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Alzheimer's Research & Therapy May 2024Alzheimer disease (AD) is a major health problem of aging, with tremendous burden on healthcare systems, patients, and families globally. Lecanemab, an FDA-approved... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Alzheimer disease (AD) is a major health problem of aging, with tremendous burden on healthcare systems, patients, and families globally. Lecanemab, an FDA-approved amyloid beta (Aβ)-directed antibody indicated for the treatment of early AD, binds with high affinity to soluble Aβ protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils. Lecanemab has been shown to be well tolerated in multiple clinical trials, although risks include an increased rate of amyloid-related imaging abnormalities (ARIA) and infusion reactions relative to placebo.
METHODS
Clarity AD was an 18-month treatment (Core study), multicenter, double-blind, placebo-controlled, parallel-group study with open-label extension (OLE) in participants with early AD. Eligible participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly). Safety evaluations included monitoring of vital signs, physical examinations, adverse events, clinical laboratory parameters, and 12-lead electrocardiograms. ARIA occurrence was monitored throughout the study by magnetic resonance imaging, read both locally and centrally.
RESULTS
Overall, 1795 participants from Core and 1612 participants with at least one dose of lecanemab (Core + OLE) were included. Lecanemab was generally well-tolerated in Clarity AD, with no deaths related to lecanemab in the Core study. There were 9 deaths during the OLE, with 4 deemed possibly related to study treatment. Of the 24 deaths in Core + OLE, 3 were due to intracerebral hemorrhage (ICH): 1 placebo in the Core due to ICH, and 2 lecanemab in OLE with concurrent ICH (1 on tissue plasminogen activator and 1 on anticoagulant therapy). In the Core + OLE, the most common adverse events in the lecanemab group (> 10%) were infusion-related reactions (24.5%), ARIA with hemosiderin deposits (ARIA-H) microhemorrhages (16.0%), COVID-19 (14.7%), ARIA with edema (ARIA-E; 13.6%), and headache (10.3%). ARIA-E and ARIA-H were largely radiographically mild-to-moderate. ARIA-E generally occurred within 3-6 months of treatment, was more common in ApoE e4 carriers (16.8%) and most common in ApoE ε4 homozygous participants (34.5%).
CONCLUSIONS
Lecanemab was generally well-tolerated, with the most common adverse events being infusion-related reactions, ARIA-H, ARIA-E. Clinicians, participants, and caregivers should understand the incidence, monitoring, and management of these events for optimal patient care.
TRIAL REGISTRATION
ClinicalTrials.gov numbers: Clarity AD NCT03887455).
Topics: Humans; Alzheimer Disease; Male; Double-Blind Method; Female; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Middle Aged; Amyloid beta-Peptides; Magnetic Resonance Imaging; Treatment Outcome
PubMed: 38730496
DOI: 10.1186/s13195-024-01441-8 -
Medicine May 2024Marfan syndrome (MFS), which is a dominantly inherited connective tissue disease resulting from a mutation in the FBN1 gene, exhibits variable manifestations affecting...
RATIONALE
Marfan syndrome (MFS), which is a dominantly inherited connective tissue disease resulting from a mutation in the FBN1 gene, exhibits variable manifestations affecting the cardiovascular, musculoskeletal, ophthalmologic, and pulmonary systems. Notably, neurologic deficiency, which involves ischemic or hemorrhagic stroke, is a rare but severe manifestation. The safety of rt-PA treatment for ischemic stroke caused by MFS is still under discussion.
PATIENT CONCERNS
In the current report, we discuss 3 atypical MFS cases presented as acute ischemic stroke, compared to those exhibiting cardiovascular and musculoskeletal abnormalities.
DIAGNOSES
Three patients were diagnosed with acute ischemic stroke accompanied by MFS based on clinical manifestations, imaging examinations, and genetic testings.
INTERVENTIONS
The first case underwent intravenous thrombolytic therapy with rt-PA, the second case received antiplatelet therapy, and the third case received anticoagulant therapy and perfusion therapy.
OUTCOMES
The neurologic deficiency of all three patients showed improvement upon discharge, and there were no symptoms of recurrence observed during the follow-up period.
LESSONS SUBSECTIONS
MFS is a rare etiology in young people with embolic stroke of undetermined source. Physicians should take MFS into consideration when they observe the characteristic symptoms during a consultation. The potential pathogenesis of ischemic stroke secondary to MFS may include cardio-embolism, arterial dissection, and hypoperfusion. Although intravenous thrombolysis is a promising therapy to treat acute ischemic stroke, further examinations should be conducted to rule out contraindications in patients with a suspicion of MFS.
Topics: Humans; Marfan Syndrome; Ischemic Stroke; Male; Adult; Female; Thrombolytic Therapy; Tissue Plasminogen Activator; Anticoagulants; Platelet Aggregation Inhibitors
PubMed: 38728516
DOI: 10.1097/MD.0000000000037924 -
CNS Neuroscience & Therapeutics May 2024To investigate the characteristics of dynamic cerebral autoregulation (dCA) after intravenous thrombolysis (IVT) and assess the relationship between dCA and prognosis.
AIMS
To investigate the characteristics of dynamic cerebral autoregulation (dCA) after intravenous thrombolysis (IVT) and assess the relationship between dCA and prognosis.
METHODS
Patients with unilateral acute ischemic stroke receiving IVT were prospectively enrolled; those who did not were selected as controls. All patients underwent dCA measurements, by quantifying the phase difference (PD) and gain, at 1-3 and 7-10 days after stroke onset. Simultaneously, two dCA-based nomogram models were established to verify the predictive value of dCA for patients with mild-to-moderate stroke.
RESULTS
Finally, 202 patients who received IVT and 238 who did not were included. IVT was positively correlated with higher PD on days 1-3 and 7-10 after stroke onset. PD values in both sides at 1-3 days after stroke onset and in the affected side at 7-10 days after onset were independent predictors of unfavorable outcomes in patients who received IVT. Additionally, in patients with mild-to-moderate stroke who received IVT, the dCA-based nomogram models significantly improved the risk predictive ability for 3-month unfavorable outcomes.
CONCLUSION
IVT has a positive effect on dCA in patients with acute stroke; furthermore, dCA may be useful to predict the prognosis of patients with IVT.
Topics: Humans; Male; Female; Aged; Middle Aged; Prognosis; Thrombolytic Therapy; Homeostasis; Ischemic Stroke; Fibrinolytic Agents; Cerebrovascular Circulation; Prospective Studies; Tissue Plasminogen Activator; Administration, Intravenous; Predictive Value of Tests; Aged, 80 and over; Nomograms; Stroke
PubMed: 38727518
DOI: 10.1111/cns.14748 -
Journal of Animal Science and... May 2024In poultry, the smooth transition of follicles from the preovulatory-to-postovulatory phase impacts egg production in hens and can benefit the poultry industry. However,...
BACKGROUND
In poultry, the smooth transition of follicles from the preovulatory-to-postovulatory phase impacts egg production in hens and can benefit the poultry industry. However, the regulatory mechanism underlying follicular ovulation in avians is a complex biological process that remains unclear.
RESULTS
Critical biochemical events involved in ovulation in domestic chickens (Gallus gallus) were evaluated by transcriptomics, proteomics, and in vitro assays. Comparative transcriptome analyses of the largest preovulatory follicle (F1) and postovulatory follicle (POF1) in continuous laying (CL) and intermittent laying (IL) chickens indicated the greatest difference between CL_F1 and IL_F1, with 950 differentially expressed genes (DEGs), and the smallest difference between CL_POF1 and IL_POF1, with 14 DEGs. Additionally, data-independent acquisition proteomics revealed 252 differentially abundant proteins between CL_F1 and IL_F1. Perivitelline membrane synthesis, steroid biosynthesis, lysosomes, and oxidative phosphorylation were identified as pivotal pathways contributing to ovulation regulation. In particular, the regulation of zona pellucida sperm-binding protein 3, plasminogen activator, cathepsin A, and lactate dehydrogenase A (LDHA) was shown to be essential for ovulation. Furthermore, the inhibition of LDHA decreased cell viability and promoted apoptosis of ovarian follicles in vitro.
CONCLUSIONS
This study reveals several important biochemical events involved in the process of ovulation, as well as crucial role of LDHA. These findings improve our understanding of ovulation and its regulatory mechanisms in avian species.
PubMed: 38725063
DOI: 10.1186/s40104-024-01019-2 -
BMC Biotechnology May 2024Venous thromboembolism (VTE), is a noteworthy complication in individuals with gastric cancer, but the current diagnosis and treatment methods lack accuracy. In this...
BACKGROUND
Venous thromboembolism (VTE), is a noteworthy complication in individuals with gastric cancer, but the current diagnosis and treatment methods lack accuracy. In this study, we developed a t-PAIC chemiluminescence kit and employed chemiluminescence to detect the tissue plasminogen activator inhibitor complex (t-PAIC), thrombin-antithrombin III complex (TAT), plasmin-α2-plasmin inhibitor complex (PIC) and thrombomodulin (TM), combined with D-dimer and fibrin degradation products (FDP), to investigate their diagnostic potential for venous thrombosis in gastric cancer patients. The study assessed variations in six indicators among gastric cancer patients at different stages.
RESULTS
The t-PAIC reagent showed LOD is 1.2 ng/mL and a linear factor R greater than 0.99. The reagents demonstrated accurate results, with all accuracy deviations being within 5%. The intra-batch and inter-batch CVs for the t-PAIC reagent were both within 8%. The correlation coefficient R between this method and Sysmex was 0.979. Gastric cancer patients exhibited elevated levels of TAT, PIC, TM, D-D, FDP compared to the healthy population, while no significant difference was observed in t-PAIC. In the staging of gastric cancer, patients in III-IV stages exhibit higher levels of the six markers compared to those in I-II stages. The ROC curve indicates an enhancement in sensitivity and specificity of the combined diagnosis of four or six indicators.
CONCLUSION
Our chemiluminescence assay performs comparably to Sysmex's method and at a reduced cost. The use of multiple markers, including t-PAIC, TM, TAT, PIC, D-D, and FDP, is superior to the use of single markers for diagnosing VTE in patients with malignant tumors. Gastric cancer patients should be screened for the six markers to facilitate proactive prophylaxis, determine the most appropriate treatment timing, ameliorate their prognosis, decrease the occurrence of venous thrombosis and mortality, and extend their survival.
Topics: Humans; Stomach Neoplasms; Male; Middle Aged; Luminescent Measurements; Female; Aged; Antithrombin III; Thrombomodulin; Fibrin Fibrinogen Degradation Products; alpha-2-Antiplasmin; Adult; Fibrinolysin; Venous Thromboembolism; Peptide Hydrolases
PubMed: 38720310
DOI: 10.1186/s12896-024-00850-9 -
Acta Cirurgica Brasileira 2024Reflux esophagitis is a condition characterized by inflammation and irritation of the esophagus, resulting from the backflow of stomach acid and other gastric contents...
PURPOSE
Reflux esophagitis is a condition characterized by inflammation and irritation of the esophagus, resulting from the backflow of stomach acid and other gastric contents into the esophagus. Columbianadin is a coumarin derivative that exhibits anti-inflammatory and antioxidant effects. In this study, we tried to scrutinize the protective effect of Columbianadin against acute reflux esophagitis in rats.
METHODS
RAW 264.7 cells were utilized to assess cell viability and measure the production of inflammatory parameters. The rats received anesthesia, and reflux esophagitis was induced via ligation of pylorus and fore stomach and corpus junction. Rats received the oral administration of Columbianadin (25, 50 and 100 mg/kg) and omeprazole (20 mg/kg). The gastric secretion volume, acidity, and pH were measured. Additionally, the levels of oxidative stress parameters, cytokines, and inflammatory markers were determined. At the end of the study, mRNA expression was assessed.
RESULTS
Columbianadin remarkably suppressed the cell viability and production of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and prostaglandin (PGE2). Columbianadin treatment remarkably suppressed the secretion of gastric volume, total acidity and enhanced the pH level in the stomach. Columbianadin remarkably altered the level of hydrogen peroxidase, free iron, calcium, and plasma scavenging activity, sulfhydryl group; oxidative stress parameters like malonaldehyde, glutathione, superoxide dismutase, catalase, glutathione peroxidase; inflammatory cytokines viz., TNF-α, IL-6, IL-1β, IL-10, IL-17, and monocyte chemoattractant protein-1; inflammatory parameters including PGE2, iNOS, COX-2, and nuclear kappa B factor (NF-κB). Columbianadin remarkably (P < 0.001) suppressed the mRNA expression TNF-α, IL-6, IL-1β and plasminogen activator inhibitor-1.
CONCLUSIONS
Columbianadin demonstrated a protective effect against acute reflux esophagitis via NF-κB pathway.
Topics: Animals; Esophagitis, Peptic; NF-kappa B; Male; Rats; Oxidative Stress; Cytokines; Disease Models, Animal; Cell Survival; Acute Disease; RAW 264.7 Cells; Mice; Rats, Wistar; Signal Transduction; Antioxidants; Anti-Inflammatory Agents
PubMed: 38716957
DOI: 10.1590/acb391824 -
Revista Da Associacao Medica Brasileira... 2024
Topics: Humans; Diabetes, Gestational; Pregnancy; Female; Plasminogen Activator Inhibitor 1; Vitronectin
PubMed: 38716956
DOI: 10.1590/1806-9282.20231607 -
Case Reports in Ophthalmological... 2024To describe a case of subretinal hemorrhage due to the Valsalva maneuver in a patient with no underlying chorioretinal disease.
PURPOSE
To describe a case of subretinal hemorrhage due to the Valsalva maneuver in a patient with no underlying chorioretinal disease.
METHODS
History and clinical examination, optical coherence tomography (OCT), fluorescein, and indocyanine green angiography.
RESULTS
We report a case of a 35-year-old man with a 4-day history of central vision loss in the left eye (OS) after a vomiting episode. His best-corrected visual acuity was 20/200 in OS. Fundus examination revealed a subretinal hemorrhage in the posterior pole, associated with a small preretinal hemorrhage in the superotemporal arcade. OCT confirmed the presence of a thick submacular hemorrhage and a focal hemorrhage beneath the inner limiting membrane along the superotemporal arcade. The patient was submitted to pars plana vitrectomy (PPV), subretinal injection of tissue plasminogen activator (tPA), and air tamponade on the following day. Most of the submacular hemorrhage was displaced, resulting in a satisfactory visual outcome (BCVA = 20/30 after 1 month of surgery). Fluorescein and indocyanine green angiography excluded conditions such as retinal arterial macroaneurysm, polypoidal chorioretinopathy, and choroidal neovascularization.
CONCLUSION
Although rare, Valsalva retinopathy may present with submacular hemorrhage in a patient with no underlying chorioretinal disease. PPV and subretinal tPA injection may provide a good visual outcome.
PubMed: 38715947
DOI: 10.1155/2024/4865222 -
Journal of Investigative Medicine : the... May 2024Patients with heart failure with reduced ejection fraction (HFrEF) are at risk for chronic kidney disease (CKD). Elevated levels of circulating biomarkers soluble...
Patients with heart failure with reduced ejection fraction (HFrEF) are at risk for chronic kidney disease (CKD). Elevated levels of circulating biomarkers soluble urokinase plasminogen activator receptor (suPAR), galectin-3, soluble suppression of tumorigenicity 2 (ST2), and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are associated with CKD progression and mortality. The predictive value of these biomarkers in a population with HFrEF and kidney disease is relatively unknown. We sought to determine whether these biomarkers were associated with longitudinal trajectory of estimated glomerular filtration rate (eGFR) in HFrEF and assess their association with mortality using a joint model to account for competing risks of ventricular assist device (VAD) implantation and heart transplantation. We included participants from the Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life with repeated eGFR measures over 2 years. Of 309 participants, mean age was 59 years, median eGFR 60 ml/min/1.73 m, 45 participants died, 33 received VAD, and 25 received orthotopic heart transplantation. Higher baseline serum standardized suPAR (β coefficient = -0.36 √(ml/min/1.73 m), 95% confidence interval (-0.48 to -0.24), p < 0.001), standardized galectin-3 (-0.14 √(ml/min/1.73 m) (-0.27 to -0.02), p = 0.02), and log NT-proBNP (-0.23 √(ml/min/1.73 m) (-0.31 to -0.15), p < 0.001) were associated with eGFR decline. ST2 and log NT-proBNP were associated with mortality. Higher baseline suPAR, galectin-3, and NT-proBNP are associated with eGFR decline in patients with HFrEF. Only ST2 and NT-proBNP are associated with greater mortality after controlling for other factors including change in eGFR. These biomarkers may provide prognostic value for kidney disease progression in HFrEF and inform candidacy for advanced heart failure therapies.
PubMed: 38715217
DOI: 10.1177/10815589241249991 -
AME Case Reports 2024Intrabdominal hematoma can be managed with angioembolization, surgical drainage, or percutaneous drainage depending on the patient factors, underlying pathology, and...
BACKGROUND
Intrabdominal hematoma can be managed with angioembolization, surgical drainage, or percutaneous drainage depending on the patient factors, underlying pathology, and size and stability of hematoma. During the past decades, advancements have been made in the percutaneous management of intrapleural fluid collections using fibrinolytics. However, intrabdominal hematoma resolution with the help of fibrinolytic-assisted percutaneous drainage has not been as widely studied as intrapleural fibrinolytics. Our case presents a scenario where effective percutaneous drainage of abdominal fluid collection using fibrinolytics avoided an operative intervention in a patient with a history of multiple abdominal surgeries. This case report in essence can help navigate future studies into exploring non-operative management options in patients with a history of multiple abdominal surgeries.
CASE DESCRIPTION
In this report, we present a 51-year-old female status post hiatal hernia repair with jejunostomy tube (J-tube) exchange complicated by walled off intraabdominal hematoma who presented with persistent abdominal pain and leakage around her J-tube. Due to her past history of multiple abdominal surgeries including multiple hiatal hernia repairs, distal esophagectomy with Roux-en-Y, and revision of the said Roux-en-Y complicated by wound dehiscence, surgical drainage was deferred in favor of trialing fibrinolytic administration via catheters. For this purpose, we employed the protocol for fibrinolytic administration used by the Second Multicenter Intrapleural Sepsis Trial (MIST2).
CONCLUSIONS
Use of tissue plasminogen activator (t-PA) and deoxyribonuclease (DNase) as per MIST2 protocol was safely replicated for intrabdominal walled off hematoma and resulted in a near complete resolution of the hematoma in 1 week. The patient was eventually discharged with no complications. This case highlights safe and efficacious use of fibrinolytics for non-operative management of intrabdominal hematomas.
PubMed: 38711892
DOI: 10.21037/acr-23-178