Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function

The glycocalyx component and sialomucin podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumor types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high and low surface levels occur in parallel subpopulations within cancer cells. Orthotopic intraprostatic xenograft of PODXL-manipulated cells or those with different surface levels of PODXL define that this axis controls metastasis in vivo. Clinically, interplay between PODXL-GAL3 stratifies prostate cancer patients with poor outcome. Our studies define the molecular mechanisms and context in which PODXL promotes invasion and metastasis

Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial

Background The optimal timing of anticoagulation for patients with acute ischaemic stoke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation. Methods We performed a multicentre, open-label, blinded-endpoint, parallel-group, phase 4, randomised controlled trial at 100 UK hospitals. Adults with atrial fibrillation and a clinical diagnosis of acute ischaemic stroke and whose physician was uncertain of the optimal timing for DOAC initiation were eligible for inclusion in the study. We randomly assigned participants (1:1) to early (ie, ≤4 days from stroke symptom onset) or delayed (ie, 7–14 days) anticoagulation initiation with any DOAC, using an independent online randomisation service with random permuted blocks and varying block length, stratified by stroke severity at randomisation. Participants and treating clinicians were not masked to treatment assignment, but all outcomes were adjudicated by a masked independent external adjudication committee using all available clinical records, brain imaging reports, and source images. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days in a modified intention-to-treat population. We used a gatekeeper approach by sequentially testing for a non-inferiority margin of 2 percentage points, followed by testing for superiority. OPTIMAS is registered with ISRCTN (ISRCTN17896007) and ClinicalTrials.gov (NCT03759938), and the trial is ongoing. FindingsBetween July 5, 2019, and Jan 31, 2024, 3648 patients were randomly assigned to early or delayed DOAC initiation. 27 participants did not fulfil the eligibility criteria or withdrew consent to include their data, leaving 3621 patients (1814 in the early group and 1807 in the delayed group; 1981 men and 1640 women) in the modified intention-to-treat analysis. The primary outcome occurred in 59 (3·3%) of 1814 participants in the early DOAC initiation group compared with 59 (3·3%) of 1807 participants in the delayed DOAC initiation group (adjusted risk difference [RD] 0·000, 95% CI –0·011 to 0·012). The upper limit of the 95% CI for the adjusted RD was less than the non-inferiority margin of 2 percentage points (pnon-inferiority =0·0003). Superiority was not identified (psuperiority =0·96). Symptomatic intracranial haemorrhage occurred in 11 (0·6%) participants allocated to the early DOAC initiation group compared with 12 (0·7%) participants allocated to the delayed DOAC initiation group (adjusted RD 0·001, –0·004 to 0·006; p=0·78). Interpretation Early DOAC initiation within 4 days after ischaemic stroke associated with atrial fibrillation was noninferior to delayed initiation for the composite outcome of ischaemic stroke, intracranial haemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Our findings do not support the current common and guideline-supported practice of delaying DOAC initiation after ischaemic stroke with atrial fibrillation

Paediatric airway management: What is new?

Airway management plays a pivotal role in Paediatric Anaesthesia. Over the last two decades many improvements in this area have helped us to overcome this final frontier. From an era where intubation with a conventional laryngoscope or blind nasal intubation was the only tool for airway management, we have come a long way. Today supraglottic airway devices have pride of place in the Operating Room and are becoming important airway devices used in routine procedures. Direct and indirect fibreoptic laryngoscopes and transtracheal devices help us overcome difficult and previously impossible airway situations. These developments mean that we need to update our knowledge on these devices. Also much of our basic understanding of the physiology and anatomy of the paediatric airway has changed. This article attempts to shed light on some of the most important advances/opinions in paediatric airway management like, cuffed endotracheal tubes, supraglottic airway devices, video laryngoscopes, rapid sequence intubation, the newly proposed algorithm for difficult airway management and the role of Ex Utero Intrapartum Treatment (EXIT) procedure in the management of the neonatal airway

Association of blood pressure and BMI to corrected QT interval in young adults

Hypertension is often associated with obesity. Uncontrolled hypertension can lead to uncorrected cardiac dysautonomia that makes cardiac repolarization abnormally prolonged. Modern dietary habits, stress, and bad lifestyle habits make young adults vulnerable to hazards of health. We planned to study the association of body mass index (BMI) and blood pressure (BP) with corrected QT (QTc) intervals in young adults. After obtaining the written informed consent, 171 subjects were randomly selected in the age group of 18–35 years. A general history and physical examination were done before recording the BMI and BP. A 12-lead electrocardiogram was recorded and QTc calculated using Bazett’s formula. The values obtained were compared and statistical analysis done. Of the 171 subjects 14.03% were hypertensive. The QTc interval was found to be prolonged in females and it is prolonged with age, BMI, and BP. QTc was significantly increased among the prehypertensive and hypertensive group and with the overweight and (or) obese BMI group compared with the normotensives and normal BMI group suggesting an altered autonomic homeostasis. This warrants lifestyle modification at a younger age to reduce the cardiovascular risk. </jats:p

ASSOCIATION OF BLOOD PRESSURE AND BMI WITH QTc INTERVAL IN YOUNG ADULTS

Background: Hypertension is often associated with obesity. Uncontrolled hypertension can lead to uncorrected cardiac dysautonomia that makes cardiac repolarization abnormally prolonged. Modern dietary habits, stress and bad life style habits makes young adults vulnerable to hazards of health. Purpose: So we planned to study the association of BMI (Body Mass Index) and BP ( Blood pressure) with QTc (corrected QT interval) in young adults. Materials and methods: After obtaining the written informed consent, 171 subjects were randomly selected in the age group of 18-35 years. A general history and physical examination was done before recording the BMI and BP. A 12 lead ECG was recorded and QTc calculated using Bazett’s formula. The values obtained were compared and statistical analysis done. Results: Of the 171 subjects 14.03% were hypertensive. The QTc interval is found to be prolonged in females and it is prolonged with age, BMI and BP. Conclusion: QTc was significantly increased among the prehypertensive and hypertensive group and with overweight / obese BMI group compared to the normotensives and normal BMI group suggesting an altered autonomic homeostasis. This warrants lifestyle modification at a younger age to reduce the cardiovascular risk.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author