Natural polymorphisms in mycobacterium tuberculosis conferring resistance to delamanid in drug-naïve patients.

Mutations in the genes of the F420 signaling pathway, including dnn, fgd1, fbiA, fbiB, fbiC, and fbiD, of Mycobacterium tuberculosis (Mtb) complex can lead to delamanid resistance. We searched for such mutations among 129 Mtb strains from Asia, South-America, and Africa using whole-genome sequencing; 70 (54%) strains had at least one mutation in one of the genes. For ten strains with mutations, we determined the minimum inhibitory concentration (MIC) of delamanid. We found one strain from a delamanid-naïve patient carrying the natural polymorphism Tyr29del (ddn) that was associated with a critical MIC to delamanid

Transmission of multidrug-resistant tuberculosis in a low-incidence setting, Switzerland, 2006 to 2012

The goal of the present study was to examine the transmission dynamics of multidrug-resistant tuberculosis (MDR-TB) in Switzerland. Between 2006 and 2012, a total of 49 MDR-TB cases were reported to the Swiss Federal Office of Public Health, 46 of which were of foreign origin. All 49 initial strains were evaluated by molecular epidemiologic methods at the Swiss National Reference Centre for Mycobacteria. In 43 strains, unique DNA fingerprint patterns were identified. Twelve strains were grouped into six clusters. Data from contact tracing suggest likely in-country transmission in four clusters, mostly among close contacts. In the remaining two clusters, no contact tracing data were available, but the identified genotypes were known to be prevalent in the countries of origin of the patients, suggesting the possibility that the infection was acquired there. While most MDR-TB cases are imported to Switzerland, at least four of the 49 MDR-TB cases were due to transmission within the country. The imported cases, however, did not lead to secondary cases outside the circles of close contacts. The results also indicate that prevention of MDR-TB transmission among immigrants may require closer monitoring

Comparison of functional and cytoarchitectonic maps of human visual areas V1, V2, V3d, V3v, and V4(v)

Cytoarchitectonic maps of human striate and extrastriate visual cortex based upon post-mortem brains can be correlated with functionally defined cortical areas using, for example, fMRI. We here assess the correspondence of anatomical maps of the visual cortex with functionally defined in vivo visual areas using retinotopic mapping. To this end, anatomical maximum probability maps (aMPM) derived from individual cytoarchitectonic maps of striate and extrastriate visual areas were compared with functional localisers for the early visual areas. Using fMRI, we delineated dorsal and ventral human retinotopic areas V1, V2, and V3, as well as a quarter-field visual field representation lateral to V3v, V4(v), in 24 healthy subjects. Based on these individual definitions, a functional maximum probability map (fMPM) was then computed in analogy to the aMPM. Functional and anatomical MPMs were highly correlated at group level: 78.5% of activated voxels in the fMPM were correctly assigned by the aMPM. The group aMPM was less effective in predicting functional retinotopic areas in the individual brain due to the large inter-individual variability in the location and extent of visual areas (mean overlap 32-69%). We conclude that cytoarchitectonic maps of striate and extrastriate visual areas may provide a valuable method for assigning functional group activations and thus add valuable a priori knowledge to the analysis of functional imaging data of the visual cortex

X-ray diffraction from isolated and strongly aligned gas-phase molecules with a free-electron laser

Contains fulltext : 133251.pdf (publisher's version ) (Open Access

Mortality of drug-resistant tuberculosis in high-burden countries: comparison of routine drug susceptibility testing with whole-genome sequencing

Background: Drug-resistance threatens global tuberculosis control. We examined mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and whole-genome sequencing (WGS). Methods: We collected pulmonary Mycobacterium tuberculosis isolates and clinical data from adult tuberculosis patients from Côte d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand, stratified by HIV status and drug resistance, from 2013 to 2016. Sites tested drug susceptibility using routinely available methods. WGS was done on Illumina HiSeq 2500 in the USA and Switzerland, and TBprofiler used to analyse the genomes. We analysed mortality in multivariable logistic regression models adjusted for sex, age, HIV-status, history of tuberculosis, and sputum positivity. Findings: We included 582 tuberculosis patients. The median age was 33 years (interquartile range 27-43 years), 225 (39%) were female, and 247 (42%) were HIV-positive. Based on WGS, 339 (58%) isolates were pan- susceptible, 35 (6%) monoresistant, 146 (25%) multidrug-resistant, and 24 (4%) pre-/ extensively drug-resistant (pre-XDR/XDR). The local results were discordant with the WGS results in 130/582 (22%) of patients. All testing methods identified isoniazid and rifampicin resistance with a high agreement. Resistance to ethambutol, pyrazinamide, and second-line drugs was rarely tested locally. Of 576 patients with known treatment, 86 (15%) patients received inappropriate treatment according to WGS results and the World Health Organization (WHO) treatment guidelines. The analysis of mortality was based on 530 patients; 63 (12%) died, and 77 patients (15%) received inappropriate treatment. Mortality ranged from 6% in patients with pan-susceptible tuberculosis (18/310) to 39% in patients with pre-XDR/XDR tuberculosis (9/23). The adjusted odds ratio for mortality was 4.92 (95% CI 2.47-9.78) among under-treated patients, compared to appropriately treated cases. Interpretation: In seven high-burden tuberculosis countries, we observed discrepancies between drug resistance patterns obtained locally and WGS. The under-diagnosis of drug resistances resulted in inappropriate treatment and higher mortality. WGS can provide accurate and detailed drug resistance information required to improve the outcomes of drug-resistant tuberculosis in high-burden settings. Our results support the WHO's call for point-of- care tests based on WGS

Laser cooling of calcium in a 'golden ratio' quasi-electrostatic lattice

A 3D lattice based on a high-power CO2 laser is considered in the context of laser cooling and trapping of atomic calcium. We expect to be able to realize a system with >10 000 lattice sites each with more than 100 atoms, and the facility to laser cool all the atoms into the vibrational ground state using the intercombination line. The configuration allows the production of an array of small Bose–Einstein condensates, enabling an investigation of the build-up of phase coherence as a function of atom number

Imaging molecular structure through femtosecond photoelectron diffraction on aligned and oriented gas-phase molecules

This paper gives an account of our progress towards performing femtosecond time-resolved photoelectron diffraction on gas-phase molecules in a pump-probe setup combining optical lasers and an X-ray free-electron laser. We present results of two experiments aimed at measuring photoelectron angular distributions of laser-aligned 1-ethynyl-4-fluorobenzene (C8H5F) and dissociating, laser-aligned 1,4-dibromobenzene (C6H4Br2) molecules and discuss them in the larger context of photoelectron diffraction on gas-phase molecules. We also show how the strong nanosecond laser pulse used for adiabatically laser-aligning the molecules influences the measured electron and ion spectra and angular distributions, and discuss how this may affect the outcome of future time-resolved photoelectron diffraction experiments

Femtosecond free-electron laser x-ray diffraction data sets for algorithm development

We describe femtosecond X-ray diffraction data sets of viruses and nanoparticles collected at the Linac Coherent Light Source. The data establish the first large benchmark data sets for coherent diffraction methods freely available to the public, to bolster the development of algorithms that are essential for developing this novel approach as a useful imaging technique. Applications are 2D reconstructions, orientation classification and finally 3D imaging by assembling 2D patterns into a 3D diffraction volume

Nanoplasma dynamics of single large Xenon clusters irradiated with superintense X-ray pulses from the Linac Coherent Light Source free-electron laser

The plasma dynamics of single mesoscopic Xe particles irradiated with intense femtosecond x-ray pulses exceeding 10¹⁶  W/cm² from the Linac Coherent Light Source free-electron laser are investigated. Simultaneous recording of diffraction patterns and ion spectra allows eliminating the influence of the laser focal volume intensity and particle size distribution. The data show that for clusters illuminated with intense x-ray pulses, highly charged ionization fragments in a narrow distribution are created and that the nanoplasma recombination is efficiently suppressed