Chemical shift encoding based double bonds quantification in triglycerides using deep image prior.

Fatty acid can potentially serve as biomarker for evaluating metabolic disorder and inflammation condition, and quantifying the double bonds is the key for revealing fatty acid information. This study presents an assessment of a deep learning approach utilizing deep image prior (DIP) for the quantification of double bonds and methylene-interrupted double bonds of triglyceride derived from chemical-shift encoded multi-echo gradient echo images, all achieved without the necessity for network training. The methodology implemented a cost function grounded in signal constraints to continually refine the neural network's parameters on a single slice of images through iterative processes.

Neuroprotective Effects of Rapid Local Ischemic Postconditioning in Successful Endovascular Thrombectomy Patients.

Background: We aim to assess the efficacy of rapid local ischemic postconditioning (RL-IPostC) following successful reperfusion in patients with acute ischemic stroke with anterior circulation large vessel occlusion who underwent endovascular thrombectomy.

Methods: We conducted an ambidirectional cohort study with 78 prospectively enrolled patients with RL-IPostC and endovascular thrombectomy and 129 retrospectively enrolled patients with endovascular thrombectomy. The RL-IPostC procedure involved 5 cycles of 15-s balloon inflation and deflation in the ipsilateral internal carotid artery.

Clinical Correlates and Prognostic Impact of Cognitive Dysfunction in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.

Background: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood.

Methods: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks.

Effect of Delayed Remote Ischemic Preconditioning on Acute Kidney Injury and Outcomes in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

Background: Remote ischemic preconditioning (RIPC) has 2 time windows for organ protection: acute and delayed. Previous studies have mainly focused on the organoprotective effects of acute RIPC. We aimed to determine whether delayed RIPC can reduce the occurrence of acute kidney injury (AKI) and postoperative complications in patients undergoing cardiac surgery.

GGT5 as a promising prognostic biomarker and its effects on tumor cell progression in gastric cancer.

Background: Gastric cancer (GC) is a gastric malignant tumor with over 1 million new cases globally each year. There are many diagnostic methods for GC, but due to the hidden early symptoms of GC, early GC is easy to be missed and misdiagnosed, which affects the follow-up treatment of patients. The early and accurate diagnosis of GC is of great significance for the treatment and survival of GC patients.

Prodrug-conjugated tumor-seeking commensals for targeted cancer therapy.

Prodrugs have been explored as an alternative to conventional chemotherapy; however, their target specificity remains limited. The tumor microenvironment harbors a range of microorganisms that potentially serve as tumor-targeting vectors for delivering prodrugs. In this study, we harness bacteria-cancer interactions native to the tumor microbiome to achieve high target specificity for prodrug delivery.

Associations of Intrapancreatic Fat Deposition With Incident Diseases of the Exocrine and Endocrine Pancreas: A UK Biobank Prospective Cohort Study.

Introduction: To investigate whether increased intrapancreatic fat deposition (IPFD) heightens the risk of diseases of the exocrine and endocrine pancreas.

Methods: A prospective cohort study was conducted using data from the UK Biobank. IPFD was quantified using MRI and a deep learning-based framework called nnUNet.

Developing the E. coli platform for efficient production of UMP-derived chemicals.

5-Methyluridine (5-MU) is a prominent intermediate for industrial synthesis of several antiviral-drugs, however, its availability over the past decades has overwhelmingly relied on chemical and enzymatic strategies. Here, we have realized efficient production of 5-MU in E. coli, for the first time, via a designer artificial pathway consisting of a two-enzyme cascade (UMP 5-methylase and phosphatase).

Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial.

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up).

A Pilot Study To Assess the Suitability of Riboflavin As a Surrogate Marker of Breast Cancer Resistance Protein in Healthy Participants.

We recently showed that riboflavin is a selected substrate of breast cancer resistance protein (BCRP) over P-glycoprotein (P-gp) and demonstrated its prediction performance in preclinical drug-drug interaction (DDI) studies. The aim of this study was to investigate the suitability of riboflavin to assess BCRP inhibition in humans. First, we assessed the substrate potential of riboflavin toward other major drug transporters using established transfected cell systems.

Role of Diuretics in Cardiovascular Events and Mortality in Systolic Blood Pressure Intervention Trial: A Post Hoc Analysis.

Background: In a post hoc analysis, we examined whether postrandomization diuretics use can explain and/or mediate the beneficial effects of intensive systolic BP lowering on cardiovascular disease and all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT).

Methods: SPRINT was a randomized, controlled trial of 9361 participants comparing the effects of intensive (systolic BP target <120 mm Hg) versus standard (systolic BP target <140 mm Hg) BP control on a primary composite cardiovascular end point in participants aged 50 years or older with systolic BP of 130-180 mm Hg. In time-varying multivariable Cox analyses, we assessed hazard ratios (HRs) of cardiovascular end points and all-cause mortality in participants on thiazide type, loop and/or potassium (K) sparing, or no diuretics.

Olgotrelvir, a dual inhibitor of SARS-CoV-2 M and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19.

Background: Oral antiviral drugs with improved antiviral potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks of rebound, drug-drug interactions, and emerging resistance.

Methods: Olgotrelvir (STI-1558) is designed as a next-generation antiviral targeting the SARS-CoV-2 main protease (M), an essential enzyme for SARS-CoV-2 replication, and human cathepsin L (CTSL), a key enzyme for SARS-CoV-2 entry into host cells.

Findings: Olgotrelvir is a highly bioavailable oral prodrug that is converted in plasma to its active form, AC1115.

Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.

Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV.

Factors Associated With Family Surrogate Decisional-Regret Trajectories.

Context/objectives: The scarce research on factors associated with surrogate decisional regret overlooks longitudinal, heterogenous decisional-regret experiences and fractionally examines factors from the three decision-process framework stages: decision antecedents, decision-making process, and decision outcomes. This study aimed to fill these knowledge gaps by focusing on factors modifiable by high-quality end-of-life (EOL) care.

Methods: This observational study used a prior cohort of 377 family surrogates of terminal-cancer patients to examine factors associated with their membership in the four preidentified distinct decisional-regret trajectories: resilient, delayed-recovery, late-emerging, and increasing-prolonged trajectories from EOL-care decision making through the first two bereavement years by multinomial logistic regression modeling using the resilient trajectory as reference.

A phase I randomized, double-blinded, placebo-controlled study assessing the safety and pharmacokinetics of RIPK1 inhibitor GFH312 in healthy subjects.

Receptor-interacting protein kinase 1 (RIPK1) mediates necroptosis and inflammation in various pathophysiologies, emerging as a pharmacological target for neurodegenerative and inflammatory indications. This phase I, first-in-human, placebo-controlled study evaluated the safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GFH312, an RIPK1 inhibitor, in healthy adults. Subjects received GFH312 as a single ascending dose up to 500 mg (part I) or once-daily repeated doses up to 200 mg for 14 days (part II).

Incidence, outcomes and costs of severe sepsis and septic shock in geriatric trauma patients: Analysis of 2,563,463 hospitalizations at 3,284 hospitals.

Background: Severe sepsis/septic shock (sepsis) is a leading cause of death in hospitalized trauma patients. Geriatric trauma patients are an increasing proportion of trauma care but little recent, large-scale, research exists in this high-risk demographic. The objectives of this study are to identify incidence, outcomes and costs of sepsis in geriatric trauma patients.

Decisional-Regret Trajectories From End-of-Life Decision Making Through Bereavement.

Context: Regret plays a central role in surrogate decision making. Research on decisional regret in family surrogates is scarce and lacks longitudinal studies to illustrate the heterogenous, dynamic evolution of decisional regret.

Objectives: To identify distinct decisional-regret trajectories from end-of-life (EOL) decision making through the first two bereavement years among surrogates of cancer patients.

Surf4 (Surfeit Locus Protein 4) Deficiency Reduces Intestinal Lipid Absorption and Secretion and Decreases Metabolism in Mice.

Background: Postprandial dyslipidemia is a causative risk factor for cardiovascular disease. The majority of absorbed dietary lipids are packaged into chylomicron and then delivered to circulation. Previous studies showed that Surf4 (surfeit locus protein 4) mediates very low-density lipoprotein secretion from hepatocytes.

Detection and Characterization of In Vitro Payload-Containing Catabolites of Noncleavable Antibody-Drug Conjugates by High-Resolution Mass Spectrometry and Multiple Data Mining Tools.

The formation and accumulation of payload-containing catabolites (PCCs) from a noncleavable antibody-drug conjugate (ADC) in targeted and normal tissues are directly associated with the therapeutic effect and toxicity of the ADC, respectively. Understanding the PCC formation is important for supporting the payload design and facilitating preclinical evaluation of ADCs. However, detection and identification of PCCs of a noncleavable ADC are challenging due to their low concentrations and unknown structures.

Neutrophil-activating therapy for the treatment of cancer.

Despite their cytotoxic capacity, neutrophils are often co-opted by cancers to promote immunosuppression, tumor growth, and metastasis. Consequently, these cells have received little attention as potential cancer immunotherapeutic agents. Here, we demonstrate in mouse models that neutrophils can be harnessed to induce eradication of tumors and reduce metastatic seeding through the combined actions of tumor necrosis factor, CD40 agonist, and tumor-binding antibody.

Changes in Corneal Power up to 2 Years After Endothelial Keratoplasty: Results From the Randomized Controlled Descemet Endothelial Thickness Comparison Trial.

Purpose: To compare changes in corneal power measurements after Descemet membrane endothelial keratoplasty (DMEK) vs ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK).

Design: Post hoc subanalysis of the randomized controlled Descemet Endothelial Thickness Comparison Trial.

Methods: A total of 50 eyes (38 patients) with endothelial dysfunction from Fuchs' endothelial dystrophy or pseudophakic bullous keratopathy were randomized to DMEK or UT-DSAEK 1 to 2 days before surgery.