The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases.

Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals.

Categorizing Hospitals by Neonatal and Pediatric Diagnoses Treated.

Background: Traditional classification of children's and nonchildren's hospitals is based on physical structure and branding. We grouped hospitals with the most similar types of pediatric patients.

Methods: Retrospective analysis of 2.

Target deconvolution of an insulin hypersecretion-inducer acting through VDAC1 with a distinct transcriptomic signature in beta-cells.

Obesity, insulin resistance, and a host of environmental and genetic factors can drive hyperglycemia, causing β-cells to compensate by increasing insulin production and secretion. In type 2 diabetes (T2D), β-cells under these conditions eventually fail. Rare β-cell diseases like congenital hyperinsulinism (HI) also cause inappropriate insulin secretion, and some HI patients develop diabetes.

Investigating the causal effects of childhood and adulthood adiposity on later life mental health outcome: a Mendelian randomization study.

Background: Obesity particularly during childhood is considered a global public health crisis and has been linked with later life health consequences including mental health. However, there is lack of causal understanding if childhood body size has a direct effect on mental health or has an indirect effect after accounting for adulthood body size.

Methods: Two-sample Mendelian randomization (MR) was performed to estimate the total effect and direct effect (accounting for adulthood body size) of childhood body size on anxiety and depression.

Convolutional Neural Networks for the segmentation of hippocampal structures in postmortem MRI scans.

Background: The hippocampus plays a crucial role in memory and is one of the first structures affected by Alzheimer's disease. Postmortem MRI offers a way to quantify the alterations by measuring the atrophy of the inner structures of the hippocampus. Unfortunately, the manual segmentation of hippocampal subregions required to carry out these measures is very time-consuming.

Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi.

Introduction: Alzheimer's disease (AD), primary age-related tauopathy (PART), and chronic traumatic encephalopathy (CTE) all feature hyperphosphorylated tau (p-tau)-immunoreactive neurofibrillary degeneration, but differ in neuroanatomical distribution and progression of neurofibrillary degeneration and amyloid beta (Aβ) deposition.

Methods: We used Nanostring GeoMx Digital Spatial Profiling to compare the expression of 70 proteins in neurofibrillary tangle (NFT)-bearing and non-NFT-bearing neurons in hippocampal CA1, CA2, and CA4 subregions and entorhinal cortex of cases with autopsy-confirmed AD (n = 8), PART (n = 7), and CTE (n = 5).

Results: There were numerous subregion-specific differences related to Aβ processing, autophagy/proteostasis, inflammation, gliosis, oxidative stress, neuronal/synaptic integrity, and p-tau epitopes among these different disorders.

Unraveling the clinical-pathological correlations of subjects with isolated and mixed neurodegenerative processes in the National Alzheimer's Coordinating Center dataset.

Although Alzheimer disease neuropathologic change (ADNC) is the most common pathology underlying clinical dementia, the presence of multiple comorbid neuropathologies is increasingly being recognized as a major contributor to the worldwide dementia burden. We analyzed 1051 subjects with specific combinations of isolated and mixed pathologies and conducted multivariate logistic regression analysis on a cohort of 4624 cases with mixed pathologies to systematically explore the independent cognitive contributions of each pathology. Alzheimer disease neuropathologic change and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) were both associated with a primary clinical diagnosis of Alzheimer disease (AD) and were characterized by an amnestic dementia phenotype, while only ADNC associated with logopenic variant primary progressive aphasia (PPA).

Hyperaminoacidemia from interrupted glucagon signaling increases pancreatic acinar cell proliferation and size via mTORC1 and YAP pathways.

Increased blood amino acid levels (hyperaminoacidemia) stimulate pancreas expansion by unclear mechanisms. Here, by genetic and pharmacological disruption of glucagon receptor (GCGR) in mice and zebrafish, we found that the ensuing hyperaminoacidemia promotes pancreatic acinar cell proliferation and cell hypertrophy, which can be mitigated by a low protein diet in mice. In addition to mammalian target of rapamycin complex 1 (mTORC1) signaling, acinar cell proliferation required , the most highly expressed amino acid transporter gene in both species.

Pheromone relay networks in the honeybee: messenger workers distribute the queen's fertility signal throughout the hive.

Background: The harmonious operation of many insect societies depends upon colony-wide dissemination of a non-volatile pheromone produced by a single queen, which informs workers of her presence. This represents a major challenge in large colonies. Honeybee colonies, which can exceed 60,000 bees, are believed to solve this challenge using 'messenger' workers that actively relay the queen pheromone throughout the hive.

Does paced bottle-feeding improve the quality and outcome of bottle-feeding interactions?

Background: Responsive feeding is recommended and occurs when caregivers use infants' behavioral cues to guide the timing, pacing, and duration of feeding. Paced bottle-feeding is an approach designed to promote responsive bottle-feeding by mimicking the behavioral benefits of breastfeeding. This study evaluates the efficacy of paced bottle-feeding compared to typical bottle-feeding and breastfeeding for promoting responsive feeding and other markers of healthy feeding outcomes, such as slower feeding rates and lower likelihood of spitting up.

Using Polarization to Increase Contrast of Water OH Raman Scattering Relative to Fluorescence of Dissolved Organic Matter.

Environmental fluorescence measurements sometimes use water Raman scattering as an internal standard to compensate for path length, lensing effects, and turbidity. Fluorescent dissolved organic matter (FDOM) in water may interfere strongly with the measurement of this reference. However, fluorescence in fluid solution is largely unpolarized, while the OH stretching Raman band of water is always strongly polarized.

Small-cohort GWAS discovery with AI over massive functional genomics knowledge graph.

Genome-wide association studies (GWASs) have identified tens of thousands of disease associated variants and provided critical insights into developing effective treatments. However, limited sample sizes have hindered the discovery of variants for uncommon and rare diseases. Here, we introduce KGWAS, a novel geometric deep learning method that leverages a massive functional knowledge graph across variants and genes to improve detection power in small-cohort GWASs significantly.

Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling.

We report the synthesis of germanyl triazoles formed via a copper-catalysed azide-alkyne cycloaddition (CuAAC) of germanyl alkynes. The reaction is often high yielding, functional group tolerant, and compatible with complex molecules. The installation of the Ge moiety enables further diversification of the triazole products, including chemoselective transition metal-catalysed cross-coupling reactions using bifunctional boryl/germyl species.

Detecting Changes in Comfort, Pain, and Mobility Over Clinical Milestones for Individuals With Lower Limb Loss.

Background: Functional mobility, comfort and the absence of pain are key goals of prosthetic treatment. Outcome measures (OMs) evaluate the impact of treatment and normative and minimal detectable change (MDC) values are key to interpreting these scores and measuring treatment outcomes.

Objectives: This study seeks to 1) present practice-based normative values of four commonly used OMs at four prosthetic milestones and 2) explore the MDC of the measures over the treatment period.

Outcome of repeat ablation for premature ventricular contractions in patients with prior ablation failure: Impact of advanced techniques.

Background: The utility of repeat ablation for premature ventricular contractions (PVCs) after prior ablation failure is not clear.

Objective: The purpose of this study was to assess the outcomes of repeat ablation and the use of different techniques in patients who failed prior PVC ablation.

Methods: We reviewed 239 consecutive patients who underwent PVC ablation.

Biophysical characterization of blood coagulation factor VIII binding to lipid nanodiscs that mimic activated platelet surfaces.

Background: Following proteolytic activation, activated blood coagulation factor (F)VIII (FVIIIa) binds to activated platelet membranes, forming the intrinsic tenase complex with activated FIX (FIXa). Previous studies have identified the C1 and C2 domains as the membrane binding domains of FVIII through conserved arginine residues. A membrane binding model for the FVIII C domains proposes that surface-exposed hydrophobic and positively charged residues at each C domain interact with the membrane, yet a comprehensive thermodynamic and structural description of this interaction is lacking.

Experiences and outcomes of patients participating in a perioperative shared decision-making pathway.

The Complex Decision Pathway (CDP) is a novel perioperative shared decision-making pathway that was established in the Bay of Plenty, New Zealand in 2018. Unique features of the pathway include the use of a structured communication tool to facilitate a goals-of-care conversation in addition to medical assessment, and the use of a tikanga Māori framework for Māori patients. From May 2019 until May 2022, 81 patients attending the CDP clinic were recruited to a prospective study of their demographics, health status and experience at the time of presentation, along with outcomes and opinions over the subsequent 12 months.

Allogeneic Hematopoietic Stem Cell Transplantation in Refractory Multiple Myeloma-A Retrospective Multicenter Analysis.

A growing list of therapies available for patients with multiple myeloma (MM) results in deep response rates, but eventually almost all patients relapse. Allogeneic hematopoietic cell transplantation (allo-SCT) is a familiar approach for MM, but responses are often short and side effects burdensome. Simultaneously, allo-SCT provides a unique platform on which novel immune therapies can be employed to improve clinical outcomes.

State of the Art: Mapping Strategies to Guide Ablation in Ischemic Heart Disease.

Catheter ablation to prevent ventricular tachycardia (VT) that emerges late after a myocardial infarction aims to interrupt the re-entry substrate. Interruption of potential channels and regions of slow conduction that can be identified during stable sinus or paced rhythm is often effective and a number of substrate markers for guiding this approach have been described. While there is substantial agreement with different markers in some patients, the different markers select different regions for ablation in others.

Emergent Ablation for Ventricular Tachycardia: Predictors of Prolonged Hospitalization and Mortality.

Background: Patients with ventricular tachycardia (VT) frequently present in unstable VT and are subject to urgent/high-risk ablation procedures. Clinical predictors of prolonged hospitalization and mortality are needed for optimal management of these patients.

Objectives: This study seeks to identify factors associated with prolonged hospitalization and mortality in emergent unplanned VT ablation procedures.