Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a 2-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer's Disease.

Introduction: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of β-amyloid (Aβ) oligomer formation in late-stage development as a potential disease-modifying therapy for Alzheimer's disease (AD). ALZ-801, a valine-conjugated prodrug, is rapidly converted to tramiprosate after oral dosing. Upon conversion to tramiprosate, it generates a single metabolite, 3-sulfopropanoic acid (3-SPA).

Modified lipoprotein-induced sFlt1 production in human placental trophoblasts is mediated by protein kinase C.

Background: Preeclampsia is prevalent in women with diabetes, but the mechanism is unclear. We previously found that oxidized, glycated lipoproteins robustly upregulated soluble fms-like tyrosine kinase-1 (sFlt1), a key mediator of preeclampsia. Here, we determined the role of protein kinase C (PKC) and its subtypes in sFlt1 regulation in placental trophoblasts, and whether this mechanism might mediate the effect of modified lipoproteins.

Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease Using Quantitative Systems Pharmacology Model.

Introduction: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD.

Methods: The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22].

An Examination of the Effect of Aspirin and Salicylic Acid on Soluble Fms-like Tyrosine Kinase-1 Release from Human Placental Trophoblasts.

Low-dose aspirin (LDA) is efficacious in preventing preeclampsia, but its mechanism of action is unclear. Conflicting evidence suggests that it may inhibit placental trophoblast release of soluble fms-like tyrosine kinase-1 (sFlt1), a key mediator of preeclampsia. We examined whether, and at what concentrations, aspirin and its principal metabolite, salicylic acid, modulate sFlt1 release and/or expression in trophoblasts.

The risk of hemorrhagic complications after anticoagulation therapy in trauma patients: A multicenter evaluation.

Background: The use of anticoagulation therapy (ACT) in trauma patients during the postinjury period presents a challenge given the increased risk of hemorrhage. Guidelines regarding whether and when to initiate ACT are lacking, and as a result, practice patterns vary widely. The purpose of this study is to describe the incidence of hemorrhagic complications in patients who received ACT during their hospitalization, identify risk factors, and characterize the required interventions.

Plasma AGE and Oxidation Products, Renal Function, and Preeclampsia in Pregnant Women with Type 1 Diabetes: A Prospective Observational Study.

Aims: We aimed to determine whether plasma advanced glycation end products or oxidation products (AGE/oxidation-P) predict altered renal function and/or preeclampsia (PE) in pregnant women with type 1 diabetes.

Methods: Prospectively, using a nested case-control design, we studied 47 pregnant women with type 1 diabetes, of whom 23 developed PE and 24 did not. Nineteen nondiabetic, normotensive pregnant women provided reference values.

Resting heart rate (variability) and cognition relationships reveal cognitively healthy individuals with pathological amyloid/tau ratio.

Introduction: Resting heart rate (HR) and heart rate variability (HRV) have been linked with cognition in the general population and in older individuals. The knowledge of this aspect of heart-brain relationship is relatively absent in older individuals with early Alzheimer's disease (AD) pathology. This study explores relationships of the HR, HRV, and cognition in cognitively healthy individuals with pathological amyloid/tau ratio (CH-PATs) in cerebral spinal fluid (CSF) compared to those with normal ratio (CH-NATs).

Adjuvant chemotherapy, not radiotherapy, prolongs survival for node-negative non-small cell lung cancer with positive surgical margins.

Objective: The study objective was to determine differences in survival depending on adjuvant therapy type, timing, and sequence in node-negative disease with positive margins after non-small cell lung cancer resection.

Methods: The National Cancer Database was queried for patients with positive margins after surgical resection of treatment-naïve cT1-4N0M0 pN0 non-small cell lung cancer who underwent adjuvant radiotherapy or chemotherapy from 2010 to 2016. Adjuvant treatment groups were defined as surgery alone, chemotherapy alone, radiotherapy alone, concurrent chemoradiotherapy, sequential chemotherapy then radiotherapy, and sequential radiotherapy then chemotherapy.

Identifying Populations at Risk for Difficulty Managing Emotions and Social Interactions After Burn Injury.

There has been conflicting data on the relationship between burn severity and psychological outcomes. The present study aims to characterize the baseline psychosocial disposition of adults attending outpatient burn clinic at a large urban safety net hospital, as well as the impact of clinical course on self-reported psychosocial well-being. Adult patients attending outpatient burn clinic completed survey questions from the National Institutes of Health Patient-Reported Outcomes Measurement Information System Managing Chronic Conditions: Self-Efficacy for Managing Social Interactions (SEMSI-4) and Managing Emotions (SEME).

Race and Ethnicity Influences Outcomes of Adult Burn Patients.

Outcomes of burn survivors is a growing field of interest; however, there is little data comparing the outcomes of burn survivors by ethnicity. This study seeks to identify any inequities in burn outcomes by racial and ethnic groups. A retrospective chart review of an ABA Certified burn center at a large urban safety net hospital identified adult inpatient admissions from 2015 to 2019.

Heart transplantation for pediatric foreign nationals in the United States.

Background: This study aimed to clarify survival outcomes, waitlist mortality, and waitlist days of heart transplantation of pediatric foreign nationals compared to pediatric United States (US) citizens.

Methods: We retrieved data from March 2012 to June 2021 in the United Network Organ Sharing (UNOS) registry.

Results: Of 5857 pediatric patients newly waitlisted, 133 (2.

Peer Support Groups: Identifying Disparities to Improve Participation.

Disparities in psychosocial outcomes after burn injury exist in patients from racial or ethnic minority groups in the United States. Peer support groups can help patients with many psychosocial aspects of recovery from burns; however, access to such support among patients of racial and ethnic minority or low socioeconomic groups are unknown. The present study examined participation rates in outpatient peer support within this patient population.

US hospital webpages on atrial fibrillation ablation: A potential source for misinformation.

Introduction: Atrial fibrillation (AF) ablation is performed worldwide. To attract patients, hospitals frequently have webpages that tout the success of the procedure. The information disseminated to the public via these webpages has not been systematically reviewed.

Comparisons of α2-Adrenergic Agents, Medetomidine and Xylazine, with Pentobarbital for Anesthesia: Important Pitfalls in Diabetic and Nondiabetic Rats.

Anesthesia is necessary to conduct rodent electroretinograms (ERGs). We evaluated utility of the α2-agonist medetomidine versus xylazine for ERG studies in nondiabetic and diabetic rats. Pentobarbital was included as a comparator.

Modelling preeclampsia: a comparative analysis of the common human trophoblast cell lines.

Preeclampsia remains a challenge without an effective therapy. Evidence supports targetability of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), which are released excessively from the placenta under ischemic and hypoxic stresses. We compared four trophoblast cell lines, BeWo, Jar, Jeg-3, and HTR-8/SVneo, in order to identify a suitable model for drug screening.

Effects of modified lipoproteins on human trophoblast cells: a role in pre-eclampsia in pregnancies complicated by diabetes.

Introduction: Pre-eclampsia (PE) is increased ~4-fold by maternal diabetes. Elevated plasma antiangiogenic factors, soluble fms-like tyrosine kinase (sFLT-1) and soluble endoglin (sENG), precede PE onset. We investigated whether diabetes-related stresses, modified lipoproteins and elevated glucose enhance trophoblast sFLT-1 and sENG release and/or alter placental barrier function and whether oxidized low-density lipoprotein (Ox-LDL) is in placental tissue.

Effects of Modified Low-Density Lipoproteins and Fenofibrate on an Outer Blood-Retina Barrier Model: Implications for Diabetic Retinopathy.

There is a lack of treatment for early diabetic retinopathy (DR), including blood-retina barrier (BRB) breakdown. The robust clinical benefit of fenofibrate in DR provides an opportunity to explore disease mechanisms and therapeutic targets. We have previously found that modified lipoproteins contribute to DR and that fenofibrate protects the inner BRB.

Differential regulation of a placental SAM68 and sFLT1 gene pathway and the relevance to maternal vitamin D sufficiency.

Objective: The goal of this study was to determine if an axis of placental gene expression associated with early onset and severe preeclampsia (EOSPE) was operative in term pregnancy and correlated with vitamin D sufficiency.

Methods: qPCR analysis of NKX2-5, SAM68, sFLT1 and membrane bound VEGFR1/FLT1 mRNA expression was conducted in placentas from 43 subjects enrolled in a vitamin D3 pregnancy supplementation trial. Pair-wise rank order correlations between patient-specific gene expression levels were calculated, and their relationship to maternal 25(OH)D status was assessed by a two-sample Wilcoxon test.

Vitamin D Metabolites and Binding Protein Predict Preeclampsia in Women with Type 1 Diabetes.

The risk for preeclampsia (PE) is enhanced ~4-fold by the presence of maternal type 1 diabetes (T1DM). Vitamin D is essential for healthy pregnancy. We assessed the total, bioavailable, and free concentrations of plasma 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)D), and vitamin D binding protein (VDBP) at ~12, ~22, and ~32 weeks' gestation ("Visits" (V) 1, 2, and 3, respectively) in 23 T1DM women who developed PE, 24 who remained normotensive, and 19 non-diabetic, normotensive women (reference controls).

Haptoglobin Phenotype Modulates Lipoprotein-Associated Risk for Preeclampsia in Women With Type 1 Diabetes.

Context: The incidence of preeclampsia (PE) is increased in women with diabetes (∼20% vs ∼5% in the general population), and first trimester lipoprotein profiles are predictive. Haptoglobin (Hp), a protein with functional genetic polymorphisms, has antioxidant, anti-inflammatory, and angiogenic effects. Among people with diabetes, the Hp 2-2 phenotype is associated with cardiorenal disease.

Correction to: Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain.

Page 856: Fig. 6 was an incorrect duplication of Fig. 5.

Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain.

Background: ALZ-801 is an oral, small-molecule inhibitor of beta amyloid (Aβ) oligomer formation in clinical development for Alzheimer's disease (AD). ALZ-801 is a prodrug of tramiprosate with improved pharmacokinetic properties and gastrointestinal tolerability. During clinical studies, we discovered that the primary metabolite of tramiprosate and its prodrug ALZ-801, 3-sulfopropanoic acid (3-SPA), is an endogenous molecule in the human brain and present in the cerebrospinal fluid (CSF) of patients with AD and other neurodegenerative brain diseases.