Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution.

Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cell types and their heterogeneity within the human liver, but the spatial organization at single-cell resolution has not yet been described. Here we apply multiplexed error robust fluorescent in situ hybridization (MERFISH) to map the zonal distribution of hepatocytes, spatially resolve subsets of macrophage and mesenchymal populations, and investigate the relationship between hepatocyte ploidy and gene expression within the healthy human liver. Integrating spatial information from MERFISH with the more complete transcriptome produced by single-nucleus RNA sequencing (snRNA-seq), also reveals zonally enriched receptor-ligand interactions.

Power and sample size calculation for non-inferiority trials with treatment switching in intention-to-treat analysis comparing RMSTs.

Background: Difference in Restricted Mean Survival Time (DRMST) has attracted attention and is increasingly used in non-inferiority (NI) trials because of its superior power in detecting treatment effects compared to hazard ratio. However, when treatment switching (also known as crossover) occurs, the widely used intention-to-treat (ITT) analysis can underpower or overpower NI trials.

Methods: We propose a simulation-based approach, named , to calculate powers and determine the necessary sample size to achieve a desired power for non-inferiority trials that allow treatment switching, in ITT analysis using DRMST.

Psychometric evaluation of the Autism Symptom Dimensions Questionnaire.

Aim: To replicate and extend previous psychometric findings for the Autism Symptom Dimensions Questionnaire (ASDQ).

Method: Using a cross-sectional design in two samples, including a total of 3366 children and adolescents (aged 2-17 years; 1399 with autism spectrum disorder) and a small case series, factor structure, measurement invariance, reliability, construct validity, screening and diagnostic efficiency, and detection of reliable change were examined for the ASDQ.

Results: Strong psychometric properties were observed, including replicable factor structure, strong measurement invariance, adequate-to-excellent scale and conditional reliability, strong convergent and discriminant validity, and good screening efficiency.

Noninvasive Assessment of Liver Fibrosis in Patients With Iron Overload.

Objective: We assessed the diagnostic performance of ultrasound two-dimensional shear wave elastography (US 2D-SWE) to predict clinically significant fibrosis (CSF) in patients with serologic iron overload (SIO) and the subgroup with histologic liver iron overload (LIO).

Methods: A single-center retrospective cross-sectional study of adults with SIO (serum ferritin ≥ 200 ng/mL in females and ≥ 300 ng/mL in males) and suspected chronic liver disease with nonfocal liver biopsy results and US 2D-SWE exams within 1 year was performed. Histopathological fibrosis stage ≥2 and liver iron ≥2+ was considered CSF and LIO, respectively.

Development of a fibrin-targeted theranostic for gastric cancer.

Patients with advanced gastric cancer (GCa) have limited treatment options, and alternative treatment approaches are necessary to improve their clinical outcomes. Because fibrin is abundant in gastric tumors but not in healthy tissues, we hypothesized that fibrin could be used as a high-concentration depot for a high-energy beta-emitting cytotoxic radiopharmaceutical delivered to tumor cells. We showed that fibrin is present in 64 to 75% of primary gastric tumors and 50 to 100% of metastatic gastric adenocarcinoma cores.

A Physician-Centered Craniofacial Asymmetry Index for the Severity of Plagiocephaly: A Comparative Study of Assessment Methods.

Background: Plagiocephaly, wherein infants' head exhibits a diagonal asymmetry, is currently diagnosed based on physicians' subjective judgment. Discrepancies between physician and parent perspectives may result in dissatisfaction with treatment outcomes. This problem highlights the need for an objective assessment system aligning with physician-made clinical diagnoses.

Input Pose is Key to Performance of Free Energy Perturbation: Benchmarking with Monoacylglycerol Lipase.

Free energy perturbation (FEP) methodologies have become commonplace methods for modeling potency in hit-to-lead and lead optimization stages of drug discovery. The conformational states of the initial poses of compounds for FEP+ calculations are often set up by alignment to a cocrystal structure ligand, but it is not clear if this method provides the best result for all proteins or all ligands. Not only are ligand conformational states potential variables in modeling compound potency in FEP but also the selection of crystallographic water molecules for inclusion in the FEP input structures can impact FEP models.

Separate anterior paraventricular thalamus projections differentially regulate sensory and affective aspects of pain.

The experience of pain is complex, involving both sensory and affective components, yet the underlying neural mechanisms remain elusive. Here, we show that formalin-induced pain behaviors coincide with increased responses in glutamatergic neurons within the anterior paraventricular nucleus of the thalamus (PVA). Furthermore, we describe non-overlapping subpopulations of PVAVgluT2 neurons involved in sensory and affective pain processing, whose activity varies across different pain states.

Fast generation of spectrally shaped disorder.

Media with correlated disorder display unexpected transport properties, but it is still a challenge to design structures with desired spectral features at scale. In this work, we introduce an optimal formulation of this inverse problem by means of the nonuniform fast Fourier transform, thus arriving at an algorithm capable of generating systems with arbitrary spectral properties, with a computational cost that scales O(NlogN) with system size. The method is extended to accommodate arbitrary real-space interactions, such as short-range repulsion, to simultaneously control short- and long-range correlations.

Capillary regression leads to sustained local hypoperfusion by inducing constriction of upstream transitional vessels.

In the brain, a microvascular sensory web coordinates oxygen delivery to regions of neuronal activity. This involves a dense network of capillaries that send conductive signals upstream to feeding arterioles to promote vasodilation and blood flow. Although this process is critical to the metabolic supply of healthy brain tissue, it may also be a point of vulnerability in disease.

The seasonal distribution of immune thrombotic thrombocytopenic purpura is influenced by geography: Epidemiologic findings from a multi-center analysis of 719 disease episodes.

Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included.

Quercetin enhances decidualization through AKT-ERK-p53 signaling and supports a role for senescence in endometriosis.

Background: Patients with endometriosis suffer with chronic pelvic pain and infertility, and from the lack of pharmacologic therapies that consistently halt disease progression. Differences in the endometrium of patients with endometriosis vs. unaffected controls are well-documented.

Evaluating the role of Day 14 bone marrow biopsy and European LeukemiaNet risk classification in predicting overall and relapse-free survival in acute myeloid leukemia.

Multivariable analysis for overall survival and relapse-free survival demonstrating lack of significant for D14 BM status.

Pericytes: Unsung heroes in myelin repair after neonatal brain hypoxia.

Preterm infants can face lasting neurodevelopmental challenges due to hypoxia-induced injury of the cerebral white matter. In this issue of Neuron, Ren et al. identify microvascular pericytes as unexpected targets for growth hormone signaling, which enhances angiogenesis and remyelination after hypoxic injury in the developing mouse brain.

A randomized control trial to compare mortality in recipients of leucoreduced and non-leucoreduced whole blood transfusion in patients with cancer in Uganda.

Background: Mortality benefit of transfusion with leucoreduced whole blood has not been demonstrated in the sub-Saharan Africa (SSA). We compared mortality in patients with cancer transfused with leucoreduced and non-leucoreduced whole blood in a SSA setting.

Methods: An open-label randomized controlled trial was conducted at the Uganda Cancer Institute where participants were randomized in a 1:1 ratio into the leucoreduced and non-leucoreduced whole blood transfusion arms.

CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype-specific Vulnerability in IDH2- and TET2-mutant Cells.

Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs.