination of central venous catheters: a pilot study

<p>Abstract</p> <p>Background</p> <p>Catheters are the most common cause of nosocomial infections and are associated with increased risk of mortality, length of hospital stay and cost. Prevention of infections and fast and correct diagnosis is highly important.</p> <p>Methods</p> <p>In this study traditional semiquantitative culture-dependent methods for diagnosis of bacteria involved in central venous catheter-related infections as described by Maki were compared with the following culture-independent molecular biological methods: Clone libraries, denaturant gradient gel electrophoresis, phylogeny and fluorescence in situ hybridization.</p> <p>Results</p> <p>In accordance with previous studies, the cultivation of central venous catheters from 18 patients revealed that <it>S. epidermidis </it>and other coagulase-negative staphylococci were most abundant and that a few other microorganisms such as <it>P. aeruginosa </it>and <it>K. pneumoniae </it>occasionally were found on the catheters. The molecular analysis using clone libraries and sequencing, denaturant gradient gel electrophoresis and sequencing provided several important results. The species found by cultivation were confirmed by molecular methods. However, many other bacteria belonging to the phyla <it>Proteobacteria, Firmicutes, Actinobacteria </it>and <it>Bacteroidetes </it>were also found, stressing that only a minor portion of the species present were found by cultivation. Some of these bacteria are known to be pathogens, some have not before been described in relation to human health, and some were not closely related to known pathogens and may represent new pathogenic species. Furthermore, there was a clear difference between the bacterial species found in biofilm on the external (exluminal) and internal (luminal) side of the central venous catheter, which can not be detected by Maki's method. Polymicrobial biofilms were observed on most of the catheters and were much more common than the cultivation-dependent methods indicated.</p> <p>Conclusion</p> <p>The results show that diagnosis based on molecular methods improves the detection of microorganisms involved in central catheter-related infections. The importance of these microorganisms needs to be investigated further, also in relation to contamination risk from improper catheter handling, as only in vivo contaminants are of interest. This information can be used for development of fast and more reliable diagnostic tools, which can be used in combination with traditional methods.</p

Search for R-Parity Violating Decays of Supersymmetric Particles in e+e−e^{+}e^{-} Collisions at Centre-of-Mass Energies near 183 GeV

Searches for pair-production of supersymmetric particles under the assumption that R-parity is violated via a single dominant $LL{\bar E}$, $LQ{\bar D}$ or ${\bar U} {\bar D} {\bar D}$ coupling are performed using the data collected by the \ALEPH\ collaboration at centre-of-mass energies of 181--184~\gev. The observed candidate events in the data are in agreement with the Standard Model expectations. Upper limits on the production cross-sections and lower limits on the masses of charginos, sleptons, squarks and sneutrinos are de rived

Production of excited beauty states in Z decays

A data sample of about 3.0 million hadronic Z decays collected by the ALEPH experiment at LEP in the years 1991 through 1994, is used to make an inclusive selection of B~hadron events. In this event sample 4227 \pm 140 \pm 252 B^* mesons in the decay B^* \to B \gamma and 1944 \pm 108 \pm 161 B^{**} mesons decaying into a B~meson and a charged pion are reconstructed. For the well established B^* meson the following quantities areobtained: \Delta M = M_{B^*} - M_{B} = (45.30\pm 0.35\pm 0.87)~\mathrm{MeV}/c^2 and N_{B^*}/(N_B+N_{B^*}) = (77.1 \pm 2.6 \pm 7.0)\%. The angular distribution of the photons in the B^* rest frame is used to measure the relative contribution of longitudinal B^* polarization states to be \sigma_L/(\sigma_L + \sigma_T)= (33 \pm 6 \pm 5)\%. \\ Resonance structure in the M(B\pi)-M(B) mass difference is observed at (424 \pm 4 \pm 10)~\mathrm{MeV}/c^2. Its shape and position is in agreement with the expectation for B^{**}_{u,d} states decaying into B_{u,d}^{(*)} \pi^\pm. The signal is therefore interpreted as arising from them. The relative production rate is determined to be \frac{BR(Z \to b \to B_{u,d}^{**})}{BR(Z \to b \to B_{u,d})} = [27.9 \pm 1.6(stat) \pm 5.9(syst) \phantom{a}^{+3.9}_{-5.6}(model)]\%. where the third error reflects the uncertainty due to different production and decay models for the broad B_{u,d}^{**} states