Health Economic Evaluation of Antimicrobial Stewardship, Procalcitonin Testing, and Rapid Blood Culture Identification in Sepsis Care: A 90-Day Model-Based, Cost-Utility Analysis.

Objective: We evaluated the cost-effectiveness of a bundled intervention including an antimicrobial stewardship program (ASP), procalcitonin (PCT) testing, and rapid blood culture identification (BCID), compared with pre-implementation standard care in critically ill adult patients with sepsis.

Methods: We conducted a decision tree model-based cost-effectiveness analysis alongside a previously published pre- and post-implementation quality improvement study. We adopted a public Canadian healthcare payer's perspective.

Datopotamab-deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer.

Reaction-induced unsaturated Mo oxycarbides afford highly active CO conversion catalysts.

Sustainable CO conversion is crucial in curbing excess emissions. Molybdenum carbide catalysts have demonstrated excellent performances for catalytic CO conversion, but harsh carburization syntheses and poor stabilities make studies challenging. Here an unsaturated Mo oxide (MoO) shows a high activity for the reverse water-gas shift reaction, without carburization pretreatments, and remains stable for 2,000 h at 600 °C.

Synthesis of Quillaic Acid through Sustainable C-H Bond Activations.

To meet the demand for quillaic acid, a multigram synthesis of quillaic acid was accomplished in 14 steps, starting from oleanolic acid, leading to an overall yield of 3.4%. Key features include C-H activation at C-16 and C-23.

Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation.

Background: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition.

Bioactive glycans in a microbiome-directed food for children with malnutrition.

Evidence is accumulating that perturbed postnatal development of the gut microbiome contributes to childhood malnutrition. Here we analyse biospecimens from a randomized, controlled trial of a microbiome-directed complementary food (MDCF-2) that produced superior rates of weight gain compared with a calorically more dense conventional ready-to-use supplementary food in 12-18-month-old Bangladeshi children with moderate acute malnutrition. We reconstructed 1,000 bacterial genomes (metagenome-assembled genomes (MAGs)) from the faecal microbiomes of trial participants, identified 75 MAGs of which the abundances were positively associated with ponderal growth (change in weight-for-length Z score (WLZ)), characterized changes in MAG gene expression as a function of treatment type and WLZ response, and quantified carbohydrate structures in MDCF-2 and faeces.

Major Facilitator Superfamily Domain Containing 5 Inhibition Reduces Lipoprotein(a) Uptake and Calcification in Valvular Heart Disease.

Background: High circulating levels of Lp(a) (lipoprotein[a]) increase the risk of atherosclerosis and calcific aortic valve disease, affecting millions of patients worldwide. Although atherosclerosis is commonly treated with low-density lipoprotein-targeting therapies, these do not reduce Lp(a) or risk of calcific aortic valve disease, which has no available drug therapies. Targeting Lp(a) production and catabolism may provide therapeutic benefit, but little is known about Lp(a) cellular uptake.

Bridging attraction of condensed bovine serum albumin solution in the presence of trivalent ions: A SANS study.

The bridging attraction of condensed bovine serum albumin (BSA) solution (DO) in the presence of yttrium chloride (YCl) was studied by small angle neutron scattering (SANS). With increasing the concentration of YCl (c) from 3 to 15 mM and from 15 to 100 mM, the intensity in low-q region increases and then decreases. Combining the tri-axial ellipsoid (TaE) geometry and the multi-component sticky hard sphere (SHS) potential, a SHS-TaE model was established to quantitatively determine the size and distribution of particles.

The Novel GlycoPEGylated FGF21 Analog Pegozafermin Activates Human FGF Receptors and Improves Metabolic and Liver Outcomes in Diabetic Monkeys and Healthy Human Volunteers.

Pegozafermin (also known as BIO89-100) is a glycoPEGylated analog of fibroblast growth factor 21 (FGF21) under development to treat nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia (SHTG). In cell-based assays, pegozafermin had a similar receptor engagement profile as recombinant FGF21, with approximately eightfold higher potency at fibroblast growth factor receptor 1c (FGFR1c). In diabetic monkeys, once-weekly and once-every-2-weeks regimens of subcutaneous pegozafermin provided rapid and robust benefits for an array of metabolic biomarkers, including triglycerides, cholesterol, fasting glucose, glycated hemoglobin, adiponectin, alanine aminotransferase, food intake, and body weight.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer.

Ocular Surface Evaluation in Immunoglobulin G4-Related Ophthalmic Disease.

Purpose: To evaluate the functional and structural changes of the meibomian glands and ocular surface in immunoglobulin G4-related ophthalmic disease (IgG4-ROD) patients.

Design: Cross-sectional, matched case-control comparison study.

Methods: This study included 64 patients with biopsy-proven IgG4-ROD (aged 63.

Spinal Cord Stimulation for Parkinson's Disease: A Systematic Review and Meta-Analysis of Pain and Motor Outcomes.

Background: Spinal cord stimulation (SCS) has been investigated as a potential therapeutic option for managing refractory symptoms in patients with Parkinson's disease (PD).

Objective: This systematic review and meta-analysis aimed to evaluate the safety and efficacy of SCS in PD.

Method: A comprehensive literature search was conducted on PubMed and Web of Science to identify SCS studies reporting Unified Parkinson Disease Rating Scale-III (UPDRS-III) or Visual Analogue Scale (VAS) score changes in PD cohorts with at least 3 patients and a follow-up period of at least 1 month.

The rational design of high-performance graphene-based single-atom electrocatalysts for the ORR using machine learning.

In this work, high-performance two-dimensional (2D) graphene-based single-atom electrocatalysts (ZZ/ZA-MNC) for the oxygen reduction reaction (ORR) were screened out using machine learning (ML). A model was built for the fast prediction of electrocatalysts and two descriptors valence electron correction (VEc) and degree of construction differences (DC) were proposed to improve the accuracy of the model prediction. Two evaluation criteria, high-performance catalyst retention rate and high-performance catalyst occupancy rate , were proposed to evaluate the accuracy of ML models in high-performance catalyst screening.

Activation of Platelet mTORC2/Akt Pathway by Anti-β2GP1 Antibody Promotes Thrombosis in Antiphospholipid Syndrome.

Background: Anti-β2GP1 (β2-glycoprotein 1) antibodies are the primary pathogenic antibody to promote thrombosis in antiphospholipid syndrome (APS), yet the underlying mechanism remains obscure. We aimed to explore the intracellular pathway that mediated platelet activation.

Methods: Platelets were isolated from patients with APS and subjected to RNA sequencing.

Cascade Anchoring Strategy for Fabricating High-Loading Pt Single Atoms as Bifunctional Catalysts for Electrocatalytic Hydrogen Evolution and Oxygen Reduction Reactions.

Carbon supports containing single-atomically dispersed metal-N (denoted as M-NC, , : coordination number) have attracted increasing attention due to their superb performance in heterogeneous catalysis. However, large-scale controllable preparation of single-atom catalysts (SACs) with high concentration of supported metal-N is still a big challenge because of the metal atom agglomeration during synthesis at high density and temperatures. Herein, we report a stepwise anchoring strategy from a 1,10--phenanthroline Pt chelate to an N-doped carbon (NC) with isolated Pt single-atom catalysts (Pt-NC) containing Pt loadings up to 5.

In Situ Solution-Processed Submicron Thick SiO C /a-SiN (O):H Composite Barrier Film for Polymer:Non-Fullerene Photovoltaics.

Aiming to improve the environmental stability of organic photovoltaics, a multilayered SiO C /a-SiN (O):H composite barrier film coated with a hydrophobic perfluoro copolymer stop layer for polymer:non-fullerene solar cells is developed. The composite film is prepared by spin-coating of polysilicone and perhydropolysilazane (PHPS) following a densification process by vacuum ultraviolet irradiation in an inert atmosphere. The transformation of polysilicone and PHPS to SiO C and a-SiN (O):H is confirmed by Fourier transform infrared and energy-dispersive X-ray spectroscopy measurement.

Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases.

Identification of therapeutic targets from genome-wide association studies (GWAS) requires insights into downstream functional consequences. We harmonized 8,613 RNA-sequencing samples from 14 brain datasets to create the MetaBrain resource and performed cis- and trans-expression quantitative trait locus (eQTL) meta-analyses in multiple brain region- and ancestry-specific datasets (n ≤ 2,759). Many of the 16,169 cortex cis-eQTLs were tissue-dependent when compared with blood cis-eQTLs.

miR-328-3p Affects Axial Length Via Multiple Routes and Anti-miR-328-3p Possesses a Potential to Control Myopia Progression.

Purpose: We previously reported miR-328-3p as a novel risk factor for myopia through a genetic association study of the PAX6 gene. In the present study, we first explored the effects of miR-328-3p on other myopia-related genes, and then tested whether anti-miR-328-3p may be used for myopia control.

Methods: The luciferase report assay and transient transfection were used to confirm miR-328-3p target genes.

Global Impact of the COVID-19 Pandemic on Stroke Volumes and Cerebrovascular Events: A 1-Year Follow-up.

Background And Objectives: Declines in stroke admission, IV thrombolysis (IVT), and mechanical thrombectomy volumes were reported during the first wave of the COVID-19 pandemic. There is a paucity of data on the longer-term effect of the pandemic on stroke volumes over the course of a year and through the second wave of the pandemic. We sought to measure the effect of the COVID-19 pandemic on the volumes of stroke admissions, intracranial hemorrhage (ICH), IVT, and mechanical thrombectomy over a 1-year period at the onset of the pandemic (March 1, 2020, to February 28, 2021) compared with the immediately preceding year (March 1, 2019, to February 29, 2020).

Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.