Automated rating of background parenchymal enhancement in MRI of extremely dense breasts without compromising the association with breast cancer in the DENSE trial.

Objectives: Background parenchymal enhancement (BPE) on dynamic contrast-enhanced MRI (DCE-MRI) as rated by radiologists is subject to inter- and intrareader variability. We aim to automate BPE category from DCE-MRI.

Methods: This study represents a secondary analysis of the Dense Tissue and Early Breast Neoplasm Screening trial.

2022 White Paper on Recent Issues in Bioanalysis: ICH M10 BMV Guideline & Global Harmonization; Hybrid Assays; Oligonucleotides & ADC; Non-Liquid & Rare Matrices; Regulatory Inputs ( - Recommendations on Mass Spectrometry, Chromatography and Sample Preparation, Novel Technologies, Novel Modalities, and Novel Challenges, ICH M10 BMV Guideline & Global Harmonization - Regulatory Agencies' Inputs on Regulated Bioanalysis/BMV, Biomarkers/CDx/BAV, Immunogenicity, Gene & Cell Therapy and Vaccine).

The 16 Workshop on Recent Issues in Bioanalysis (16 WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.

Assessing Quantitative Parenchymal Features at Baseline Dynamic Contrast-enhanced MRI and Cancer Occurrence in Women with Extremely Dense Breasts.

Background Automated identification of quantitative breast parenchymal enhancement features on dynamic contrast-enhanced (DCE) MRI scans could provide added value in assessment of breast cancer risk in women with extremely dense breasts. Purpose To automatically identify quantitative properties of the breast parenchyma on baseline DCE MRI scans and assess their association with breast cancer occurrence in women with extremely dense breasts. Materials and Methods This study represents a secondary analysis of the Dense Tissue and Early Breast Neoplasm Screening trial.

Validation of Combined Deep Learning Triaging and Computer-Aided Diagnosis in 2901 Breast MRI Examinations From the Second Screening Round of the Dense Tissue and Early Breast Neoplasm Screening Trial.

Objectives: Computer-aided triaging (CAT) and computer-aided diagnosis (CAD) of screening breast magnetic resonance imaging have shown potential to reduce the workload of radiologists in the context of dismissing normal breast scans and dismissing benign disease in women with extremely dense breasts. The aim of this study was to validate the potential of integrating CAT and CAD to reduce workload and workup on benign lesions in the second screening round of the DENSE trial, without missing cancer.

Methods: We included 2901 breast magnetic resonance imaging scans, obtained from 8 hospitals in the Netherlands.

A Delphi study to guide the development of a clinical indicator tool for palliative care in South Africa.

Background:  The South African National Policy Framework and Strategy on Palliative Care (NPFSPC) recommends that when integrating palliative care (PC) into the health system, a PC indicators tool should be used to guide clinicians to recognise a patient who should receive PC. The policy document recommends 'a simple screening tool developed for use in South Africa that would assist healthcare professionals (HCPs) to recognise patients who may have unmet palliative care needs'.

Aim:  This research study sought to develop South African consensus on indicators for PC to assist clinicians to recognise a patient in need of PC.

Deep Learning for Automated Triaging of 4581 Breast MRI Examinations from the DENSE Trial.

Background Supplemental screening with MRI has proved beneficial in women with extremely dense breasts. Most MRI examinations show normal anatomic and physiologic variation that may not require radiologic review. Thus, ways to triage these normal MRI examinations to reduce radiologist workload are needed.

Toward Computer-Assisted Triaging of Magnetic Resonance Imaging-Guided Biopsy in Preoperative Breast Cancer Patients.

Objectives: Incidental MR-detected breast lesions (ie, additional lesions to the index cancer) pose challenges in the preoperative workup of patients with early breast cancer. We pursue computer-assisted triaging of magnetic resonance imaging (MRI)-guided breast biopsy of additional lesions at high specificity.

Materials And Methods: We investigated 316 consecutive female patients (aged 26 to 76 years; mean, 54 years) with early breast cancer who received preoperative multiparametric breast MRI between 2013 and 2016.

Computer-Aided Diagnosis in Multiparametric Magnetic Resonance Imaging Screening of Women With Extremely Dense Breasts to Reduce False-Positive Diagnoses.

Objectives: To reduce the number of false-positive diagnoses in the screening of women with extremely dense breasts using magnetic resonance imaging (MRI), we aimed to predict which BI-RADS 3 and BI-RADS 4 lesions are benign. For this purpose, we use computer-aided diagnosis (CAD) based on multiparametric assessment.

Materials And Methods: Consecutive data were used from the first screening round of the DENSE (Dense Tissue and Early Breast Neoplasm Screening) trial.

Knowledge-based and deep learning-based automated chest wall segmentation in magnetic resonance images of extremely dense breasts.

Purpose: Segmentation of the chest wall, is an important component of methods for automated analysis of breast magnetic resonance imaging (MRI). Methods reported to date show promising results but have difficulties delineating the muscle border correctly in breasts with a large proportion of fibroglandular tissue (i.e.

Eligibility of patients for minimally invasive breast cancer therapy based on MRI analysis of tumor proximity to skin and pectoral muscle.

There is growing interest in minimally invasive breast cancer therapy. Eligibility of patients is, however, dependent on several factors related to the tumor and treatment technology. The aim of this study is to assess the proportion of patients eligible for minimally invasive breast cancer therapy for different safety and treatment margins based on breast tumor location.

ROS-mediated decline in maximum Ca2+-activated force in rat skeletal muscle fibers following in vitro and in vivo stimulation.

We hypothesised that normal skeletal muscle stimulated intensely either in vitro or in situ would exhibit reactive oxygen species (ROS)-mediated contractile apparatus changes common to many pathophysiological conditions. Isolated soleus (SOL) and extensor digitorum longus (EDL) muscles of the rat were bubbled with 95% O(2) and stimulated in vitro at 31°C to give isometric tetani (50 Hz for 0.5 s every 2 s) until maximum force declined to ≤30%.

Sorafenib-induced hypothyroidism is associated with increased type 3 deiodination.

Background: Therapy with tyrosine kinase inhibitors is associated with thyroid dysfunction. Decreased serum thyroid hormone levels during tyrosine kinase inhibitors are also observed in athyreotic patients with thyroid carcinoma. We therefore hypothesized that tyrosine kinase inhibitors may influence thyroid hormone metabolism.

Involvement of calpains in Ca2+-induced disruption of excitation-contraction coupling in mammalian skeletal muscle fibers.

In skeletal muscle fibers, the coupling between excitation of the surface membrane and the release of Ca(2+) from the sarcoplasmic reticulum is irreversibly disrupted if cytoplasmic Ca(2+) concentration ([Ca(2+)]) is raised to micromolar levels for a prolonged period. This excitation-contraction (EC) uncoupling may contribute to muscle weakness after some types of exercise and in certain muscle diseases and has been linked to structural alteration of the triad junctions, but its molecular basis is unclear. Both mu-calpain, a ubiquitous Ca(2+)-activated protease, and muscle-specific calpain-3 become autolytically activated at micromolar Ca(2+) and have been suggested to be responsible for the uncoupling.

Stereoselective metabolism of prasugrel in humans using a novel chiral liquid chromatography-tandem mass spectrometry method.

A liquid chromatography-tandem mass spectrometry method was developed to chromatographically separate the four stereoisomers of the active metabolite of prasugrel, R-138727, in human plasma after derivatization with bromomethoxyacetophenone to stabilize the molecule. This technique was designed to determine the relative contribution of each stereoisomer, based on statistical analyses of each stereoisomer's chromatographic peak areas. The methodology was validated and used for the analysis of clinical samples in which R-138727 had been derivatized at the time of blood collection.

Ca2+ activation of diffusible and bound pools of mu-calpain in rat skeletal muscle.

Skeletal muscle fibres contain ubiquitous and muscle-specific calcium-dependent proteases known as calpains. During normal activity, intracellular [Ca(2+)] in muscle fibres increases to high levels ( approximately 2-20 microm), and it is not apparent how this can be reconciled with the activation properties of the calpains. Calpains evidently do not cause widespread proteolytic damage within muscle fibres under normal circumstances, but do have a role in necrosis in dystrophic muscle fibres.

Long-lasting muscle fatigue: partial disruption of excitation-contraction coupling by elevated cytosolic Ca2+ concentration during contractions.

The repeated elevation of cytosolic Ca(2+) concentration ([Ca(2+)](i)) above resting levels during contractile activity has been associated with long-lasting muscle fatigue. The mechanism underlying this fatigue appears to involve elevated [Ca(2+)](i) levels that induce disruption of the excitation-contraction (E-C) coupling process at the triad junction. Unclear, however, are which aspects of the activity-related [Ca(2+)](i) changes are responsible for the deleterious effects, in particular whether they depend primarily on the peak [Ca(2+)](i) reached locally at particular sites or on the temporal summation of the increased [Ca(2+)] in the cytoplasm as a whole.

Temperature-dependent skeletal muscle dysfunction in rats with congestive heart failure.

Abnormalities in the excitation-contraction coupling of slow-twitch muscle seem to explain the slowing and increased fatigue observed in congestive heart failure (CHF). However, it is not known which elements of the excitation-contraction coupling might be affected. We hypothesize that the temperature sensitivity of contractile properties of the soleus muscle might be altered in CHF possibly because of alterations of the temperature sensitivity of intracellular Ca(2+) handling.

Disruption of excitation-contraction coupling and titin by endogenous Ca2+-activated proteases in toad muscle fibres.

This study investigated the effects of elevated, physiological levels of intracellular free [Ca(2+)] on depolarization-induced force responses, and on passive and active force production by the contractile apparatus in mechanically skinned fibres of toad iliofibularis muscle. Excitation-contraction (EC) coupling was retained after skinning and force responses could be elicited by depolarization of the transverse-tubular (T-) system. Raising the cytoplasmic [Ca(2+)] to approximately 1 microm or above for 3 min caused an irreversible reduction in the depolarization-induced force response by interrupting the coupling between the voltage sensors in the T-system and the Ca(2+) release channels in the sarcoplasmic reticulum.

Contractile properties of in situ perfused skeletal muscles from rats with congestive heart failure.

We hypothesized that in congestive heart failure (CHF) slow-twitch but not fast-twitch muscles exhibit decreased fatigue resistance in the sense of accelerated reduction of muscle force during activity. Experiments were carried out on anaesthetized rats 6 weeks after induction of myocardial infarction or a sham operation (Sham). Animals with left ventricular end-diastolic pressure (LVEDP) > 15 mmHg under anaesthesia were selected for the CHF group.

Muscle contractile properties during intermittent nontetanic stimulation in rat skeletal muscle.

To examine changes in contractile properties and mechanisms of fatigue during submaximal nontetanic skeletal muscle activity, in situ perfused soleus (60-min protocol) and extensor digitorum longus (EDL; 10-min protocol) muscles of the rat were electrically stimulated intermittently at low frequency. The partly fused trains of contractions showed a two-phase change in appearance. During the first phase, relaxation slowed, one-half relaxation time increased, and maximal relaxation first derivative of force (dF/dt) decreased.

Loss of potassium from muscle during moderate exercise in humans: a result of insufficient activation of the Na+-K+-pump?

In this study, we have investigated whether the muscle net potassium (K+) loss, observed during two-legged intermittent static knee-extensions at 30% MVC (n = 9), is caused by an insufficient activation of the Na+-K+-pumps. Furthermore, we have investigated whether the changes in the K+ homeostasis can be causally related to fatigue. K+ loss was calculated from the arterio-venous concentration difference and plasma flow.

Skeletal muscle fatigue in normal subjects and heart failure patients. Is there a common mechanism?

Skeletal muscle fatigue develops gradually during all forms of exercise, and develops more rapidly in heart failure patients. The fatigue mechanism is still not known, but is most likely localized to the muscle cells themselves. During high intensity exercise the perturbations of the Na+ and K+ balance in the exercising muscle favour depolarization, smaller action potentials and inexcitability.

Atrial contractile dysfunction after short-term atrial fibrillation is reduced by verapamil but increased by BAY K8644.

Background: Reduced atrial contractility occurs after cessation of atrial fibrillation. Its mechanism is unknown, and no pharmacological treatment exists. It has been hypothesized that this atrial contractile dysfunction results from intracellular calcium overload due to rapid depolarizations during fibrillation.

Muscular function, metabolism and electrolyte shifts during prolonged repetitive exercise in humans.

Marked functional changes occur in human skeletal muscle during prolonged repetitive exercise. The maximum voluntary contraction force (MVC) falls gradually and may reach 50% of control within 30-60 min. The twitch tension declines faster and to a larger extent.

Absence of an effect of fatigue on muscle efficiency during high-intensity exercise in rat skeletal muscle.

The effect of fatigue was studied on rat skeletal muscle efficiency during maximal dynamic exercise of 10s duration. After the initial 4s of exercise, power output decreased rapidly to 46.2 +/- 6.