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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 -
Nature Biotechnology Jul 2023Oxytocin (OT), a peptide hormone and neuromodulator, is involved in diverse physiological and pathophysiological processes in the central nervous system and the...
Oxytocin (OT), a peptide hormone and neuromodulator, is involved in diverse physiological and pathophysiological processes in the central nervous system and the periphery. However, the regulation and functional sequences of spatial OT release in the brain remain poorly understood. We describe a genetically encoded G-protein-coupled receptor activation-based (GRAB) OT sensor called GRAB. In contrast to previous methods, GRAB enables imaging of OT release ex vivo and in vivo with suitable sensitivity, specificity and spatiotemporal resolution. Using this sensor, we visualize stimulation-induced OT release from specific neuronal compartments in mouse brain slices and discover that N-type calcium channels predominantly mediate axonal OT release, whereas L-type calcium channels mediate somatodendritic OT release. We identify differences in the fusion machinery of OT release for axon terminals versus somata and dendrites. Finally, we measure OT dynamics in various brain regions in mice during male courtship behavior. Thus, GRAB provides insights into the role of compartmental OT release in physiological and behavioral functions.
Topics: Male; Mice; Animals; Oxytocin; Neurons; Brain; Signal Transduction; Central Nervous System
PubMed: 36593404
DOI: 10.1038/s41587-022-01561-2 -
Military Psychology : the Official... 2023The reported that 39.1% of the civilian workforce in the United States performs physically demanding jobs that require lifting, carrying, pushing/pulling, kneeling,... (Review)
Review
The reported that 39.1% of the civilian workforce in the United States performs physically demanding jobs that require lifting, carrying, pushing/pulling, kneeling, stooping, crawling, and climbing activities in varied environmental conditions. United States military occupations are similar to those in the civilian sector involving equipment installation, emergency rescues, and maintenance, along with combat arms occupations. This article provides an overview of the types of criterion measures used to assess the physical domain and approaches for designing and evaluating the criteria. It also includes a method for generating criterion measures that are applicable across multiple jobs.
Topics: Humans; Military Personnel; Occupations; Posture; United States; Workforce
PubMed: 37352446
DOI: 10.1080/08995605.2022.2063008 -
Environmental Research Jun 2024Glyphosate is the most widely used herbicide worldwide, both in domestic and industrial settings. Experimental research in animal models has demonstrated changes in...
BACKGROUND
Glyphosate is the most widely used herbicide worldwide, both in domestic and industrial settings. Experimental research in animal models has demonstrated changes in muscle physiology and reduced contractile strength associated with glyphosate exposure, while epidemiological studies have shown associations between glyphosate exposure and adverse health outcomes in critical biological systems affecting muscle function.
METHODS
This study used data from a nationally representative survey of the non-institutionalized U.S. general population (NHANES, n = 2132). Urine glyphosate concentrations were determined by ion chromatography with tandem mass spectrometry. Hand grip strength (HGS) was measured using a Takei Dynamometer, and relative strength estimated as the ratio between HGS in the dominant hand and the appendicular lean mass (ALM) to body mass index (ALMBMI) ratio. Low HGS and low relative HGS were defined as 1 sex-, age- and race-specific SD below the mean. Physical function limitations were identified as significant difficulty or incapacity in various activities.
RESULTS
In fully-adjusted models, the Mean Differences (MD) and 95% confidence intervals [95%CI] per doubling increase in glyphosate concentrations were -0.55 [-1.09, -0.01] kg for HGS in the dominant hand, and -0.90 [-1.58. -0.21] kg for HGS/ALMBMI. The Odds Ratios (OR) [95% CI] for low HGS, low relative HGS and functional limitations by glyphosate concentrations were 1.27 [1.03, 1.57] for low HGS; 1.43 [1.05; 1.94] for low relative HGS; 1.33 [1.08, 1.63] for stooping, crouching or kneeling difficulty; 1.17 [0.91, 1.50] for lifting or carrying items weighting up to 10 pounds difficulty; 1.21 [1.01, 1.40] for standing up from armless chair difficulty; and 1.47 [1.05, 2.29] for ascending ten steps without pause difficulty.
CONCLUSIONS
Glyphosate exposure may be a risk factor for decreased grip strength and increased physical functional limitations. More studies investigating the influence of this and other environmental pollutants on functional aging are needed.
Topics: Glyphosate; Glycine; Humans; Male; Middle Aged; Female; Aged; Herbicides; Hand Strength; Environmental Exposure; Nutrition Surveys
PubMed: 38452917
DOI: 10.1016/j.envres.2024.118547 -
IScience Jul 2023Galectins are a group of carbohydrate-binding proteins with a presumed immunomodulatory role and an elusive function on antigen-presenting cells. Here we analyzed the...
Galectins are a group of carbohydrate-binding proteins with a presumed immunomodulatory role and an elusive function on antigen-presenting cells. Here we analyzed the expression of galectin-1 and found upregulation of galectin-1 in the extracellular matrix across multiple tumors. Performing an in-depth and dynamic proteomic and phosphoproteomic analysis of human macrophages stimulated with galectin-1, we show that galectin-1 induces a tumor-associated macrophage phenotype with increased expression of key immune checkpoint protein programmed cell death 1 ligand 1 (PD-L1/CD274) and immunomodulator indoleamine 2,3-dioxygenase-1 (IDO1). Galectin-1 induced IDO1 and its active metabolite kynurenine in a dose-dependent manner through JAK/STAT signaling. In a 3D organotypic tissue model system equipped with genetically engineered tumorigenic epithelial cells, we analyzed the cellular source of galectin-1 in the extracellular matrix and found that galectin-1 is derived from epithelial and stromal cells. Our results highlight the potential of targeting galectin-1 in immunotherapeutic treatment of human cancers.
PubMed: 37534161
DOI: 10.1016/j.isci.2023.106984 -
Annals of Surgery Oct 2023Examine the potential benefit of total pancreatectomy (TP) as an alternative to pancreatoduodenectomy (PD) in patients at high risk for postoperative pancreatic fistula... (Meta-Analysis)
Meta-Analysis
Systematic Review and Meta-analysis of the Role of Total Pancreatectomy as an Alternative to Pancreatoduodenectomy in Patients at High Risk for Postoperative Pancreatic Fistula: Is it a Justifiable Indication?
OBJECTIVE
Examine the potential benefit of total pancreatectomy (TP) as an alternative to pancreatoduodenectomy (PD) in patients at high risk for postoperative pancreatic fistula (POPF).
SUMMARY BACKGROUND DATA
TP is mentioned as an alternative to PD in patients at high risk for POPF, but a systematic review is lacking.
METHODS
Systematic review and meta-analyses using Pubmed, Embase (Ovid), and Cochrane Library to identify studies published up to October 2022, comparing elective single-stage TP for any indication versus PD in patients at high risk for POPF. The primary endpoint was short-term mortality. Secondary endpoints were major morbidity (i.e., Clavien-Dindo grade ≥IIIa) on the short-term and quality of life.
RESULTS
After screening 1212 unique records, five studies with 707 patients (334 TP and 373 high-risk PD) met the eligibility criteria, comprising one randomized controlled trial and four observational studies. The 90-day mortality after TP and PD did not differ (6.3% vs. 6.2%; RR=1.04 [95%CI 0.56-1.93]). Major morbidity rate was lower after TP compared to PD (26.7% vs. 38.3%; RR=0.65 [95%CI 0.48-0.89]), but no significance was seen in matched/randomized studies (29.0% vs. 36.9%; RR = 0.73 [95%CI 0.48-1.10]). Two studies investigated quality of life (EORTC QLQ-C30) at a median of 30-52 months, demonstrating comparable global health status after TP and PD (77% [±15] vs. 76% [±20]; P =0.857).
CONCLUSIONS
This systematic review and meta-analysis found no reduction in short-term mortality and major morbidity after TP as compared to PD in patients at high risk for POPF. However, if TP is used as a bail-out procedure, the comparable long-term quality of life is reassuring.
Topics: Humans; Pancreatectomy; Pancreaticoduodenectomy; Pancreatic Fistula; Quality of Life; Pancreas; Postoperative Complications
PubMed: 37161977
DOI: 10.1097/SLA.0000000000005895 -
Alzheimer's Research & Therapy Apr 2024Neurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in...
BACKGROUND
Neurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in cerebral amyloid angiopathy (CAA), but studies investigating the potential of NFL and GFAP as markers for CAA are lacking. We aimed to investigate NFL and GFAP as biomarkers for neuroaxonal damage and astrocytosis in CAA.
METHODS
For this cross-sectional study serum and cerebrospinal fluid (CSF) samples were collected between 2010 and 2020 from controls, (pre)symptomatic Dutch-type hereditary (D-CAA) mutation-carriers and participants with sporadic CAA (sCAA) from two prospective CAA studies at two University hospitals in the Netherlands. NFL and GFAP levels were measured with Simoa-assays. The association between NFL and GFAP levels and age, cognitive performance (MoCA), CAA-related MRI markers (CAA-CSVD-burden) and Aβ40 and Aβ42 levels in CSF were assessed with linear regression adjusted for confounders. The control group was divided in age < 55 and ≥55 years to match the specific groups.
RESULTS
We included 187 participants: 28 presymptomatic D-CAA mutation-carriers (mean age 40 years), 29 symptomatic D-CAA participants (mean age 58 years), 59 sCAA participants (mean age 72 years), 33 controls < 55 years (mean age 42 years) and 38 controls ≥ 55 years (mean age 65 years). In presymptomatic D-CAA, only GFAP in CSF (7.7*10pg/mL vs. 4.4*10pg/mL in controls; P<.001) was increased compared to controls. In symptomatic D-CAA, both serum (NFL:26.2pg/mL vs. 12.5pg/mL; P=0.008, GFAP:130.8pg/mL vs. 123.4pg/mL; P=0.027) and CSF (NFL:16.8*10pg/mL vs. 7.8*10pg/mL; P=0.01 and GFAP:11.4*10pg/mL vs. 7.5*10pg/mL; P<.001) levels were higher than in controls and serum levels (NFL:26.2pg/mL vs. 6.7pg/mL; P=0.05 and GFAP:130.8pg/mL vs. 66.0pg/mL; P=0.004) were higher than in pre-symptomatic D-CAA. In sCAA, only NFL levels were increased compared to controls in both serum (25.6pg/mL vs. 12.5pg/mL; P=0.005) and CSF (20.0*10pg/mL vs 7.8*10pg/mL; P=0.008). All levels correlated with age. Serum NFL correlated with MoCA (P=0.008) and CAA-CSVD score (P<.001). NFL and GFAP in CSF correlated with Aβ42 levels (P=0.01/0.02).
CONCLUSIONS
GFAP level in CSF is an early biomarker for CAA and is increased years before symptom onset. NFL and GFAP levels in serum and CSF are biomarkers for advanced CAA.
Topics: Humans; Neurofilament Proteins; Glial Fibrillary Acidic Protein; Female; Male; Middle Aged; Cross-Sectional Studies; Biomarkers; Aged; Cerebral Amyloid Angiopathy; Amyloid beta-Peptides; Adult; Prospective Studies; Magnetic Resonance Imaging
PubMed: 38654326
DOI: 10.1186/s13195-024-01457-0 -
Scientific Reports Oct 2023Linguistic experience plays a clear role in accounting for variability in sentence comprehension behavior across individuals and across sentence types. We aimed to...
Linguistic experience plays a clear role in accounting for variability in sentence comprehension behavior across individuals and across sentence types. We aimed to understand how individual differences in reading experience predict reading behavior. Corpus analyses revealed the frequencies with which our experimental items appeared in written and spoken language. We hypothesized that reading experience should affect sentence comprehension most substantially for sentence types that individuals primarily encounter through written language. Readers with more text exposure were faster and more accurate readers overall, but they read sentence types biased to written language particularly faster than did readers with less text exposure. We see clear effects of text exposure on sentence comprehension in ways that allow explicit links between written and spoken corpus statistics and behavior. We discuss theoretical implications of effects of text exposure for experience-based approaches to sentence processing.
Topics: Humans; Comprehension; Individuality; Language; Linguistics; Reading
PubMed: 37798346
DOI: 10.1038/s41598-023-43801-8