Estimands for Early-Phase Dose Optimization Trials in Oncology.

Phase I dose escalation trials in oncology generally aim to find the maximum tolerated dose. However, with the advent of molecular-targeted therapies and antibody drug conjugates, dose-limiting toxicities are less frequently observed, giving rise to the concept of optimal biological dose (OBD), which considers both efficacy and toxicity. The estimand framework presented in the addendum of the ICH E9(R1) guidelines strengthens the dialogue between different stakeholders by bringing in greater clarity in the clinical trial objectives and by providing alignment between the targeted estimand under consideration and the statistical analysis methods.

Reimagining Outcomes: A Perspective Review of Advances in Remote Monitoring Technologies in Post-Arthroplasty Patient Care.

Arthroplasty surgery is a common and successful end-stage intervention for advanced osteoarthritis. Yet, postoperative outcomes vary significantly among patients, leading to a plethora of measures and associated measurement approaches to monitor patient outcomes. Traditional approaches rely heavily on patient-reported outcome measures (PROMs), which are widely used, but often lack sensitivity to detect function changes (e.

ASO Practice Guidelines Series: Soft Tissue Sarcoma of the Extremities and Superficial Trunk.

Soft tissue sarcomas (STS) are a heterogeneous group of rare malignant tumors arising from mesenchymal tissues, with extremity and superficial trunk STS (eSTS) comprising the majority of cases. The management of localized eSTS requires a multidisciplinary approach to optimize oncologic and functional outcomes. This review outlines the natural history, diagnostic workup, and treatment principles for localized eSTS, emphasizing the role of histology-specific considerations in guiding management strategies.

Drugs Withdrawn from the Canadian Market for Safety and Effectiveness Reasons, 1990-2024: A Cross-Sectional Study.

Introduction: At times it is necessary to withdraw drugs after they have been approved because of lack of effectiveness or safety concerns. Health Canada does not keep a list of withdrawn drugs.

Objective: The aim of this study was to generate a list of all drugs approved since 1990 and subsequently withdrawn from the Canadian market for safety or effectiveness reasons until the end of 2024.

The Practical Value of Bayesian Inference in Describing the Epidemiology of Sports Injuries.

Sports injury surveillance programs have been vital in advancing the understanding of injury epidemiology across various athlete populations. Surveillance-based epidemiological measures of injury occurrence are ubiquitous in the sports medicine literature, and the injury rate is one such commonly used measure. Traditional approaches to calculating injury rates have predominantly relied on frequentist methods, which, while informative, have limitations in addressing certain practical questions.

Redox-driven mineral and organic associations in Jezero Crater, Mars.

The Perseverance rover has explored and sampled igneous and sedimentary rocks within Jezero Crater to characterize early Martian geological processes and habitability and search for potential biosignatures. Upon entering Neretva Vallis, on Jezero Crater's western edge, Perseverance investigated distinctive mudstone and conglomerate outcrops of the Bright Angel formation. Here we report a detailed geological, petrographic and geochemical survey of these rocks and show that organic-carbon-bearing mudstones in the Bright Angel formation contain submillimetre-scale nodules and millimetre-scale reaction fronts enriched in ferrous iron phosphate and sulfide minerals, likely vivianite and greigite, respectively.

DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution.

Aberrant DNA methylation has been described in nearly all human cancers, yet its interplay with genomic alterations during tumor evolution is poorly understood. To explore this, we performed reduced representation bisulfite sequencing on 217 tumor and matched normal regions from 59 patients with non-small cell lung cancer from the TRACERx study to deconvolve tumor methylation. We developed two metrics for integrative evolutionary analysis with DNA and RNA sequencing data.

Molecular subtypes of human skeletal muscle in cancer cachexia.

Cancer-associated muscle wasting is associated with poor clinical outcomes, but its underlying biology is largely uncharted in humans. Unbiased analysis of the RNAome (coding and non-coding RNAs) with unsupervised clustering using integrative non-negative matrix factorization provides a means of identifying distinct molecular subtypes and was applied here to muscle of patients with colorectal or pancreatic cancer. Rectus abdominis biopsies from 84 patients were profiled using high-throughput next-generation sequencing.

Long-range PM pollution and health impacts from the 2023 Canadian wildfires.

Smoke from extreme wildfires in Canada adversely affected air quality in many regions in 2023. Here we use satellite observations, machine learning and a chemical transport model to quantify global and regional PM (particulate matter less than 2.5 μm in diameter) exposure and human health impacts related to the 2023 Canadian wildfires.

Trans-synaptic interaction with mGluR6 contributes to ELFN1 presynaptic enrichment in rod photoreceptors.

At the glutamatergic synapses between rod photoreceptors and ON-type bipolar cells, neurotransmitter is detected by the postsynaptic metabotropic glutamate receptor mGluR6. This receptor forms trans-synaptic interactions with ELFN1, a presynaptic cell adhesion molecule expressed in rods, and ELFN1 is important for mGluR6 localization at bipolar cell dendritic tips. Here, we show that in mice of either sex lacking mGluR6, the presynaptic localization of ELFN1 is disrupted.

Prevalence of vision impairment and refractive error in rural Nepalese children under five years of age.

Clinical Relevance: Good vision is critical for childhood development and education. Pre-school vision screening is important for early detection and treatment of visual problems, and prevention of life-long vision loss.

Background: The aim of this study was to determine the prevalence of vision impairment (VI) and refractive error (RE) in rural Nepalese children under five years of age.

Ketamine and Esketamine for Late-Life Depression: A Systematic Review of Efficacy, Safety, and Tolerability.

Ketamine has emerged as a promising treatment for major depression, though its efficacy and safety remain incompletely characterized in older adults. This systematic review synthesizes current evidence for ketamine in geriatric depression. A search of PubMed, EMBASE, and PsycINFO was conducted.

Hybrid AI in synthetic biology: next era in agriculture.

Synthetic biology holds great potential to transform agriculture, yet its progress is constrained by the complexity of multigenomic, multitrait, and multi-environment data. Desirable traits often arise from complex gene networks acting across diverse conditions, making them difficult to predict and optimize manually. In the past decade, artificial intelligence (AI) has supported this process, but its large data needs and poor integration limit its role to pattern recognition rather than explanatory trait design.

Leg blood flow and cardiac output are cyclically reduced during low-intensity exercise with intermittent KAATSU cuff inflation in young adults.

The present investigation sought to determine the cardiovascular responses to a commercially available KAATSU cuff system with rhythmic cuff inflation-deflation periods during leg exercise. Seventeen participants performed two-legged knee flexion/extension exercise at 25% of peak work rate (WR) with bilateral KAATSU cuffs applied to the proximal thigh (KAATSU) or work-rate matched control exercise (CTL). During KAATSU trials, the cuffs were set to Cycle Mode (repeated 30-s inflation; 5-s deflation) at progressively increasing cuff pressure (150-220 mmHg).

Influence of titanium-base and universal abutment heights on the adaptation and fracture of screw-and-cemented-retained lithium disilicate crowns.

Purpose: This in vitro study evaluated the adaptation and fracture resistance of screw- and cement-retained implant-supported restorations using lithium disilicate crowns cemented onto titanium bases and universal abutments of different heights.

Methods: Thirty crowns were designed, milled, and divided into three groups: TBA (titanium base abutment - 4.7-mm-height and 4.

Reported use of implementation science theories, models, and frameworks in 151 implementation trials: secondary analysis of a systematic review targeting nursing practice.

Background: Theories, models, and frameworks (TMFs) are central to the development and evaluation of implementation strategies supporting evidence-based practice (EBP). However, evidence on how and to what extent TMFs are used in implementation trials remains limited.

Purpose: This study aimed to examine the nature and extent of TMF use in implementation trials, identify which TMFs are most frequently employed, and explore temporal trends in their use.

Relevance of Georg Grosz's Weimar-era drawings to promoting social justice and health equity in contemporary society.

The arts and humanities can direct attention to the health-threatening effects of adverse living and working conditions and the political and economic systems that spawn them. Most of these efforts aim to improve healthcare by promoting empathy and sensitivity among health professionals towards patients and improving clinical skills. However, less effort is devoted towards improving living and working conditions-the structural and social determinants of health-that cause illness and make managing illness difficult.

From digital trace to evidence: Challenges and insights from a trial case study.

Technology's rapid evolution has made digital traces a common part of our lives, holding significant value for investigations and legal cases across various national jurisdictions. However, law enforcement and judicial systems often struggle to adapt to these changes, resulting in possible misinterpretations of digital evidence in criminal trials. Drawing on insights from a qualitative analysis of a terrorism-related court case, this research aims to gain a deeper understanding of the fundamental challenges of decision-making in digital forensics and how they can impact a criminal case.

Enhancing driving safety with customized music: A simulator study using entropy weight and Bayesian Networks.

Introduction: Listening to music while driving is a common practice. Extensive research has explored its effects on driving performance, with a growing consensus suggesting that the optimal complexity of music varies depending on different driving scenarios to maintain drivers' arousal levels. However, these optimal levels can vary significantly among individuals.