Fast variability from black-hole binaries

Currently available information on fast variability of the X-ray emission from accreting collapsed objects constitutes a complex phenomenology which is difficult to interpret. We review the current observational standpoint for black-hole binaries and survey models that have been proposed to interpret it. Despite the complex structure of the accretion flow, key observational diagnostics have been identified which can provide direct access to the dynamics of matter motions in the close vicinity of black holes and thus to the some of fundamental properties of curved spacetimes, where strong-field general relativistic effects can be observed.Comment: 20 pages, 11 figures. Accepted for publication in Space Science Reviews. Also to appear in hard cover in the Space Sciences Series of ISSI "The Physics of Accretion onto Black Holes" (Springer Publisher

Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity

The enzyme NUDT15 efficiently hydrolyzes the active metabolites of thiopurine drugs, which are routinely used for treating cancer and inflammatory diseases. Loss-of-function variants in NUDT15 are strongly associated with thiopurine intolerance, such as leukopenia, and preemptive NUDT15 genotyping has been clinically implemented to personalize thiopurine dosing. However, understanding the molecular consequences of these variants has been difficult, as no structural information was available for NUDT15 proteins encoded by clinically actionable pharmacogenetic variants because of their inherent instability. Recently, the small molecule NUDT15 inhibitor TH1760 has been shown to sensitize cells to thiopurines, through enhanced accumulation of 6-thio-guanine in DNA. Building upon this, we herein report the development of the potent and specific NUDT15 inhibitor, TH7755. TH7755 demonstrates a greatly improved cellular target engagement and 6-thioguanine potentiation compared with TH1760, while showing no cytotoxicity on its own. This potent inhibitor also stabilized NUDT15, enabling analysis by X-ray crystallography. We have determined high-resolution structures of the clinically relevant NUDT15 variants Arg139Cys, Arg139His, Val18Ile, and V18_V19insGlyVal. These structures provide clear insights into the structural basis for the thiopurine intolerance phenotype observed in patients carrying these pharmacogenetic variants. These findings will aid in predicting the effects of new NUDT15 sequence variations yet to be discovered in the clinic

Development of a chemical probe against NUDT15

The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (VT) size was 500 ml, or 7 to 9 ml kg1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P < 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P < 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high VT and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications: LAS VEGAS - An observational study in 29 countries

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (V T) size was 500 ml, or 7 to 9 ml kg−1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P ˂ 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P ˂ 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high V T and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome.</p

Registration of 2D x-ray images to 3D MRI by generating pseudo-CT data

Spatial and soft tissue information provided by magnetic resonance imaging can be very valuable during image-guided procedures, where usually only realtime two-dimensional (2D) x-ray images are available. Registration of 2D x-ray images to three-dimensional (3D) magnetic resonance imaging (MRI) data, acquired prior to the procedure, can provide optimal information to guide the procedure. However, registering x-ray images to MRI data is not a trivial task because of their fundamental difference in tissue contrast. This paper presents a technique that generates pseudo-computed tomography (CT) data from multi-spectral MRI acquisitions which is sufficiently similar to real CT data to enable registration of x-ray to MRI with comparable accuracy as registration of x-ray to CT. The method is based on a k-nearest-neighbors (kNN)-regression strategy which labels voxels of MRI data with CT Hounsfield Units. The regression method uses multi-spectral MRI intensities and intensity gradients as features to discriminate between various tissue types. The efficacy of using pseudo-CT data for registration of x-ray to MRI was tested on ex vivo animal data. 2D-3D registration experiments using CT and pseudo-CT data of multiple subjects were performed with a commonly used 2D-3D registration algorithm. On average, the median target registration error for registration of two x-ray images to MRI data was approximately 1 mm larger than for x-ray to CT registration. The authors have shown that pseudo-CT data generated from multi-spectral MRI facilitate registration of MRI to x-ray images. From the experiments it could be concluded that the accuracy achieved was comparable to that of registering x-ray images to CT data. © 2011 Institute of Physics and Engineering in Medicine

Registration of 2D x-ray images to 3D MRI by generating pseudo-CT data

Spatial and soft tissue information provided by magnetic resonance imaging can be very valuable during image-guided procedures, where usually only realtime two-dimensional (2D) x-ray images are available. Registration of 2D x-ray images to three-dimensional (3D) magnetic resonance imaging (MRI) data, acquired prior to the procedure, can provide optimal information to guide the procedure. However, registering x-ray images to MRI data is not a trivial task because of their fundamental difference in tissue contrast. This paper presents a technique that generates pseudo-computed tomography (CT) data from multi-spectral MRI acquisitions which is sufficiently similar to real CT data to enable registration of x-ray to MRI with comparable accuracy as registration of x-ray to CT. The method is based on a k-nearest-neighbors (kNN)-regression strategy which labels voxels of MRI data with CT Hounsfield Units. The regression method uses multi-spectral MRI intensities and intensity gradients as features to discriminate between various tissue types. The efficacy of using pseudo-CT data for registration of x-ray to MRI was tested on ex vivo animal data. 2D-3D registration experiments using CT and pseudo-CT data of multiple subjects were performed with a commonly used 2D-3D registration algorithm. On average, the median target registration error for registration of two x-ray images to MRI data was approximately 1 mm larger than for x-ray to CT registration. The authors have shown that pseudo-CT data generated from multi-spectral MRI facilitate registration of MRI to x-ray images. From the experiments it could be concluded that the accuracy achieved was comparable to that of registering x-ray images to CT data. © 2011 Institute of Physics and Engineering in Medicine

Still alive and kicking: A significant outburst in changing-look AGN Mrk 1018

International audienceChanging-look active galactic nuclei (CL-AGN) have been observed to change optical spectral type. Mrk 1018 is unique: first classified as a type 1.9 Seyfert galaxy, it transitioned to a type 1 before returning to its initial classification after approximately 30 years. We present a high-cadence monitoring programme that caught a major outburst in 2020. Due to sunblock, only the decline could be observed. We studied X-ray, UV, optical, and IR before and after the outburst to investigate the responses of the AGN structures. We derived a u'-band light curve of the AGN contribution alone. The flux increased by a factor of the order of 13. We confirmed this in other optical bands and determined the shape and speed of the decline in each waveband. The shapes of H beta and H alpha were analysed before and after the event. Two XMM-Newton observations from before and after the outburst were also exploited. The outburst is asymmetric, with a swifter rise than decline. The decline is best fit by a linear function, ruling out a tidal disruption event. The optical spectrum shows no change approximately 8 months before and 17 months after. The UV flux increased slightly after the outburst but the X-ray primary flux is unchanged. However, the 6.4 keV Iron line has doubled in strength. IR data taken 13 days after the observed optical peak show an increased emission level. Calculating the distance of the broad-line region and inner edge of the torus from the supermassive black hole can explain the multi-wavelength response to the outburst, in particular: i) the unchanged H beta and H alpha lines, ii) the unchanged primary X-ray spectral components, iii) the rapid and extended infrared response, as well as iv) the enhanced emission of the reflected 6.4 keV line. The outburst was due to a dramatic and short-lasting change in the intrinsic accretion rate. We discuss different models as potential causes

NICER Discovers the Ultracompact Orbit of the Accreting Millisecond Pulsar IGR J17062-6143

International audienceWe present results of recent Neutron Star Interior Composition Explorer observations of the accreting millisecond X-ray pulsar IGR J17062-6143 that show that it resides in a circular, ultracompact binary with a 38 minute orbital period. NICER observed the source for approximately 26 ksec over a 5.3 day span in 2017 August, and again for 14 and 11 ksec in 2017 October and November, respectively. A power spectral analysis of the August exposure confirms the previous detection of pulsations at 163.656 Hz in Rossi X-ray Timing Explorer data, and reveals phase modulation due to orbital motion of the neutron star. A coherent search for the orbital solution using the Z^2 method finds a best-fitting circular orbit with a period of 2278.21 s (37.97 min), a projected semi-major axis of 0.00390 lt-sec, and a barycentric pulsar frequency of 163.6561105 Hz. This is currently the shortest known orbital period for an AMXP. The mass function is 9.12 e-8} solar masses, presently the smallest known for a stellar binary. The minimum donor mass ranges from about 0.005 - 0.007 solar masses, for a neutron star mass from 1.2 - 2 solar masses. Assuming mass transfer is driven by gravitational radiation, we find donor mass and binary inclination bounds of 0.0175 - 0.0155 solar masses and 19 deg < i < 27.5 deg, where the lower and upper bounds correspond to 1.4 and 2 solar mass neutron stars, respectively. Folding the data accounting for the orbital modulation reveals a sinusoidal profile with fractional amplitude 2.04 +- 0.11 % (0.3 - 3.2 keV)