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The New England Journal of Medicine Jun 2023The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear.
METHODS
We performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Assessors were unaware of the trial-group assignments. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days.
RESULTS
Of 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and 41 participants (4.1%) in the later-treatment group (risk difference, -1.18 percentage points; 95% confidence interval [CI], -2.84 to 0.47) by 30 days. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29 to 1.07) by 30 days and in 18 participants (1.9%) and 30 participants (3.1%), respectively, by 90 days (odds ratio, 0.60; 95% CI, 0.33 to 1.06). Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups by 30 days.
CONCLUSIONS
In this trial, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher (based on the 95% confidence interval) with early than with later use of DOACs. (Funded by the Swiss National Science Foundation and others; ELAN ClinicalTrials.gov number, NCT03148457.).
Topics: Humans; Anticoagulants; Atrial Fibrillation; Embolism; Hemorrhage; Intracranial Hemorrhages; Ischemic Stroke; Stroke; Treatment Outcome; Time Factors; Factor Xa Inhibitors; Recurrence
PubMed: 37222476
DOI: 10.1056/NEJMoa2303048 -
Expert Review of Clinical Pharmacology Aug 2020Methylphenidate remains a first-line medication for treating ADHD in children and adults. However, its behavioral pharmacological similarities to methamphetamine and... (Review)
Review
INTRODUCTION
Methylphenidate remains a first-line medication for treating ADHD in children and adults. However, its behavioral pharmacological similarities to methamphetamine and cocaine have historically created concern for its potential as a drug of abuse. In September 2019, the FDA published a docket requesting comments for the development of abuse deterrent formulations for CNS stimulants, emphasizing the abuse of methylphenidate as a public health concern.
AREAS COVERED
We conducted a narrative review of research on the clinical pharmacology, therapeutic efficacy, and abuse potential of methylphenidate.
EXPERT OPINION
Several studies indicate that methylphenidate has at least some abuse potential. Methylphenidate, amphetamine, methamphetamine, and cocaine overlap in their subjective, reinforcing, and discriminative stimulus effects. Regardless, methylphenidate remains an efficacious treatment for ADHD in children and adults when properly adhered to, especially when paired with non-pharmacological treatments. The development of abuse deterrent formulations of methylphenidate is warranted.
Topics: Abuse-Deterrent Formulations; Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Humans; Methylphenidate; Substance-Related Disorders
PubMed: 32715789
DOI: 10.1080/17512433.2020.1796636 -
Journal of Alternative and... Oct 2020The aim of this systematic review with meta-analysis was to describe the status on the effects of physical scar treatments on pain, pigmentation, pliability, pruritus,... (Meta-Analysis)
Meta-Analysis
The aim of this systematic review with meta-analysis was to describe the status on the effects of physical scar treatments on pain, pigmentation, pliability, pruritus, scar thickening, and surface area. Systematic review and meta-analysis. Adults with any kind of scar tissue. Physical scar management versus control or no scar management. Pain, pigmentation, pliability, pruritus, surface area, scar thickness. The overall results revealed that physical scar management is beneficial compared with the control treatment regarding the management of pain ( = 0.012), pruritus ( < 0.001), pigmentation ( = 0.010), pliability ( < 0.001), surface area ( < 0.001), and thickness ( = 0.022) of scar tissue in adults. The observed risk of bias was high for blinding of participants and personnel (47%) and low for other bias (100%). Physical scar management demonstrates moderate-to-strong effects on improvement of scar issues as related to signs and symptoms. These results show the importance of specific physical management of scar tissue.
Topics: Cicatrix; Female; Humans; Male; Pigmentation Disorders; Postoperative Complications; Pruritus; Wound Healing
PubMed: 32589450
DOI: 10.1089/acm.2020.0109 -
Journal of Neurochemistry Sep 2019Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease and is estimated to affect approximately 1-4% of individuals aged over... (Review)
Review
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease and is estimated to affect approximately 1-4% of individuals aged over 60 years old. Although considerable efforts have been invested into developing disease-modifying therapies for Parkinson's disease, such efforts have been confounded by the difficulty in accurately diagnosing Parkinson's disease during life to enable accurate patient stratification for clinical trialling of candidate therapeutics. Therefore, the search for effective biomarkers that can be accurately evaluated during life with non-invasive means is a pressing issue in the field. Since the discovery of α-synuclein (α-syn) as a protein linked to a familial form of Parkinson's disease, later identified as the major protein component of the neuropathological hallmark of idiopathic Parkinson's disease, considerable interest has focused on this protein and its distinct conformers. We describe here the progress that has been made in the area of Parkinson's disease biomarker discovery with a focus on α-synuclein. In particular, we highlight the novel assays that have been employed and the increasing complexity in evaluating α-synuclein with regard to the considerable diversity of conformers that exist in the biofluids and peripheral tissues under disease conditions. "This article is part of the Special Issue Synuclein."
Topics: Biomarkers; Blotting, Western; Body Fluids; Brain; Cross-Sectional Studies; Disease Progression; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Gonads; Humans; Longitudinal Studies; Mass Spectrometry; Mucous Membrane; Organ Specificity; Parkinson Disease; Phosphorylation; Positron-Emission Tomography; Protein Aggregates; Protein Processing, Post-Translational; Salivary Glands; Skin; alpha-Synuclein
PubMed: 31265130
DOI: 10.1111/jnc.14809 -
Brain : a Journal of Neurology Apr 2023Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of...
Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aβ-status (i.e. abnormal CSF Aβ42/40) at baseline; and 45 of these Aβ-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ status [area under curve (AUC) = 0.947; Pdiff < 0.015] or progression to Alzheimer's dementia (AUC = 0.932; Pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886-0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange 0.835-0.872; Pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUCrange 0.642-0.813; Pdiff ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; Pdiff = 0.003 versus p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange 0.320-0.669). In conclusion, our findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aβ or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aβ-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future.
Topics: Humans; Female; Aged; Male; Alzheimer Disease; tau Proteins; Amyloid beta-Peptides; Cognitive Dysfunction; Brain; Biomarkers
PubMed: 36087307
DOI: 10.1093/brain/awac333 -
International Journal of Sports... 2022Lifting something off the ground is an essential task and lifting is a documented risk factor for low back pain (LBP). The standard lifting techniques are stoop (lifting...
UNLABELLED
Lifting something off the ground is an essential task and lifting is a documented risk factor for low back pain (LBP). The standard lifting techniques are stoop (lifting with your back), squat (lifting with your legs), and semi-squat (midway between stoop and squat). Most clinicians believe the squat technique is optimal; however, training on squat lifting does not prevent LBP and utilizing greater lumbar flexion (i.e. stoop) when lifting is not a risk factor for LBP. The disconnect between what occurs in clinical practice and what the evidence suggests has resulted in ongoing debate. Clinicians must ask the right questions in order to apply the evidence appropriately. A proposed clinical framework of calm tissue down, build tissue up, improve work capacity can be used to determine which lifting technique is optimal for a patient at any given time. When applying this clinical framework, clinicians should consider metabolic, biomechanical, physical stress tolerance, and pain factors in order to address the movement system. For example, stoop lifting is more metabolically efficient and less challenging to the cardiopulmonary system. There may be few biomechanical differences in spinal postures and gross loads on the lumbar spine between stoop, squat, and semi-squat lifting; however, each lift has distinct kinematic patterns that affects muscle activation patterns, and ultimately the movement system. Clinicians must find the optimal dosage of physical stress to address all aspects of the movement system to minimize the risk of injury. There is no universal consensus on the optimal lifting technique which will satisfy every situation; however, there may be a lifting technique that optimizes movement to achieve a specific outcome. The calm tissue down, build tissue up, improve work capacity framework offers an approach to determine the best lifting technique for an individual patient at any give time.
LEVEL OF EVIDENCE
5.
PubMed: 35024210
DOI: 10.26603/001c.30023 -
Nature Oct 2021Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue. There are no...
Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue. There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development.
Topics: Animals; Antiviral Agents; Dengue; Dengue Virus; Disease Models, Animal; Female; Male; Membrane Proteins; Mice; RNA Helicases; Serine Endopeptidases; Viral Load; Viral Nonstructural Proteins; Viremia; Virus Replication
PubMed: 34616043
DOI: 10.1038/s41586-021-03990-6 -
Evidence-based Dentistry Mar 2020Design Systematic reviewStudy population Orthodontic patients undergoing treatment with removable thermoplastic retainers compared with conventional fixed orthodontic...
Design Systematic reviewStudy population Orthodontic patients undergoing treatment with removable thermoplastic retainers compared with conventional fixed orthodontic appliances. The mean age of patients was between 15 and 33 years. Data sources Six electronic databases including: Scopus, Web-of-Science, PubMed, Cochrane, Clinical Trials and Grey Literature were searched in addition to a search of references in eligible studies with no restriction of language. Out of 559 studies, 55 were eligible. Only four articles were included; three non-randomised and one randomised controlled trial (RCT) involving 96-182 patients. The studies included were completed within 2005-2016.Study selection Clinical trials involving orthodontic patients undergoing treatment using thermoplastic removeable aligners, namely Invisalign, in comparison to conventional fixed orthodontic appliances of either self-ligating or tip-edge bracket systems were included.Data extraction and synthesis Two members of the research team independently selected articles which fulfilled the inclusion criteria and compared results prior to data collection. A third party examiner was available to resolve disagreements. The study quality was analysed for presence of bias; three non-randomised studies were evaluated and scored using the Methodological Index for Non-Randomised Studies (MINORS), one study was considered high methodological quality, two were considered moderate. The RCT was assessed using the Cochrane Collaboration Common Scheme for Bias and was deemed to be low risk of bias. Results The results suggest that Invisalign can provide successful alignment, however, it poses difficulties in achieving occlusal contacts, buccolingual inclination and vertical movement of teeth. One study found that Invisalign cases are more susceptible to relapse, which can be explained through the tipping mechanism compared to bodily movement, of conventional fixed appliances. Furthermore some studies show that although using aligners can result in overall shorter treatment time the final occlusion was not favourable. The outcome of the RCT, showed that aligners can be successful in treating class I malocclusions in extraction cases.Conclusions This systematic review found that the use of clear aligners made no significant difference to treatment time compared with conventional appliances. Additionally, removable aligners were effective in crowding cases but had limitations in achieving favourable outcomes in the anterior-posterior position and final occlusion, as well as being more likely to relapse post treatment.
Topics: Adolescent; Adult; Esthetics, Dental; Humans; Malocclusion; Malocclusion, Angle Class I; Orthodontic Appliances, Fixed; Orthodontic Appliances, Removable; Young Adult
PubMed: 32221494
DOI: 10.1038/s41432-020-0079-5 -
Nature Neuroscience Apr 2023Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for...
Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience.
Topics: Rats; Animals; Brain; Brain Mapping; Consensus; Neuroimaging; Magnetic Resonance Imaging
PubMed: 36973511
DOI: 10.1038/s41593-023-01286-8