Biologically-targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma.

Inherited genetics represents an important contributor to risk of esophageal adenocarcinoma (EAC), and its precursor Barrett's esophagus (BE). Genome-wide association studies have identified ∼30 susceptibility variants for BE/EAC, yet genetic interactions remain unexamined. To address challenges in large-scale G×G scans, we combined knowledge-guided filtering and machine learning approaches, focusing on genes with (A) known/plausible links to BE/EAC pathogenesis (n=493) or (B) prior evidence of biological interactions (n=4,196).

Coffee and tea consumption and the risk of head and neck cancer: An updated pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.

Introduction: The relations between coffee and tea consumption and head and neck cancer (HNC) incidence are unclear. With increasing global HNC burden, this study aims to examine the association between coffee, tea, and HNC.

Methods: A pooled analysis of 9548 HNC cases and 15,783 controls from 14 individual-level case-control studies was conducted from the International Head and Neck Cancer Epidemiology consortium.

Preclinical and Clinical Pharmacokinetics of JNJ-75220795, an siRNA Therapeutic Targeting PNPLA3, for Metabolic Dysfunction-Associated Steatohepatitis.

JNJ-75220795 or ARO-PNPLA3 is an investigational small interfering ribonucleic acid agent conjugated with N-acetyl-d-galactosamine that targets the PNPLA3 gene, currently being developed for metabolic dysfunction-associated steatohepatitis (MASH). This study evaluated the pharmacokinetics (PK) profile of single subcutaneous doses of JNJ-75220795 in preclinical species as well as in human subjects with homozygous or heterozygous PNPLA3 I148M mutation in two phase 1 studies-a first-in-human study in the United States and a first-in-Japanese study in Japan. Preclinical PK in rats and non-human primates (NHP) showed a rapid systemic absorption and elimination following single subcutaneous doses.

A multi-domain computational framework investigating the short- and long-term viability of bioabsorbable magnesium fixation for tibial fractures.

This study presents a multi-domain computational framework to investigate the long-term performance of permanent and bioabsorbable magnesium fixation devices in orthopaedic fracture applications. The framework integrates a coupled model for bone fracture healing and remodeling, with an enhanced surface-based corrosion model to predict the performance of bioabsorbable magnesium devices. It was found that plated fracture fixation enabled fracture healing outcomes compare to non-plated models by facilitating direct fracture healing.

EpiFusion: Joint inference of the effective reproduction number by integrating phylodynamic and epidemiological modelling with particle filtering.

Accurately estimating the effective reproduction number (Rt) of a circulating pathogen is a fundamental challenge in the study of infectious disease. The fields of epidemiology and pathogen phylodynamics both share this goal, but to date, methodologies and data employed by each remain largely distinct. Here we present EpiFusion: a joint approach that can be used to harness the complementary strengths of each field to improve estimation of outbreak dynamics for large and poorly sampled epidemics, such as arboviral or respiratory virus outbreaks, and validate it for retrospective analysis.

Estimating pathogen spread using structured coalescent and birth-death models: A quantitative comparison.

Elucidating disease spread between subpopulations is crucial in guiding effective disease control efforts. Genomic epidemiology and phylodynamics have emerged as key principles to estimate such spread from pathogen phylogenies derived from molecular data. Two well-established structured phylodynamic methodologies - based on the coalescent and the birth-death model - are frequently employed to estimate viral spread between populations.

The Fossilised Birth-Death Model is Identifiable.

Time-dependent birth-death sampling models have been used in numerous studies for inferring past evolutionary dynamics in different biological contexts, e.g. speciation and extinction rates in macroevolutionary studies, or effective reproductive number in epidemiological studies.

MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients.

Introduction: Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides.

Methods: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ, the pathogenic self-aggregating species of Aβ.

Results: MEDI1814 reduces free Aβ without impacting Aβ in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration.

An investigation of composition, morphology, mechanical properties, and microdamage accumulation of human type 2 diabetic bone.

This study investigates the biomechanics of type 2 diabetic bone fragility through a multiscale experimental strategy that considers structural, mechanical, and compositional components of ex vivo human trabecular and cortical bone. Human tissue samples were obtained from the femoral heads of patients undergoing total hip replacement. Mechanical testing was carried out on isolated trabecular cores using monotonic and cyclic compression loading and nanoindentation experiments, with bone microdamage analysed using micro-computed tomography (CT) imaging.

Machine learning designs new GCGR/GLP-1R dual agonists with enhanced biological potency.

Several peptide dual agonists of the human glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R) are in development for the treatment of type 2 diabetes, obesity and their associated complications. Candidates must have high potency at both receptors, but it is unclear whether the limited experimental data available can be used to train models that accurately predict the activity at both receptors of new peptide variants. Here we use peptide sequence data labelled with in vitro potency at human GCGR and GLP-1R to train several models, including a deep multi-task neural-network model using multiple loss optimization.

Exploring the hierarchical structure of lamellar bone and its impact on fracture behaviour: A computational study using a phase field damage model.

Bone is a naturally occurring composite material composed of a stiff mineral phase and a compliant organic matrix of collagen and non-collagenous proteins (NCP). While diverse mineral morphologies such as platelets and grains have been documented, the precise role of individual constituents, and their morphology, remains poorly understood. To understand the role of constituent morphology on the fracture behaviour of lamellar bone, a damage based representative volume element (RVE) was developed, which considered various mineral morphologies and mineralised collagen fibril (MCF) configurations.

Micromechanical modelling of transverse fracture behaviour of lamellar bone using a phase-field damage model: The role of non-collagenous proteins and mineralised collagen fibrils.

At the tissue-scale and above, there are now well-established structure-property relationships that provide good approximations of the biomechanical performance of bone through, for example, power-law relationships that relate tissue mineral density to elastic properties. However, below the tissue-level, the individual role of the constituents becomes prominent and these simple relationships tend to break down, with more detailed theoretical and computational models are required to describe the mechanical response. In this study, a two-dimensional micromechanics damage-based representative volume element (RVE) of lamellar bone was developed, which included a novel implementation of a phase-field damage model to describe the behaviour of non-collagenous proteins at mineral-mineral and mineral-fibril interface regions.

Sustainable Bombyx mori's silk fibroin for biomedical applications as a molecular biotechnology challenge: A review.

Silk is a natural engineering material with a unique set of properties. The major constituent of silk is fibroin, a protein widely used in the biomedical field because of its mechanical strength, toughness and elasticity, as well as its biocompatibility and biodegradability. The domestication of silkworms allows large amounts of fibroin to be extracted inexpensively from silk cocoons.

An integrated mechanical degradation model to explore the mechanical response of a bioresorbable polymeric scaffold.

Simulation of bioresorbable medical devices is hindered by the limitations of current material models. Useful simulations require that both the short- and long-term response must be considered; existing models are not physically-based and provide limited insight to guide performance improvements. This study presents an integrated degradation framework which couples a physically-based degradation model, which predicts changes in both crystallinity (X) and molecular weight (M), with the results of a micromechanical model, which predicts the effective properties of the semicrystalline polymer.

Shape-Setting of Self-Expanding Nickel-Titanium Laser-Cut and Wire-Braided Stents to Introduce a Helical Ridge.

Purpose: Altered hemodynamics caused by the presence of an endovascular device may undermine the success of peripheral stenting procedures. Flow-enhanced stent designs are under investigation to recover physiological blood flow patterns in the treated artery and reduce long-term complications. However, flow-enhanced designs require the development of customised manufacturing processes that consider the complex behaviour of Nickel-Titanium (Ni-Ti).

Elucidating the role of diverse mineralisation paradigms on bone biomechanics - a coarse-grained molecular dynamics investigation.

Bone as a hierarchical composite structure plays a myriad of roles in vertebrate skeletons including providing the structural stability of the body. Despite this critical role, the mechanical behaviour at the sub-micron levels of bone's hierarchy remains poorly understood. At this scale, bone is composed of Mineralised Collagen Fibrils (MCF) embedded within an extra-fibrillar matrix that consists of hydroxyapatite minerals and non-collagenous proteins.

ReMASTER: improved phylodynamic simulation for BEAST 2.7.

Summary: Phylodynamic models link phylogenetic trees to biologically-relevant parameters such as speciation and extinction rates (macroevolution), effective population sizes and migration rates (ecology and phylogeography), and transmission and removal/recovery rates (epidemiology) to name a few. Being able to simulate phylogenetic trees and population dynamics under these models is the basis for (i) developing and testing of phylodynamic inference algorithms, (ii) performing simulation studies which quantify the biases stemming from model-misspecification, and (iii) performing so-called model adequacy assessments by simulating samples from the posterior predictive distribution. Here I introduce ReMASTER, a package for the phylogenetic inference platform BEAST 2 that provides a simple and efficient approach to specifying and simulating the phylogenetic trees and population dynamics arising from phylodynamic models.

Experimental and computational analysis of energy absorption characteristics of three biomimetic lattice structures under compression.

The objective of this study is to evaluate the mechanical properties and energy absorption characteristics of the gyroid, dual-lattice and spinodoid structures, as biomimetic lattices, through finite element analysis and experimental characterisation. As part of the study, gyroid and dual-lattice structures at 10% volume fraction were 3D-printed using an elastic resin, and mechanically tested under uniaxial compression. Computational models were calibrated to the observed experimental data and the response of higher volume fraction structures were simulated in an explicit finite element solver.

Estimates of early outbreak-specific SARS-CoV-2 epidemiological parameters from genomic data.

We estimate the basic reproductive number and case counts for 15 distinct Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks, distributed across 11 populations (10 countries and one cruise ship), based solely on phylodynamic analyses of genomic data. Our results indicate that, prior to significant public health interventions, the reproductive numbers for 10 (out of 15) of these outbreaks are similar, with median posterior estimates ranging between 1.4 and 2.

Hiatal hernia repair after previous laparoscopic Roux-en-Y gastric bypass.

Background: Symptomatic hiatal hernia (HH) with pouch migration after previous laparoscopic Roux-en-Y gastric bypass (RYGB) is an uncommon complication, with limited extant evidence for the utility of surgical repair.

Objective: To evaluate the presentation and resolution of symptoms in patients with HH repair after previous RYGB.

Setting: Multicenter University Hospital.

Evidence for Decision-Making: The Importance of Systematic Data Collection as an Essential Component of Responsive Feedback.

The authors discuss the importance of systematic data collection as a central component of the responsive feedback process and highlight several case studies that illustrate continuous learning and improvement.

Can perioperative electroencephalogram and adverse hemodynamic events predict neurodevelopmental outcomes in infants with congenital heart disease?

Objective: The study objective was to characterize preoperative and postoperative continuous electroencephalogram metrics and hemodynamic adverse events as predictors of neurodevelopment in congenital heart disease infants undergoing cardiac surgery.

Methods: From 2010 to 2021, 320 infants underwent congenital heart disease surgery at our institution, of whom 217 had perioperative continuous electroencephalogram monitoring and were included in our study. Neurodevelopment was assessed in 76 patients by the Bayley Scales of Infant and Toddler Development, 3rd edition, consisting of cognitive, communication, and motor scaled scores.

Rapid discovery of high-affinity antibodies via massively parallel sequencing, ribosome display and affinity screening.

Developing therapeutic antibodies is laborious and costly. Here we report a method for antibody discovery that leverages the Illumina HiSeq platform to, within 3 days, screen in the order of 10 antibody-antigen interactions. The method, which we named 'deep screening', involves the clustering and sequencing of antibody libraries, the conversion of the DNA clusters into complementary RNA clusters covalently linked to the instrument's flow-cell surface on the same location, the in situ translation of the clusters into antibodies tethered via ribosome display, and their screening via fluorescently labelled antigens.

How ICP-OES changed the face of trace element analysis: Review of the global application landscape.

The 50th anniversary of Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-OES) will be observed in 2024. ICP-OES was first commercially available in 1974, and since then, it has become one of the most widely used analytical techniques in the world. ICP-OES is a powerful tool for the determination of trace and ultratrace elemental concentrations in a wide variety of samples specifically for multielement analysis.