The azimuthal anisotropy coefficient v2 of prompt D0, D+, D∗+, and Ds+ mesons was measured in midcentral (30%-50% centrality class) Pb-Pb collisions at a center-of-mass energy per nucleon pair ...sNN=5.02 TeV, with the ALICE detector at the LHC. The D mesons were reconstructed via their hadronic decays at midrapidity, |y|
Summary Background As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be ...assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen. Methods We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21 457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment. Findings In oestrogen receptor (ER)-positive disease (n=10 645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 SE 0·03 during years 0–4 and RR 0·68 0·06 during years 5–9 both 2p<0·00001; but RR 0·97 0·10 during years 10–14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10–19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 0·08). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 0·05 during years 0–4, 0·66 0·05 during years 5–9, and 0·68 0·08 during years 10–14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality. Interpretation 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen. Funding Cancer Research UK, British Heart Foundation, and Medical Research Council.
Uncertainty about the definition and diagnosis of blunt cardiac injury (BCI) leads to unnecessary hospitalization and cost while trying to rule it out. The purpose of this study was to examine ...whether the combination of two simple tests, electrocardiography (ECG) and serum troponin I (TnI) level, may serve as reliable predictors of BCI or the absence of it.
Over a period of 30 months (September 1999-February 2002), 333 consecutive patients with significant blunt thoracic trauma were followed prospectively. Serial ECG and TnI tests were performed routinely and echocardiography was performed selectively. Clinically significant BCI (SigBCI) was defined as the presence of cardiogenic shock, arrhythmias requiring treatment, or posttraumatic structural deficits.
SigBCI was diagnosed in 44 patients (13%). Of 80 patients with abnormal ECG and TnI, 27 (34%) developed SigBCI. Of 131 with normal serial ECG and TnI, none developed SigBCI. Of patients with abnormal ECG only or TnI only, 22% and 7%, respectively, developed SigBCI. The positive and negative predictive values were 29% and 98% for ECG, 21% and 94% for TnI, and 34% and 100% for the combination of ECG and TnI. The admission ECG or TnI was abnormal in 43 of 44 patients with SigBCI. Only one patient had initially normal ECG and TnI and developed abnormalities 8 hours after admission. Forty-one patients without other significant injuries stayed 1 to 3 days in the hospital only to rule out SigBCI and could have been discharged earlier. Besides ECG and TnI, other independent risk factors of SigBCI were an Injury Severity Score > 15, the presence of significant skeletal trauma, and history of cardiac disease.
The combination of normal ECG and TnI at admission and 8 hours later rules out the diagnosis of SigBCI. In the absence of other reasons for hospitalization, such patients can be safely discharged.
Individuals who were born very preterm (VPT; <33 gestational weeks) are at risk of experiencing deficits in tasks involving executive function in childhood and beyond. In addition, the type and ...severity of neonatal brain injury associated with very preterm birth may exert differential effects on executive functioning by altering its neuroanatomical substrates. Here we addressed this question by investigating with functional magnetic resonance imaging (fMRI) the haemodynamic response during executive-type processing using a phonological verbal fluency and a working memory task in VPT-born young adults who had experienced differing degrees of neonatal brain injury. 12 VPT individuals with a history of periventricular haemorrhage and ventricular dilatation (PVH+VD), 17 VPT individuals with a history of uncomplicated periventricular haemorrhage (UPVH), 13 VPT individuals with no history of neonatal brain injury and 17 controls received an MRI scan whilst completing a verbal fluency task with two cognitive loads ('easy' and 'hard' letters). Two groups of VPT individuals (PVH+VD; n = 10, UPVH; n = 8) performed an n-back task with three cognitive loads (1-, 2-, 3-back). Results demonstrated that VPT individuals displayed hyperactivation in frontal, temporal, and parietal cortices and in caudate nucleus, insula and thalamus compared to controls, as demands of the verbal fluency task increased, regardless of type of neonatal brain injury. On the other hand, during the n-back task and as working memory load increased, the PVH+VD group showed less engagement of the frontal cortex than the UPVH group. In conclusion, this study suggests that the functional neuroanatomy of different executive-type processes is altered following VPT birth and that neural activation associated with specific aspects of executive function (i.e., working memory) may be particularly sensitive to the extent of neonatal brain injury.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular ...disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
Some types of collagens, including transmembrane MACIT collagens and C. elegans cuticle collagens, are N-terminally cleaved at a dibasic site that resembles the consensus for furin or other ...proprotein convertases of the subtilisin/kexin (PCSK) family. Such cleavage may release transmembrane collagens from the plasma membrane and affect extracellular matrix assembly or structure. However, the functional consequences of such cleavage are unclear and evidence for the role of specific PCSKs is lacking. Here, we used endogenous collagen fusions to fluorescent proteins to visualize the secretion and assembly of the first collagen-based cuticle in C. elegans and then tested the role of the PCSK BLI-4 in these processes. Unexpectedly, we found that cuticle collagens SQT-3 and DPY-17 are secreted into the extraembryonic space several hours before cuticle matrix assembly. Furthermore, this early secretion depends on BLI-4/PCSK; in bli-4 and cleavage-site mutants, SQT-3 and DPY-17 are not efficiently secreted and instead form large intracellular puncta. Their later assembly into cuticle matrix is reduced but not entirely blocked. These data reveal a role for collagen N-terminal processing in intracellular trafficking and the control of matrix assembly in vivo. Our observations also prompt a revision of the classic model for C. elegans cuticle matrix assembly and the pre-cuticle-to-cuticle transition, suggesting that cuticle layer assembly proceeds via a series of regulated steps and not simply by sequential secretion and deposition.
Among patients undergoing emergency laparotomy, 30-day postoperative mortality is around 10–15%. The risk of death among these patients, however, varies greatly because of their clinical ...characteristics. We developed a risk prediction model for 30-day postoperative mortality to enable better comparison of outcomes between hospitals.
We analysed data from the National Emergency Laparotomy Audit (NELA) on patients having an emergency laparotomy between December 2013 and November 2015. A prediction model was developed using multivariable logistic regression, with potential risk factors identified from existing prediction models, national guidelines, and clinical experts. Continuous risk factors were transformed if necessary to reflect their non-linear relationship with 30-day mortality. The performance of the model was assessed in terms of its calibration and discrimination. Interval validation was conducted using bootstrap resampling.
There were 4458 (11.5%) deaths within 30-days among the 38 830 patients undergoing emergency laparotomy. Variables associated with death included (among others): age, blood pressure, heart rate, physiological variables, malignancy, and ASA physical status classification. The predicted risk of death among patients ranged from 1% to 50%. The model demonstrated excellent calibration and discrimination, with a C-statistic of 0.863 (95% confidence interval, 0.858–0.867). The model retained its high discrimination during internal validation, with a bootstrap derived C-statistic of 0.861.
The NELA risk prediction model for emergency laparotomies discriminates well between low- and high-risk patients and is suitable for producing risk-adjusted provider mortality statistics.
Increased use and improved methodology of carbonate clumped isotope thermometry has greatly enhanced our ability to interrogate a suite of Earth‐system processes. However, interlaboratory ...discrepancies in quantifying carbonate clumped isotope (Δ47) measurements persist, and their specific sources remain unclear. To address interlaboratory differences, we first provide consensus values from the clumped isotope community for four carbonate standards relative to heated and equilibrated gases with 1,819 individual analyses from 10 laboratories. Then we analyzed the four carbonate standards along with three additional standards, spanning a broad range of δ47 and Δ47 values, for a total of 5,329 analyses on 25 individual mass spectrometers from 22 different laboratories. Treating three of the materials as known standards and the other four as unknowns, we find that the use of carbonate reference materials is a robust method for standardization that yields interlaboratory discrepancies entirely consistent with intralaboratory analytical uncertainties. Carbonate reference materials, along with measurement and data processing practices described herein, provide the carbonate clumped isotope community with a robust approach to achieve interlaboratory agreement as we continue to use and improve this powerful geochemical tool. We propose that carbonate clumped isotope data normalized to the carbonate reference materials described in this publication should be reported as Δ47 (I‐CDES) values for Intercarb‐Carbon Dioxide Equilibrium Scale.
Key Points
The exclusive use of carbonate reference materials is a robust method for the standardization of clumped isotope measurements
Measurements using different acid temperatures, designs of preparation lines, and mass spectrometers are statistically indistinguishable
We propose new consensus values for a set of seven carbonate reference materials and updated guidelines to report clumped isotope measurements
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