Detection and management of drug-resistant tuberculosis in HIV-infected patients in lower-income countries.

SETTING Drug resistance threatens tuberculosis (TB) control, particularly among human immunodeficiency virus (HIV) infected persons. OBJECTIVE To describe practices in the prevention and management of drug-resistant TB under antiretroviral therapy (ART) programs in lower-income countries. DESIGN We used online questionnaires to collect program-level data on 47 ART programs in Southern Africa (n = 14), East Africa (n = 8), West Africa (n = 7), Central Africa (n = 5), Latin America (n = 7) and the Asia-Pacific (n = 6 programs) in 2012. Patient-level data were collected on 1002 adult TB patients seen at 40 of the participating ART programs. RESULTS Phenotypic drug susceptibility testing (DST) was available in 36 (77%) ART programs, but was only used for 22% of all TB patients. Molecular DST was available in 33 (70%) programs and was used in 23% of all TB patients. Twenty ART programs (43%) provided directly observed therapy (DOT) during the entire course of treatment, 16 (34%) during the intensive phase only, and 11 (23%) did not follow DOT. Fourteen (30%) ART programs reported no access to second-line anti-tuberculosis regimens; 18 (38%) reported TB drug shortages. CONCLUSIONS Capacity to diagnose and treat drug-resistant TB was limited across ART programs in lower-income countries. DOT was not always implemented and drug supplies were regularly interrupted, which may contribute to the global emergence of drug resistance.

Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: a multicohort European case-control study using centralized ultrasensitive 454 pyrosequencing.

OBJECTIVES It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART. METHODS This Europe-wide case-control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%-25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression. RESULTS Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%), were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR = 2.75, 95% CI = 1.35-5.60, P = 0.005); similar associations were observed for at least one MV versus no NRTI MVs (OR = 2.27, 95% CI = 0.76-6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12-5.18, P = 0.024). A dose-effect relationship between virological failure and mutational load was found. CONCLUSIONS Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART.

A Passive WiFi Source Localization System based on Fine-grained Power-based Trilateration

Indoor localization systems become more interesting for researchers because of the attractiveness of business cases in various application fields. A WiFi-based passive localization system can provide user location information to third-party providers of positioning services. However, indoor localization techniques are prone to multipath and Non-Line Of Sight (NLOS) propagation, which lead to significant performance degradation. To overcome these problems, we provide a passive localization system for WiFi targets with several improved algorithms for localization. Through Software Defined Radio (SDR) techniques, we extract Channel Impulse Response (CIR) information at the physical layer. CIR is later adopted to mitigate the multipath fading problem. We propose to use a Nonlinear Regression (NLR) method to relate the filtered power information to propagation distances, which significantly improves the ranging accuracy compared to the commonly used log-distance path loss model. To mitigate the influence of ranging errors, a new trilateration algorithm is designed as well by combining Weighted Centroid and Constrained Weighted Least Square (WC-CWLS) algorithms. Experiment results show that our algorithm is robust against ranging errors and outperforms the linear least square algorithm and weighted centroid algorithm.

GROMOS-C, a novel ground-based microwave radiometer for ozone measurement campaigns

Stratospheric ozone is of major interest as it absorbs most harmful UV radiation from the sun, allowing life on Earth. Ground-based microwave remote sensing is the only method that allows for the measurement of ozone profiles up to the mesopause, over 24 hours and under different weather conditions with high time resolution. In this paper a novel ground-based microwave radiometer is presented. It is called GROMOS-C (GRound based Ozone MOnitoring System for Campaigns), and it has been designed to measure the vertical profile of ozone distribution in the middle atmosphere by observing ozone emission spectra at a frequency of 110.836 GHz. The instrument is designed in a compact way which makes it transportable and suitable for outdoor use in campaigns, an advantageous feature that is lacking in present day ozone radiometers. It is operated through remote control. GROMOS-C is a total power radiometer which uses a pre-amplified heterodyne receiver, and a digital fast Fourier transform spectrometer for the spectral analysis. Among its main new features, the incorporation of different calibration loads stands out; this includes a noise diode and a new type of blackbody target specifically designed for this instrument, based on Peltier elements. The calibration scheme does not depend on the use of liquid nitrogen; therefore GROMOS-C can be operated at remote places with no maintenance requirements. In addition, the instrument can be switched in frequency to observe the CO line at 115 GHz. A description of the main characteristics of GROMOS-C is included in this paper, as well as the results of a first campaign at the High Altitude Research Station at Jungfraujoch (HFSJ), Switzerland. The validation is performed by comparison of the retrieved profiles against equivalent profiles from MLS (Microwave Limb Sounding) satellite data, ECMWF (European Centre for Medium-Range Weather Forecast) model data, as well as our nearby NDACC (Network for the Detection of Atmospheric Composition Change) ozone radiometer measuring at Bern.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06)

BACKGROUND Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, number NCT00544700.

Power Games in Strategy Formation Processes – A Performative Interpretation

The article approaches an understanding of power within strategy formation processes established by verbal and bodily communication. On this note, we examined concepts of power constituted by hierarchy and developed a conceptual framework for a performative interpretation of power. In line with Austin’s (1962) and Butler’s (1990, 1993, 1997) concept of performativity as well as strategy-as-practice research (Balogun et al., 2007; Jarzabkowski & Spee, 2009) we ask: How is persuasion achieved by strategic actors during strategy formation processes? To explore verbal and bodily communication empirically we developed an experimental setting in a small high-tech company located in Germany in December, 2012. The Results indicate that (1) during critical incidents – when perspectives clash – actors use arguments to gain persuasion. (2) The data illustrates that independently of their hierarchical position within the company, strategic actors show an equal distribution of argumentative techniques.

Detection efficiency of microchannel plates for e(-) and pi(-) in the momentum range from 17.5 to 345 MeV/c

High-energy e(-) and pi(-) were measured by the multichannel plate (MCP) detector at the PiM1 beam line of the High Intensity Proton Accelerator Facilities located at the Paul Scherrer Institute, Villigen, Switzerland. The measurements provide the absolute detection efficiencies for these particles: 5.8% +/- 0.5% for electrons in the beam momenta range 17.5-300 MeV/c and 6.0% +/- 1.3% for pions in the beam momenta range 172-345 MeV/c. The pulse height distribution determined from the measurements is close to an exponential function with negative exponent, indicating that the particles penetrated the MCP material before producing the signal somewhere inside the channel. Low charge extraction and nominal gains of the MCP detector observed in this study are consistent with the proposed mechanism of the signal formation by penetrating radiation. A very similar MCP ion detector will be used in the Neutral Ion Mass (NIM) spectrometer designed for the JUICE mission of European Space Agency (ESA) to the Jupiter system, to perform measurements of the chemical composition of the Galilean moon exospheres. The detection efficiency for penetrating radiation determined in the present studies is important for the optimisation of the radiation shielding of the NIM detector against the high-rate and high-energy electrons trapped in Jupiter's magnetic field. Furthermore, the current studies indicate that MCP detectors can be useful to measure high-energy particle beams at high temporal resolution. (C) 2015 AIP Publishing LLC.

COSIMA calibration for the detection and characterization of the cometary solid organic matter

On the orbiter of the Rosetta spacecraft, the Cometary Secondary Ion Mass Analyser (COSIMA) will provide new in situ insights about the chemical composition of cometary grains all along 67P/Churyumov–Gerasimenko (67P/CG) journey until the end of December 2015 nominally. The aim of this paper is to present the pre-calibration which has already been performed as well as the different methods which have been developed in order to facilitate the interpretation of the COSIMA mass spectra and more especially of their organic content. The first step was to establish a mass spectra library in positive and negative ion mode of targeted molecules and to determine the specific features of each compound and chemical family analyzed. As the exact nature of the refractory cometary organic matter is nowadays unknown, this library is obviously not exhaustive. Therefore this library has also been the starting point for the research of indicators, which enable to highlight the presence of compounds containing specific atom or structure. These indicators correspond to the intensity ratio of specific peaks in the mass spectrum. They have allowed us to identify sample containing nitrogen atom, aliphatic chains or those containing polyaromatic hydrocarbons. From these indicators, a preliminary calibration line, from which the N/C ratio could be derived, has also been established. The research of specific mass difference could also be helpful to identify peaks related to quasi-molecular ions in an unknown mass spectrum. The Bayesian Positive Source Separation (BPSS) technique will also be very helpful for data analysis. This work is the starting point for the analysis of the cometary refractory organic matter. Nevertheless, calibration work will continue in order to reach the best possible interpretation of the COSIMA observations.

Who Is Influential and Why? The Determinants of Reputational Power

Power is one of the most fundamental concepts in political science, and it is a crucial aspect of decision-making structures. The distribution of power between political actors and coalitions of actors informs us about who is actually able to influence decision-making processes. It is thus no surprise that power is a centerpiece of our assessment of political decision-making in Switzerland. In line with the main argument of this book, Chapter 3 has uncovered important changes in decision-making structures, which resulted in a rebalancing of power between governing parties, interest groups and state executive actors. Conjecturing about the reasons that may account for these changes, we pointed to factors of an organizational and institutional nature. For example, we put forward the decline of pre-parliamentary procedures oriented towards corporatist intermediation as a possible explanation for the weakening of interest groups. More generally, in several chapters it has been suggested that there is a relationship between the institutional design of a decision-making process, the related importance of decision-making phases and an actor's participation in these phases on the one hand, and the power of actors (and coalitions of actors) on the other. In addition, the analyses carried out in Chapters 2 to 5 draw our attention to the differences in power structure across decision-making processes or types of processes.