Abstract
Oral anticoagulation in patients presenting with non-valvular atrial fibrillation and a CHA2DS2-VASc score of 1 (CHA2DS2-VASc of 2 in women) remains a challenging approach in clinical ...practice. Therapeutic decisions need to balance the individual benefit of reducing thromboembolic risk against the potential harm due to an increase in bleeding risk in this intermediate risk patient population. Within the current opinion statement of the European Society of Cardiology working group of cardiovascular pharmacotherapy and the European Society of Cardiology council on stroke the currently available evidence on the anti-thrombotic management in patients presenting with a CHA2DS2-VASc of 1 is summarized. Easily applicable tools for a personalized refinement of the individual thromboembolic risk in patients with atrial fibrillation and a CHA2DS2-VASc score of 1 that guide clinicians through the question whether to anticoagulate or not are provided.
Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse ...summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
Abstract Use of glyburide in gestational diabetes (GDM) has raised concerns about fetal and neonatal side effects, including increased birth weight. Placental nutrient transport is a key determinant ...of fetal growth, however the effect of glyburide on placental nutrient transporters is largely unknown. We hypothesized that glyburide treatment in GDM pregnancies is associated with increased expression of nutrient transporters in the syncytiotrophoblast plasma membranes. We collected placentas from GDM pregnancies who delivered at term and were treated with either diet modification (n = 15) or glyburide (n = 8). Syncytiotrophoblast microvillous (MVM) and basal (BM) plasma membranes were isolated and expression of glucose (glucose transporter 1; GLUT1), amino acid (sodium-coupled neutral amino acid transporter 2; SNAT2 and L-type amino acid transporter 1; LAT1) and fatty acid (fatty acid translocase; FAT/CD36, fatty acid transporter 2 and 4; FATP2, FATP4) transporters was determined by Western blot. Additionally, we determined GLUT1 expression by confocal microscopy in cultured primary human trophoblasts (PHT) after exposure to glyburide. Birth weight was higher in the glyburide-treated group as compared to diet-treated GDM women (3764 ± 126 g vs . 3386 ± 75 g; p < 0.05). GLUT1 expression was increased in both MVM (+50%; p < 0.01) and BM (+75%; p < 0.01). In contrast, MVM FAT/CD36 (−65%; p = 0.01) and FATP2 (−65%; p = 0.02) protein expression was reduced in mothers treated with glyburide. Glyburide increased membrane expression of GLUT1 in a dose-dependent manner in cultured PHT. This data is the first to show that glyburide increases GLUT1 expression in syncytiotrophoblast MVM and BM in GDM pregnancies, and may promote transplacental glucose delivery contributing to fetal overgrowth.
The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage ...disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.
Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.
The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.
Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron–positron colliders SLC and LEP. The data consist of 17 ...million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLD experiment using a polarised beam at SLC. The measurements include cross-sections, forward–backward asymmetries and polarised asymmetries. The mass and width of the Z boson,
m
Z
and
Γ
Z
, and its couplings to fermions, for example the
ρ
parameter and the effective electroweak mixing angle for leptons, are precisely measured:
m
Z
=
91.1875
±
0.0021
GeV
,
Γ
Z
=
2.4952
±
0.0023
GeV
,
ρ
ℓ
=
1.0050
±
0.0010
,
sin
2
θ
eff
lept
=
0.23153
±
0.00016
.
The number of light neutrino species is determined to be
2.9840
±
0.0082
, in agreement with the three observed generations of fundamental fermions.
The results are compared to the predictions of the Standard Model (SM). At the Z-pole, electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward–backward asymmetry in b-quark production shows the largest difference with respect to its SM expectation, at the level of 2.8 standard deviations.
Through radiative corrections evaluated in the framework of the Standard Model, the Z-pole data are also used to predict the mass of the top quark,
m
t
=
173
-
10
+
13
GeV
, and the mass of the W boson,
m
W
=
80.363
±
0.032
GeV
. These indirect constraints are compared to the direct measurements, providing a stringent test of the SM. Using in addition the direct measurements of
m
t
and
m
W
, the mass of the as yet unobserved SM Higgs boson is predicted with a relative uncertainty of about 50% and found to be less than
285
GeV
at 95% confidence level.
Abstract The purpose of this study was to determine if cobalt and chromium ion levels can predict soft tissue damage at total hip revision. This study included 90 metal-on-metal total hip patients ...with preoperative cobalt and chromium ion levels. Tissue damage noted at revision surgery was graded on a 4-point scale. Sensitivity, specificity, and predictive values were calculated for various threshold values. Receiver operating characteristic analysis was conducted. Using 7 ppb as a threshold, cobalt and chromium ion levels had poor sensitivity and specificity (Co, 65% and 56%; Cr, 29% and 75%). Positive predictive values for cobalt and chromium were only 48% and 26% respectively. The area under the curve was 0.37 for cobalt and 0.44 for chromium. The length of time to revision significantly correlated with tissue damage ( P = .001). Ion levels are unreliable predictors of periarticular soft tissue damage and should not be used in isolation as surgical intervention triggers.
With statins, the reported rate of adverse events differs widely between randomized clinical trials (RCTs) and observations in clinical practice, the rates being 1-2% in RCTs vs. 10-20% in the ...so-called real world. One possible explanation is the claim that RCTs mostly use a run-in period with a statin. This would exclude intolerant patients from remaining in the trial and therefore favour a bias towards lower rates of intolerance. We here review data from RCTs with more than 1000 participants with and without a run-in period, which were included in the Cholesterol Treatment Trialists Collaboration. Two major conclusions arise: (i) the majority of RCTs did not have a test dose of a statin in the run-in phase. (ii) A test dose in the run-in phase was not associated with a significantly improved adherence rate within that trial when compared to trials without a test dose. Taken together, the RCTs of statins reviewed here do not suggest a bias towards an artificially higher adherence rate because of a run-in period with a test dose of the statin. Other possible explanations for the apparent disparity between RCTs and real-world observations are also included in this review albeit mostly not supported by scientific data.
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