Observations are reported of different sources of CP violation from an amplitude analysis of B^{+}→π^{+}π^{+}π^{-} decays, based on a data sample corresponding to an integrated luminosity of 3 ...fb^{-1} of pp collisions recorded with the LHCb detector. A large CP asymmetry is observed in the decay amplitude involving the tensor f_{2}(1270) resonance, and in addition significant CP violation is found in the π^{+}π^{-}S wave at low invariant mass. The presence of CP violation related to interference between the π^{+}π^{-}S wave and the P wave B^{+}→ρ(770)^{0}π^{+} amplitude is also established; this causes large local asymmetries but cancels when integrated over the phase space of the decay. The results provide both qualitative and quantitative new insights into CP -violation effects in hadronic B decays.
Long-lived particles decaying to
e
±
μ
∓
ν
, with masses between 7 and
50
GeV/
c
2
and lifetimes between 2 and
50
ps
, are searched for by looking at displaced vertices containing electrons and muons ...of opposite charges. The search is performed using
5.4
fb
-
1
of
p
p
collisions collected with the LHCb detector at a centre-of-mass energy of
s
=
13
TeV
. Three mechanisms of production of long-lived particles are considered: the direct pair production from quark interactions, the pair production from the decay of a Standard-Model-like Higgs boson with a mass of
125
GeV/
c
2
, and the charged current production from an on-shell
W
boson with an additional lepton. No evidence of these long-lived states is obtained and upper limits on the production cross-section times branching fraction are set on the different production modes.
Following electrical stimulation of perianal skin, short latency evoked electromyographic (EMG) responses from the external and sphincter have been interpreted as the electrophysiological correlate ...of the anal reflex. Delayed responses in patients with idiopathic faecal incontinence have been interpreted as evidence for denervation of the external anal sphincter. Electrically evoked responses were studied in normal subjects, either before and during spinal anaesthesia (n = 8), or before and during competitive neuromuscular blockade (n = 4), instituted for operative purposes. Short latency responses persisted unchanged in either latency or duration during spinal anaesthesia whereas long latency responses were completely abolished. Both short and long latency responses were abolished during competitive neuromuscular blockade. Short latency responses are not spinal reflex in nature, but due to stimulus activation of alpha-motoneuronal terminal branches. Delayed responses in incontinent patients cannot be interpreted as evidence for pudendal neuropathy. Long latency (i.e. greater than 40 ms) responses demand a functional sacral spinal cord and represent the true anal reflex. Their wide range of latency in normal subjects suggests this measurement will be of little use in confirming the presence or absence of pudendal neuropathy, and that other measures of neuropathy may be more appropriate.
Neoadjuvant intratumoral cisplatin has the potential to generate substantial cytotoxicity and immune priming within the tumor environment, while minimizing systemic, off-target, adverse events. We ...initiated a phase 1A, 3+3 dose-ranging study of neoadjuvant, intratumoral cisplatin, delivered through endobronchial ultrasound bronchoscopy, in the same procedure as the initial diagnosis. There were no dose-limiting toxicity identified at the 20mg level
By means of high-resolution cosmological hydrodynamical simulations of Milky Way (MW) like disc galaxies, we conduct an analysis of the associated stellar metallicity distribution functions (MDFs). ...After undertaking a kinematic decomposition of each simulation into spheroid and disc subcomponents, we compare the predicted MDFs to those observed in the solar neighbourhood and the Galactic bulge. The effects of the star formation density threshold are visible in the star formation histories, which show a modulation in their behaviour driven by the threshold. The derived MDFs show median metallicities lower by 0.2-0.3 dex than the MDF observed locally in the disc and in the Galactic bulge. Possible reasons for this apparent discrepancy include the use of low stellar yields and/or centrally concentrated star formation. The dispersions are larger than the one of the observed MDF; this could be due to simulated discs being kinematically hotter relative to the MW. The fraction of low-metallicity stars is largely overestimated, visible from the more negatively skewed MDF with respect to the observational sample. For our fiducial MW analogue, we study the metallicity distribution of the stars born in situ relative to those formed via accretion (from disrupted satellites), and demonstrate that this low-metallicity tail to the MDF is populated primarily by accreted stars. Enhanced supernova and stellar radiation energy feedback to the surrounding interstellar media of these pre-disrupted satellites is suggested as an important regulator of the MDF skewness.
Early and complete restoration of target vessel patency in ST-elevation myocardial infarction (STEMI) is associated with improved outcomes. Oral P2Y12 inhibitors have failed to demonstrate either ...improved patency or reduced mortality when administered in the prehospital setting. Thus, there is a need for antiplatelet agents that achieve prompt and potent platelet inhibition, and that restore patency in the prehospital setting. Zalunfiban, a novel subcutaneously administered glycoprotein IIb/IIIa inhibitor designed for prehospital administration, has shown to achieve rapid, high-grade platelet inhibition that exceeds that of P2Y12 inhibitors. Whether prehospital administration of zalunfiban can improve clinical outcome is unknown.
The present study is designed to assess the hypothesis that a single, prehospital injection of zalunfiban given in the ambulance, in addition to standard-of-care in patients with STEMI with intent to undergo primary percutaneous coronary intervention (PCI) will improve clinical outcome compared to standard-of-care with placebo.
The ongoing CELEBRATE trial (NCT04825743) is a phase 3, randomized, double-blinded, placebo-controlled, international trial. Patients with STEMI intended to undergo primary PCI will receive treatment with a single subcutaneous injection containing either zalunfiban dose 1 (0.110 mg/kg), zalunfiban dose 2 (0.130 mg/kg) or placebo, and the study drug will be administered in the ambulance before transportation to the hospital. A target of 2499 patients will be randomly assigned to one of the treatment groups in a 1:1:1 ratio, ie, to have approximately 833 evaluable patients per group. The primary efficacy outcome is a ranked 7-point scale on clinical outcomes. The primary safety outcome is severe or life-threatening bleeding according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria.
The CELEBRATE trial will assess whether a single prehospital subcutaneous injection of zalunfiban in addition to standard-of-care in patients with STEMI with intent to undergo primary PCI will result in improved clinical outcome.
We have demonstrated in canines that somatic nerve transfer to vesical branches of the inferior hypogastric plexus (IHP) can be used for bladder reinnervation after spinal root injury. Yet, the ...complex anatomy of the IHP hinders the clinical application of this repair strategy. Here, using human cadavers, we clarify the spatial relationships of the vesical branches of the IHP and nearby pelvic ganglia, with the ureteral orifice of the bladder. Forty-four pelvic regions were examined in 30 human cadavers. Gross post-mortem and intra-operative approaches (open anterior abdominal, manual laparoscopic, and robot-assisted) were used. Nerve branch distances and diameters were measured after thorough visual inspection and gentle dissection, so as to not distort tissue. The IHP had between 1 to 4 vesical branches (2.33 ± 0.72, mean ± SD) with average diameters of 0.51 ± 0.06 mm. Vesical branches from the IHP arose from a grossly visible pelvic ganglion in 93% of cases (confirmed histologically). The pelvic ganglion was typically located 7.11 ± 6.11 mm posterolateral to the ureteral orifice in 69% of specimens. With this in-depth characterization, vesical branches from the IHP can be safely located both posterolateral to the ureteral orifice and emanating from a more proximal ganglionic enlargement during surgical procedures.
Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we ...report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the alpha 2 delta family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 ( alpha 2 delta 3) also exhibit impaired behavioral heat pain sensitivity. In addition, in humans, alpha 2 delta 3 SNP variants associate with reduced sensitivity to acute noxious heat and chronic back pain. Functional imaging in alpha 2 delta 3 mutant mice revealed impaired transmission of thermal pain-evoked signals from the thalamus to higher-order pain centers. Intriguingly, in alpha 2 delta 3 mutant mice, thermal pain and tactile stimulation triggered strong cross-activation, or synesthesia, of brain regions involved in vision, olfaction, and hearing.
Heterogeneity in disease course and treatment response among patients with MCD/FSGS necessitates a granular evaluation of kidney tissue features. This study aimed to identify histologic and ...ultrastructural descriptors of structural changes most predictive of clinical outcomes in the Nephrotic Syndrome Study Network (NEPTUNE).
Forty-eight histologic (37 glomerular, 9 tubulointerstitial, 2 vascular) and 20 ultrastructural descriptors were quantified by applying the NEPTUNE Digital Pathology Scoring System to NEPTUNE kidney biopsies. Outcomes included time from biopsy to disease progression, first complete remission of proteinuria, and treatment response. Relative importance of pathology and clinical predictors was obtained from random forest models, and predictive discrimination was assessed.
Among 224 participants (34% Black, 24% Hispanic), model performance was excellent, with predictive discrimination of 0.9 for disease progression, 0.85 for complete remission, and 0.81 for treatment response. The most predictive descriptors of outcomes included both conventional-
, global sclerosis or segmental sclerosis and interstitial fibrosis/tubular atrophy-and novel features, including adhesion, interstitial foam cells, deflation, periglomerular fibrosis, mononuclear white blood cells, endothelial cell abnormalities, microvillous transformation, and acute tubular injury.
The most predictive descriptors of clinical outcomes among MCD/FSGS patients reflected structural changes in multiple renal compartments. Reporting these descriptors should be standardized to guide prognostication of proteinuric glomerular diseases.
Symptomatic intracranial hemorrhage (sICH) is a serious complication of stroke thrombolytic therapy. Many stroke centers have adopted 0.25-mg/kg tenecteplase instead of alteplase for stroke ...thrombolysis based on evidence from randomized comparisons to alteplase as well as for its practical advantages. There have been no significant differences in symptomatic intracranial hemorrhage (sICH) reported from randomized clinical trials or published case series for the 0.25-mg/Kg dose.
To assess the risk of sICH following ischemic stroke in patients treated with tenecteplase compared to those treated with alteplase.
This was a retrospective observational study using data from the large multicenter international Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) collaboration comprising deidentified data on patients with ischemic stroke treated with intravenous thrombolysis. Data from more than 100 hospitals in New Zealand, Australia, and the US that used alteplase or tenecteplase for patients treated between July 1, 2018, and June 30, 2021, were included for analysis. Participating centers included a mix of nonthrombectomy- and thrombectomy-capacity comprehensive stroke centers. Standardized data were abstracted and harmonized from local or regional clinical registries. Consecutive patients with acute ischemic stroke who were considered eligible and received thrombolysis at the participating stroke registries during the study period were included. All 9238 patients who received thrombolysis were included in this retrospective analysis.
sICH was defined as clinical worsening of at least 4 points on the National Institutes of Health Stroke Scale (NIHSS), attributed to parenchymal hematoma, subarachnoid, or intraventricular hemorrhage. Differences between tenecteplase and alteplase in the risk of sICH were assessed using logistic regression, adjusted for age, sex, NIHSS score, and thrombectomy.
Of the 9238 patients included in the analysis, the median (IQR) age was 71 (59-80) years, and 4449 patients (48%) were female. Tenecteplase was administered to 1925 patients. The tenecteplase group was older (median IQR, 73 61-81 years vs 70 58-80 years; P < .001), more likely to be male (1034 of 7313 54% vs 3755 of 1925 51%; P < .01), had higher NIHSS scores (median IQR, 9 5-17 vs 7 4-14; P < .001), and more frequently underwent endovascular thrombectomy (38% vs 20%; P < .001). The proportion of patients with sICH was 1.8% for tenecteplase and 3.6% for alteplase (P < .001), with an adjusted odds ratio (aOR) of 0.42 (95% CI, 0.30-0.58; P < .01). Similar results were observed in both thrombectomy and nonthrombectomy subgroups.
In this large study, ischemic stroke treatment with 0.25-mg/kg tenecteplase was associated with lower odds of sICH than treatment with alteplase. The results provide evidence supporting the safety of tenecteplase for stroke thrombolysis in real-world clinical practice.
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