Risk score stratification of cutaneous melanoma patients based on whole slide images analysis by deep learning.

Background: There is a need to improve risk stratification of primary cutaneous melanomas to better guide adjuvant therapy. Taking into account that haematoxylin and eosin (HE)-stained tumour tissue contains a huge amount of clinically unexploited morphological informations, we developed a weakly-supervised deep-learning approach, SmartProg-MEL, to predict survival outcomes in stages I to III melanoma patients from HE-stained whole slide image (WSI).

Methods: We designed a deep neural network that extracts morphological features from WSI to predict 5-y overall survival (OS), and assign a survival risk score to each patient.

Discovery of Truncated Cyclic Peptides Targeting an Induced-Fit Pocket on PCSK9.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDL-R) degradation. We previously identified and optimized 13-mer cyclic peptides that bind to a novel, induced-fit pocket adjacent to the binding interface of PCSK9 and LDL-R and effectively disrupted the PCSK9/LDL-R protein-protein interaction (PPI) both in vitro and in vivo. However this series of large cyclic peptides required charged groups for function and lacked oral bioavailability in rodents.

Harnessing RNA Interference for Cholesterol Lowering: The Bench-to-Bedside Story of Inclisiran.

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes.

Competency Framework for Podiatric Medicine Training: A Validation Report Based on an Adapted E-Delphi Across Canada.

Objectives: Competency-based medical education has been introduced into many health professional curricula. Based on CanMEDs, a framework has recently been developed for podiatric medicine education in Canada. This study aimed to validate the framework through a consensus of various podiatric medicine experts across Canada.

Measuring Health Care Work-Related Contextual Factors: Development of the McGill Context Tool.

Introduction: Contextual factors can influence healthcare professionals' (HCPs) competencies, yet there is a scarcity of research on how to optimally measure these factors. The aim of this study was to develop and validate a comprehensive tool for HCPs to document the contextual factors likely to influence the maintenance, development, and deployment of professional competencies.

Methods: We used DeVellis' 8-step process for scale development and Messick's unified theory of validity to inform the development and validation of the context tool.

Microsecond Motion of the Bacterial Transporter EmrE in Lipid Bilayers.

The bacterial transporter EmrE is a homo-dimeric membrane protein that effluxes cationic polyaromatic substrates against the concentration gradient by coupling to proton transport. As the archetype of the small multidrug resistance family of transporters, EmrE structure and dynamics provide atomic insights into the mechanism of transport by this family of proteins. We recently determined high-resolution structures of EmrE in complex with a cationic substrate, tetra(4-fluorophenyl)phosphonium (F-TPP), using solid-state NMR spectroscopy and an S64V-EmrE mutant.

Charge neutralization of the active site glutamates does not limit substrate binding and transport by small multidrug resistance transporter EmrE.

EmrE, a small multidrug resistance transporter from Escherichia coli, confers broad-spectrum resistance to polyaromatic cations and quaternary ammonium compounds. Previous transport assays demonstrate that EmrE transports a +1 and a +2 substrate with the same stoichiometry of two protons:one cationic substrate. This suggests that EmrE substrate binding capacity is limited to neutralization of the two essential glutamates, E14 and E14 (one from each subunit in the antiparallel homodimer), in the primary binding site.

Activating alternative transport modes in a multidrug resistance efflux pump to confer chemical susceptibility.

Small multidrug resistance (SMR) transporters contribute to antibiotic resistance through proton-coupled efflux of toxic compounds. Previous biophysical studies of the E. coli SMR transporter EmrE suggest that it should also be able to perform proton/toxin symport or uniport, leading to toxin susceptibility rather than resistance in vivo.

Loss of Hepatic Leucine-Rich Repeat-Containing G-Protein Coupled Receptors 4 and 5 Promotes Nonalcoholic Fatty Liver Disease.

The roof plate-specific spondin-leucine-rich repeat-containing G-protein coupled receptor 4/5 (LGR4/5)-zinc and ring finger 3 (ZNRF3)/ring finger protein 43 (RNF43) module is a master regulator of hepatic Wnt/β-catenin signaling and metabolic zonation. However, its impact on nonalcoholic fatty liver disease (NAFLD) remains unclear. The current study investigated whether hepatic epithelial cell-specific loss of the Wnt/β-catenin modulator Lgr4/5 promoted NAFLD.

Competency Framework for Podiatric Medicine Training in Canada: An Adapted Delphi Study.

Purpose: Podiatrists are generally defined as professionals with high-level skills in the prevention and management of local foot conditions that are not systemic diseases. Across countries, different academic trainings are implemented due to the specific context and practice of podiatric medicine. It is thus essential to support country-specific podiatry education for the development of highly skilled podiatrists.

Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state.

PPM1D encodes a serine/threonine phosphatase that regulates numerous pathways including the DNA damage response and p53. Activating mutations and amplification of PPM1D are found across numerous cancer types. GSK2830371 is a potent and selective allosteric inhibitor of PPM1D, but its mechanism of binding and inhibition of catalytic activity are unknown.

Identification of a PCSK9-LDLR disruptor peptide with in vivo function.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors.

Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction.

PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes.

What occupational therapists' say about their competencies' enactment, maintenance and development in practice? A two-phase mixed methods study.

Background: Understanding how professional competencies are actually enacted in clinical practice can help university programs better prepare their graduates. The study aimed to describe 1) the perceived competency level of occupational therapists holding an entry-to-practice master's degree 2) the factors perceived as impacting the enactment of competencies; and 3) the strategies used to maintain and further develop level of competency in the seven practice roles: expert in enabling occupation, communicator, collaborator, practice manager, change agent, scholarly practitioner and professional.

Methods: Descriptive two-phase mixed methods sequential design.

MeCP2 is involved in random mono-allelic expression for a subset of human autosomal genes.

Widespread random monoallelic gene expression (RMAE) effects influence about 10% of human genes. However, the mechanisms by which RME of autosomal genes is established and those by which it is maintained both remain open questions. Because the choice of allelic expression is randomly performed cell-by-cell, the RMAE mechanism is not observable in non-clonal cell populations or in whole tissues.

Discovery of a Novel Piperidine-Based Inhibitor of Cholesteryl Ester Transfer Protein (CETP) That Retains Activity in Hypertriglyceridemic Plasma.

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency.

Synthetic phospholipids as specific substrates for plasma endothelial lipase.

We designed and prepared synthetic phospholipids that generate lyso-phosphatidylcholine products with a unique mass for convenient detection by LC-MS in complex biological matrices. We demonstrated that compound 4, formulated either as a Triton X-100 emulsion or incorporated in synthetic HDL particles can serve as a substrate for plasma EL with useful specificity.

Montreal Cognitive Assessment Memory Index Score (MoCA-MIS) as a predictor of conversion from mild cognitive impairment to Alzheimer's disease.

Objectives: To assess the usefulness of the Montreal Cognitive Assessment (MoCA) total score (MoCA-TS) and Memory Index Score (MoCA-MIS) in predicting conversion to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI).

Design: Retrospective chart review.

Setting: Community-based memory clinic.

[Conceptualization of the role of expert in enabling occupation by occupational therapy fieldwork supervisors].

Background: The use of occupation-focused language in clinical settings is essential to supervision of student occupational therapists since training is based, at least in part, on the competencies described in The Profile of Occupational Therapy Practice in Canada (Canadian Association of Occupational Therapists, 2007).

Purpose: This article describes how occupational therapists conceptualize the competencies related to the role of "expert in enabling occupation."

Methods: Qualitative data collected from 56 occupational therapists across eight focus groups were categorized using content analysis through a process of constant comparison.

Effects of CETP inhibition on triglyceride-rich lipoprotein composition and apoB-48 metabolism.

Cholesteryl ester transfer protein (CETP) facilitates the transfer of HDL cholesteryl ester to triglyceride-rich lipoproteins (TRL). This study aimed to determine the effects of CETP inhibition with torcetrapib on TRL composition and apoB-48 metabolism. Study subjects with low HDL cholesterol (<40 mg/dl), either untreated (n = 9) or receiving atorvastatin 20 mg daily (n = 9), received placebo for 4 weeks, followed by torcetrapib 120 mg once daily for the next 4 weeks.

Sexual coercion within mixed-sex couples: the roles of sexual motives, revictimization, and reperpetration.

Research suggests that a history of childhood sexual abuse, and previous experiences of sexual coercion, may predict sexual coercion victimization and perpetration. More recently, sexual motivation has been found to correlate with both consensual and non-consensual sexual activity. However, sexual motivation has not been examined in association with previous experiences of abuse and sexual coercion.

[Theoretical perspectives in health education and record keeping].

Background: Are occupational therapists involved in health education and promotion, as required by Quebec's Professional code? In practice, they do intervene in health education. However, their lack of theoretical referents makes it difficult to acknowledge that specific component of their profession. Therefore, concepts related to health education need to be clarified.

Common genetic variation in multiple metabolic pathways influences susceptibility to low HDL-cholesterol and coronary heart disease.

A low level of HDL-C is the most common plasma lipid abnormality observed in men with established coronary heart disease (CHD). To identify allelic variants associated with susceptibility to low HDL-C and CHD, we examined 60 candidate genes with key roles in HDL metabolism, insulin resistance, and inflammation using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT; cases, n = 699) and the Framingham Offspring Study (FOS; controls, n = 705). VA-HIT was designed to examine the benefits of HDL-raising with gemfibrozil in men with low HDL-C (≤40 mg/dl) and established CHD.