Many different definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different ...patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare-associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided.
Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment ...options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.
We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.
Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval CI, 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.
In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).
We present the first results of the Fermilab National Accelerator Laboratory (FNAL) Muon g-2 Experiment for the positive muon magnetic anomaly a_{μ}≡(g_{μ}-2)/2. The anomaly is determined from the ...precision measurements of two angular frequencies. Intensity variation of high-energy positrons from muon decays directly encodes the difference frequency ω_{a} between the spin-precession and cyclotron frequencies for polarized muons in a magnetic storage ring. The storage ring magnetic field is measured using nuclear magnetic resonance probes calibrated in terms of the equivalent proton spin precession frequency ωover ˜_{p}^{'} in a spherical water sample at 34.7 °C. The ratio ω_{a}/ωover ˜_{p}^{'}, together with known fundamental constants, determines a_{μ}(FNAL)=116 592 040(54)×10^{-11} (0.46 ppm). The result is 3.3 standard deviations greater than the standard model prediction and is in excellent agreement with the previous Brookhaven National Laboratory (BNL) E821 measurement. After combination with previous measurements of both μ^{+} and μ^{-}, the new experimental average of a_{μ}(Exp)=116 592 061(41)×10^{-11} (0.35 ppm) increases the tension between experiment and theory to 4.2 standard deviations.
We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, ...hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NAT). A parallel effort on a second unrelated family converged on the same variant. The absence of this variant in controls, the amino acid conservation of this region of the protein, the predicted disruptive change, and the co-occurrence in two unrelated families with the same rare disorder suggest that this is the pathogenic mutation. We confirmed this by demonstrating a significantly impaired biochemical activity of the mutant hNaa10p, and from this we conclude that a reduction in acetylation by hNaa10p causes this disease. Here we provide evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans.
Somatosensory loss following stroke is common, with negative consequences for functional outcome. However, existing studies typically do not include quantitative measures of discriminative ...sensibility. The aim of this study was to quantify the proportion of stroke patients presenting with discriminative sensory loss of the hand in the post-acute rehabilitation phase.
Prospective cohort study of stroke survivors presenting for rehabilitation.
Fifty-one consecutive patients admitted to a metropolitan rehabilitation centre over a continuous 12-month period who met selection criteria.
Quantitative measures of touch discrimination and limb position sense, with high re-test reliability, good discriminative test properties and objective criteria of abnormality, were employed. Both upper limbs were tested, in counterbalanced order.
Impaired touch discrimination was identified in the hand contralateral to the lesion in 47% of patients, and in the ipsilesional hand in 16%. Forty-nine percent showed impaired limb position sense in the contralesional limb and 20% in the ipsilesional limb. Sixty-seven percent demonstrated impairment of at least one modality in the contralesional limb. Ipsilesional impairment was less severe.
Discriminative sensory impairment was quantified in the contralesional hand in approximately half of stroke patients presenting for rehabilitation. A clinically significant number also experienced impairment in the ipsilesional "unaffected" hand.
The goal of the present study was to identify differences in gene expression between SAT, VAT and EAT depots in Class III severely obese individuals.
Human subcutaneous (SAT) and visceral (VAT) ...adipose tissues exhibit differential gene expression profiles. There is little information, however, about the other proximal white adipose tissue, epigastric (EAT), in terms of its function and contribution to metabolism.
Using RNA from adipose biospecimens obtained from Class III severely obese patients undergoing open Roux-en-Y gastric bypass surgery, we compared gene expression profiles between SAT, VAT and EAT, using microarrays validated by real-time quantitative PCR.
The three depots were found to share 1907 genes. VAT had the greatest number of genes (66) expressed exclusively in this depot, followed by SAT (23), and then EAT (14). Moreover, VAT shared more genes with EAT (65) than with SAT (38). Further analyses using ratios of SAT/EAT, VAT/EAT and SAT/VAT identified specific as well as overlapping networks and pathways of genes representing dermatological diseases, inflammation, cell cycle and growth, cancer and development. Targeted analysis of genes, having a role in adipose tissue development and function, revealed that Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1-α) that regulates the precursor of the hormone Irisin (FNCD5) were abundantly expressed in all three fat depots, along with fibroblast growth factors (FGF) FGF1, FGF7 and FGF10, whereas, FGF19 and FGF21 were undetectable.
These data indicate that EAT has more in common with VAT, suggesting similar metabolic potential. The human epigastric adipose depot could have a significant functional role in metabolic diseases and should be further investigated.
Caldera-forming eruptions of island volcanoes generate tsunamis by the interaction of different eruptive phenomena with the sea. Such tsunamis are a major hazard, but forward models of their impacts ...are limited by poor understanding of source mechanisms. The caldera-forming eruption of Santorini in the Late Bronze Age is known to have been tsunamigenic, and caldera collapse has been proposed as a mechanism. Here, we present bathymetric and seismic evidence showing that the caldera was not open to the sea during the main phase of the eruption, but was flooded once the eruption had finished. Inflow of water and associated landsliding cut a deep, 2.0-2.5 km
, submarine channel, thus filling the caldera in less than a couple of days. If, as at most such volcanoes, caldera collapse occurred syn-eruptively, then it cannot have generated tsunamis. Entry of pyroclastic flows into the sea, combined with slumping of submarine pyroclastic accumulations, were the main mechanisms of tsunami production.
Using x-ray magnetic circular dichroism, we have detected the very interfacial spins that are responsible for the horizontal loop shift in three different exchange bias sandwiches, chosen because of ...their potential for device applications. The "pinned" uncompensated interfacial spins constitute only a fraction of a monolayer and do not rotate in an external magnetic field since they are tightly locked to the antiferromagnetic lattice. A simple extension of the Meiklejohn and Bean model is proposed to account quantitatively for the exchange bias fields in the three studied systems from the experimentally determined number of pinned moments and their sizes.
We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving ...neoadjuvant chemotherapy.
We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence.
Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10−4 (range 7.9 × 10−7-4.9 × 10−1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12.
Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.
•We carried out a case-control study of patients with TNBC receiving neoadjuvant chemotherapy enrolled on the TBCRC030 trial.•Using a highly sensitive mutation enrichment approach (MAESTRO), we showed a strong association between ctDNA TFx and RCB.•Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders.•In 58% of patients, TFx dropped below the threshold of commercially available assays, showing the need for sensitive tests.
ABSTRACT We present a combined analysis of the observations of the gravitational microlensing event OGLE-2015-BLG-0479 taken both from the ground and by the Spitzer Space Telescope. The light curves ...seen from the ground and from space exhibit a time offset of ∼13 days between the caustic spikes, indicating that the relative lens-source positions seen from the two places are displaced by parallax effects. From modeling the light curves, we measure the space-based microlens parallax. Combined with the angular Einstein radius measured by analyzing the caustic crossings, we determine the mass and distance of the lens. We find that the lens is a binary composed of two G-type stars with masses of ∼1.0 M and ∼0.9 M located at a distance of ∼3 kpc. In addition, we are able to constrain the complete orbital parameters of the lens thanks to the precise measurement of the microlens parallax derived from the joint analysis. In contrast to the binary event OGLE-2014-BLG-1050, which was also observed by Spitzer, we find that the interpretation of OGLE-2015-BLG-0479 does not suffer from the degeneracy between ( , ) and ( , ) solutions, confirming that the four-fold parallax degeneracy in single-lens events collapses into the two-fold degeneracy for the general case of binary-lens events. The location of the blend in the color-magnitude diagram is consistent with the lens properties, suggesting that the blend is the lens itself. The blend is bright enough for spectroscopy and thus this possibility can be checked from future follow-up observations.
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