Homogenized finite element analysis of distal tibia sections: Achievements and limitations.

High-resolution peripheral quantitative computed tomography (HR-pQCT) based micro-finite element (μFE) analysis allows accurate prediction of stiffness and ultimate load of standardised (∼1 cm) distal radius and tibia sections. An alternative homogenized finite element method (hFE) was recently validated to compute the ultimate load of larger (∼2 cm) distal radius sections that include Colles' fracture sites. Since the mechanical integrity of the weight-bearing distal tibia is gaining clinical interest, it has been shown that the same properties can be used to predict the strength of both distal segments of the radius and the tibia.

A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results.

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival.

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors.

A multi-stack registration technique to improve measurement accuracy and precision across longitudinal HR-pQCT scans.

Background: Recent applications of high-resolution peripheral quantitative computed tomography (HR-pQCT) have demonstrated that changes in local bone remodelling can be quantified in vivo using longitudinal three-dimensional image registration. However, certain emerging applications, such as fracture healing and joint analysis, require larger multi-stack scan regions that can result in stack shift image artifacts. These artifacts can be detrimental to the accurate alignment of the bone structure across multiple timepoints.

Pd-Catalyzed Domino Narasaka-Heck/C-H Activation/Amination Reactions: Synthesis of Bis-heterocyclic Spirocycles.

The palladium-catalyzed synthesis of bis-heterocyclic spirocycles containing both pyrroline and indoline motifs is reported. Di--butyldiaziridinone is used to functionalize palladacycles generated domino Narasaka-Heck/C-H activation reactions. The reaction is readily scalable, and the spirocyclic products can undergo deprotection, reduction, and (3 + 2) cycloadditions, highlighting their synthetic utility.

Personalized loading conditions for homogenized finite element analysis of the distal sections of the radius.

The microstructure of trabecular bone is known to adapt its morphology in response to mechanical loads for achieving a biomechanical homeostasis. Based on this form-function relationship, previous investigators either simulated the remodeling of bone to predict the resulting density and architecture for a specific loading or retraced physiological loading conditions from local density and architecture. The latter inverse approach includes quantifying bone morphology using computed tomography and calculating the relative importance of selected load cases by minimizing the fluctuation of a tissue loading level metric.

Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results.

Checkpoint inhibitor (CPI) therapies provide limited benefit to patients with tumors of low immune reactivity. T cell-inducing vaccines hold promise to exert long-lasting disease control in combination with CPI therapy. Safety, tolerability and recommended phase 2 dose (RP2D) of an individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based neoantigen vaccine in combination with nivolumab and ipilimumab were assessed as primary endpoints in an ongoing phase 1/2 study in patients with advanced metastatic solid tumors (NCT03639714).

Unified validation of a refined second-generation HR-pQCT based homogenized finite element method to predict strength of the distal segments in radius and tibia.

Introduction: HR-pQCT based micro finite element (μFE) analyses are considered as "gold standard" for virtual biomechanical analyses of peripheral bone sites such as the distal segment of radius and tibia. An attractive alternative for clinical use is a homogenized finite element method (hFE) based on constitutive models, because of its much shorter evaluation times and modest computational resource requirements. Such hFE models have been experimentally validated for the distal segment of the radius, but neither for the distal segments of the tibia nor for both measurement sites together.

Bone Microarchitecture and Strength in Long-Standing Type 1 Diabetes.

Type 1 diabetes (T1DM) is associated with an increased fracture risk, specifically at nonvertebral sites. The influence of glycemic control and microvascular disease on skeletal health in long-standing T1DM remains largely unknown. We aimed to assess areal (aBMD) and volumetric bone mineral density (vBMD), bone microarchitecture, bone turnover, and estimated bone strength in patients with long-standing T1DM, defined as disease duration ≥25 years.

Fabric-elasticity relationships of tibial trabecular bone are similar in osteogenesis imperfecta and healthy individuals.

Osteogenesis Imperfecta (OI) is an inherited form of bone fragility characterised by impaired synthesis of type I collagen, altered trabecular bone architecture and reduced bone mass. High resolution peripheral computed tomography (HR-pQCT) is a powerful method to investigate bone morphology at peripheral sites including the weight-bearing distal tibia. The resulting 3D reconstructions can be used as a basis of micro-finite element (FE) or homogenized finite element (hFE) models for bone strength estimation.

Conventional finite element models estimate the strength of metastatic human vertebrae despite alterations of the bone's tissue and structure.

Introduction: Pathologic vertebral fractures are a major clinical concern in the management of cancer patients with metastatic spine disease. These fractures are a direct consequence of the effect of bone metastases on the anatomy and structure of the vertebral bone. The goals of this study were twofold.

In vivo repeatability of homogenized finite element analysis based on multiple HR-pQCT sections for assessment of distal radius and tibia strength.

Introduction: Micro finite element analysis (μFE) is a widely applied tool in biomedical research for assessing in vivo mechanical properties of bone at measurement sites, including the ultra-distal radius and tibia. A finite element approach (hFE) based on homogenized constitutive models for trabecular bone offers an attractive alternative for clinical use, as it is computationally less expensive than traditional μFE. The respective patient-specific models for in vivo bone strength estimation are usually based on standard clinical high-resolution peripheral quantitative CT (HR-pQCT) measurements.

Reference values and clinical predictors of bone strength for HR-pQCT-based distal radius and tibia strength assessments in women and men.

Unlabelled: Reference values for radius and tibia strength using multiple-stack high-resolution peripheral quantitative computed tomography (HR-pQCT) with homogenized finite element analysis are presented in order to derive critical values improving risk prediction models of osteoporosis. Gender and femoral neck areal bone mineral density (aBMD) were independent predictors of bone strength.

Introduction: The purpose was to obtain reference values for radius and tibia bone strength computed by using the homogenized finite element analysis (hFE) using multiple stacks with a HR-pQCT.

Sickle cell disease in Germany: Results from a national registry.

Background: Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the treatment modalities for patients with SCD in Germany.

Procedure: A nationwide German registry for patients with SCD documents basic data on diagnosis and patient history retrospectively at the time of registration.

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions.

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson's disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes.

Absorption spectra of early stool from preterm infants need to be considered in abdominal NIRS oximetry.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of the preterm infant. Low abdominal tissue oxygen saturation (StO) measured by near-infrared spectroscopy (NIRS) oximetry may be an early sign of NEC relevant for treating or even preventing NEC. However, current commercial NIRS oximeters provide inaccurate StO readings because they neglect stool as an abdominal absorber.

Signs of enhanced formation of gist memory in children with autism spectrum disorder - a study of memory functions of sleep.

Background: Autism spectrum disorder (ASD) is characterized by impaired cognitive and social skills, including emotional dysregulation, and symptoms have been suspected to partly arise from impaired formation of memory representations regulating these behaviours. Sleep, which is subjectively impaired in ASD, is critical for forming long-term memories and abstracted gist-based representations. We expected a generally reduced memory benefit from sleep in children with ASD, and a diminished enhancement of gist representations, in particular.

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression.

Objective: To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD.

Recommendations of the Global Multiple System Atrophy Research Roadmap Meeting.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease.

Sorting Through the Spheres of Influence: Using Modified Pile Sorting to Describe Who Influences Dairy Farmers' Decision-Making About Safety.

Objectives: The primary goal of this study was to describe the mutually perceived influence of bankers and insurers on their agricultural clients' decision-making regarding health and safety.

Methods: Semistructured interviews were conducted with 10 dairy farmers, 11 agricultural bankers, and 10 agricultural insurers from central Wisconsin. Three of the interview questions involved pile sorting.

Amplification of overlapping DNA amplicons in a single-tube multiplex PCR for targeted next-generation sequencing of BRCA1 and BRCA2.

Current PCR-based target enrichment methods for next generation sequencing (NGS) of overlapping amplicons often requires separate PCR reactions and subsequent pooling of amplicons from the different reactions. The study presents a novel method, deemed stem-loop inhibition mediated amplification (SLIMamp), for amplifying overlapping or tiled amplicons in a single multiplex PCR reaction. During a SLIMamp PCR reaction, a stem loop structure formed by the overlapping amplicon suppresses additional amplification of itself by preventing the annealing of the primers.

Evidence for transcriptome-wide RNA editing among Sus scrofa PRE-1 SINE elements.

Background: RNA editing by ADAR (adenosine deaminase acting on RNA) proteins is a form of transcriptional regulation that is widespread among humans and other primates. Based on high-throughput scans used to identify putative RNA editing sites, ADAR appears to catalyze a substantial number of adenosine to inosine transitions within repetitive regions of the primate transcriptome, thereby dramatically enhancing genetic variation beyond what is encoded in the genome.

Results: Here, we demonstrate the editing potential of the pig transcriptome by utilizing DNA and RNA sequence data from the same pig.

Anti-α-synuclein immunotherapy reduces α-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy.

Neurodegenerative disorders such as Parkinson's Disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB) are characterized by progressive accumulation of α-synuclein (α-syn) in neurons. Recent studies have proposed that neuron-to-neuron propagation of α-syn plays a role in the pathogenesis of these disorders. We have previously shown that antibodies against the C-terminus of α-syn reduce the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy, probably by abrogating the axonal transport and accumulation of α-syn in in vivo models.

First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers.

Background: α-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets α-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce α-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human α-synuclein transgenic mice.

Methods: This first-in-human, randomized, double-blind, placebo-controlled, phase 1 study assessed the impact of PRX002 administered to 40 healthy participants in 5 ascending-dose cohorts (n = 8/cohort) in which participants were randomly assigned to receive a single intravenous infusion of study drug (0.