TLR4 downregulation protects against cisplatin-induced ototoxicity in adult and pediatric patients with cancer.

Cisplatin causes permanent hearing loss or cisplatin-induced ototoxicity in over 50% of treated patients with cancer, leading to significant social and functional limitations. Interindividual variability in developing hearing loss suggests the role of genetic predispositions to cisplatin-induced hearing loss. We investigated genetic associations between cisplatin-induced ototoxicity and toll-like receptor 4 (TLR4), an immune receptor known to mediate inflammatory responses to cisplatin.

Deep learning-based clustering for endotyping and post-arthroplasty response classification using knee osteoarthritis multiomic data.

Objectives: Primary knee osteoarthritis (KOA) is a heterogeneous disease with clinical and molecular contributors. Biofluids contain microRNAs and metabolites that can be measured by omic technologies. Multimodal deep learning is adept at uncovering complex relationships within multidomain data.

Comparing subsampling strategies for metagenomic analysis in microbial studies using amplicon sequence variants versus operational taxonomic units.

The microbiome is increasingly regarded as a key component of human health, and analysis of microbiome data can aid in the development of precision medicine. Due to the high cost of shotgun metagenomic sequencing (SM-seq), microbiome analyses can be done cost-effectively in two phases: Phase 1-sequencing of 16S ribosomal RNA, and Phase 2-SM-seq of an informative subsample. Existing research suggests strategies to select the subsample based on biological diversity and dissimilarity metrics calculated using operational taxonomic units (OTUs).

TRPC1 links calcium signaling to cellular senescence in the protection against posttraumatic osteoarthritis.

Transient receptor potential channel 1 (TRPC1) is a widely expressed mechanosensitive ion channel located within the endoplasmic reticulum membrane, crucial for refilling depleted internal calcium stores during activation of calcium-dependent signaling pathways. Here, we have demonstrated that TRPC1 activity is protective within cartilage homeostasis in the prevention of cellular senescence-associated cartilage breakdown during mechanical and inflammatory challenge. We revealed that TRPC1 loss is associated with early stages of osteoarthritis (OA) and plays a nonredundant role in calcium signaling in chondrocytes.

A scoping review of statistical methods to investigate colocalization between genetic associations and microRNA expression in osteoarthritis.

Background: Genetic colocalization analysis is a statistical method that evaluates whether two traits (e.g., osteoarthritis [OA] risk and microRNA [miRNA] expression levels) share the same or distinct genetic association signals in a locus typically identified in genome-wide association studies (GWAS).

MicroRNA signature for early prediction of knee osteoarthritis structural progression using integrated machine and deep learning approaches.

Objective: Conventional methodologies are ineffective in predicting the rapid progression of knee osteoarthritis (OA). MicroRNAs (miRNAs) show promise as biomarkers for patient stratification. We aimed to develop a miRNA prognosis model for identifying knee OA structural progressors/non-progressors using integrated machine/deep learning tools.

Molecular Classification of Endometrial Cancers Using an Integrative DNA Sequencing Panel.

Background And Objectives: Adoption of molecular classification in endometrial cancer (EC) into clinical practice remains challenging due to complexity in coordination of multiple assays. We aimed to develop a simple molecular technique to classify ECs into four subgroups using our custom-designed targeted sequencing panel.

Methods: Patients with newly diagnosed ECs were prospectively recruited from three cancer centres in Ontario, Canada.

Applying survey weights to ordinal regression models for improved inference in outcome-dependent samples with ordinal outcomes.

Researchers often use outcome-dependent sampling to study the exposure-outcome association. The case-control study is a widely used example of outcome-dependent sampling when the outcome is binary. When the outcome is ordinal, standard ordinal regression models generally produce biased coefficients when the sampling fractions depend on the values of the outcome variable.

Impact of the Early Phase of the COVID-19 Pandemic on the Quality of Care for Colorectal and Anal Cancers at Comprehensive Cancer Centers on Two Continents.

Purpose: The early phase of the COVID-19 pandemic affected cancer care globally. Evaluating the impact of the pandemic on the quality of cancer care delivery is crucial for understanding how changes in care delivery may influence outcomes. Our study compared care delivered during the early phase of the pandemic with the same period in the previous year at two institutions across continents (Princess Margaret Cancer Center [PM] in Canada and A.

Cross-sectional and prospective associations between sleep health and multimorbidity in middle to older-aged adults: Results from the Canadian Longitudinal Study on Aging (CLSA).

Objective: Middle-aged to older adults often exhibit the co-existence of poor sleep health and multimorbidity. We examined cross-sectional and prospective associations of pooled index of sleep health with prevalent and incident multimorbidity in the framework of an ongoing cohort study in Canada.

Methods: Data were from approximately 24,000 individuals from the Canadian Longitudinal Study on Aging (CLSA), an ongoing national study of community-dwelling adults aged 45-85 years at baseline.

Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study.

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls.

Healthy First-Degree Relatives From Multiplex Families vs Simplex Families Have Higher Subclinical Intestinal Inflammation, a Distinct Fecal Microbial Signature, and Harbor a Higher Risk of Developing Crohn's Disease.

Background & Aims: Unaffected first-degree relatives (FDRs) from families with ≥2 affected FDRs with Crohn's disease (CD, multiplex families) have a high risk of developing CD, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between FDRs from multiplex vs simplex families and investigate the risk of future CD onset accounting for potential confounders.

Methods: We assessed the Crohn's and Colitis Canada Genetic Environmental Microbial cohort of healthy FDRs of patients with CD.

Outcomes in older adults with metastatic esophageal and gastric carcinoma treated with palliative chemotherapy.

Background: The incidence of esophageal and gastric carcinoma (GEC) in elderly patients is increasing, yet patients ≥75 years have historically been underrepresented in clinical trials. We sought to investigate palliative chemotherapy administration patterns and survival outcomes in older adults.

Materials And Methods: A retrospective analysis identified patients aged 65-74 (young-old) and ≥75 years (older-old) diagnosed with advanced GEC.

Impact of an Inter-Professional Clinic on Pancreatic Cancer Outcomes: A Retrospective Cohort Study.

Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in diagnosis, staging, and appropriate treatment. Furthermore, patients with PDAC often experience complex symptomatology and psychosocial implications that require multi-disciplinary and inter-professional supportive care management from health professionals. Despite these hurdles, the implementation of inter-professional clinic approaches showed promise in enhancing clinical outcomes.

Environmental Factors Associated With Risk of Crohn's Disease Development in the Crohn's and Colitis Canada - Genetic, Environmental, Microbial Project.

Background & Aims: To date, it is unclear how environmental factors influence Crohn's disease (CD) risk and how they interact with biological processes. This study investigates the association between environmental exposures and CD risk and evaluates their association with pre-disease biomarkers.

Methods: We studied 4289 healthy first-degree relatives (FDRs) of patients with CD from the Crohn's and Colitis Canada - Genetic, Environmental, Microbial (CCC-GEM) project.

A latent class linear mixed model for monotonic continuous processes measured with error.

Motivated by measurement errors in radiographic diagnosis of osteoarthritis, we propose a Bayesian approach to identify latent classes in a model with continuous response subject to a monotonic, that is, non-decreasing or non-increasing, process with measurement error. A latent class linear mixed model has been introduced to consider measurement error while the monotonic process is accounted for via truncated normal distributions. The main purpose is to classify the response trajectories through the latent classes to better describe the disease progression within homogeneous subpopulations.

First impressions: A prospective evaluation of patient-physician concordance and satisfaction following the initial medical oncology consultation.

Background: An especially significant event in the patient-oncologist relationship is the initial consultation, where many complex topics-diagnosis, treatment intent, and often, prognosis-are discussed in a relatively short period of time. This study aimed to measure patients' understanding of the information discussed during their first medical oncology visit and their satisfaction with the communication from medical oncologists.

Methods: Between January and August 2021, patients without prior systemic treatment of their gastrointestinal malignancy (GI) attending the Princess Margaret Cancer Centre (PMCC) were approached within 24 h of their initial consultation to complete a paper-based questionnaire assessing understanding of their disease (diagnosis, treatment plan/intent, and prognosis) and satisfaction with the consultation.

Association of synovial fluid and urinary C2C-HUSA levels with surgical outcomes post-total knee arthroplasty.

Objectives: After total knee arthroplasty (TKA), ∼30% of knee osteoarthritis (KOA) patients show little symptomatic improvement. Earlier studies have correlated urinary (u) type 2 collagen C terminal cleavage peptide assay (C2C-HUSA), which detects a fragment of cartilage collagen breakdown, with KOA progression. This study determines whether C2C levels in urine, synovial fluid, or their ratio, are associated with post-surgical outcomes.

Characterization of direct and/or indirect genetic associations for multiple traits in longitudinal studies of disease progression.

When quantitative longitudinal traits are risk factors for disease progression and subject to random biological variation, joint model analysis of time-to-event and longitudinal traits can effectively identify direct and/or indirect genetic association of single nucleotide polymorphisms (SNPs) with time-to-event. We present a joint model that integrates: (1) a multivariate linear mixed model describing trajectories of multiple longitudinal traits as a function of time, SNP effects, and subject-specific random effects and (2) a frailty Cox survival model that depends on SNPs, longitudinal trajectory effects, and subject-specific frailty accounting for dependence among multiple time-to-event traits. Motivated by complex genetic architecture of type 1 diabetes complications (T1DC) observed in the Diabetes Control and Complications Trial (DCCT), we implement a 2-stage approach to inference with bootstrap joint covariance estimation and develop a hypothesis testing procedure to classify direct and/or indirect SNP association with each time-to-event trait.

Gut Microbiome Composition Is Associated With Future Onset of Crohn's Disease in Healthy First-Degree Relatives.

Background & Aims: The cause of Crohn's disease (CD) is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with CD have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of CD or is the result of inflammation or drug treatment.

Methods: In this prospective cohort study, 3483 healthy first-degree relatives (FDRs) of patients with CD were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing CD.

Multimodal immunogenomic biomarker analysis of tumors from pediatric patients enrolled to a phase 1-2 study of single-agent atezolizumab.

We report herein an exploratory biomarker analysis of refractory tumors collected from pediatric patients before atezolizumab therapy (iMATRIX-atezolizumab, NCT02541604 ). Elevated levels of CD8 T cells and PD-L1 were associated with progression-free survival and a diverse baseline infiltrating T-cell receptor repertoire was prognostic. Differential gene expression analysis revealed elevated expression of CALCA (preprocalcitonin) and CCDC183 (highly expressed in testes) in patients who experienced clinical activity, suggesting that tumor neoantigens from these genes may contribute to immune response.