Birth characteristics and the risk of childhood brain tumors: A case-control study in Ontario, Canada.

Various birth characteristics may influence healthy childhood development, including the risk of developing childhood brain tumors (CBTs). In this study, we aimed to investigate the association between delivery methods, obstetric history, and birth anthropometrics with the risk of CBTs. This study used data from the Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) which included children 0-15 years of age and newly diagnosed with CBTs from 1997 to 2003.

qTAG: an adaptable plasmid scaffold for CRISPR-based endogenous tagging.

Endogenous tagging enables the study of proteins within their native regulatory context, typically using CRISPR to insert tag sequences directly into the gene sequence. Here, we introduce qTAG, a collection of repair cassettes that makes endogenous tagging more accessible. The cassettes support N- and C-terminal tagging with commonly used selectable markers and feature restriction sites for easy modification.

Clinical Utility of Genomic Sequencing for Hereditary Cancer Syndromes: An Observational Cohort Study.

Purpose: Genomic sequencing (GS) is increasingly used to improve diagnoses and inform targeted therapies. GS can also be used to identify the 10% of cancer patients with an underlying hereditary cancer syndrome (HCS), who can benefit from surveillance and preventive surgery that reduce morbidity/mortality. However, the evidence on clinical utility of GS for HCS is limited: we aimed to fill this gap by assessing yield of all cancer results and associated recommendations for patients undergoing GS for HCS.

3D electron microscopy for analyzing nanoparticles in the tumor endothelium.

Delivering medical agents to diseased tissues has been challenging, leading researchers to study the in vivo transport process in the body for improving delivery. Many imaging techniques exist for mapping the distribution of medical agent-carrying nanoparticles in tissues, but they cannot capture the three-dimensional context of tissues with single nanoparticle resolution. Here, we developed 3DEM-NPD, a three-dimensional electron microscopy (3D EM) machine learning strategy to image and map single nanoparticle distributions (NPD) in tissues.

Optogenetic elevation of postsynaptic cGMP in the hippocampal dentate gyrus enhances LTP and modifies mouse behaviors.

A major intracellular messenger implicated in synaptic plasticity and cognitive functions both in health and disease is cyclic GMP (cGMP). Utilizing a photoactivatable guanylyl cyclase (BlgC) actuator to increase cGMP in dentate granule neurons of the hippocampus by light, we studied the effects of spatiotemporal cGMP elevations in synaptic and cognitive functions. At medial perforant path to dentate gyrus (MPP-DG) synapses, we found enhanced long-term potentiation (LTP) of synaptic responses when postsynaptic cGMP was elevated during the induction period.

The effect of body mass index at diagnosis on survival of patients with squamous cell head and neck carcinoma.

The aim of this study is to investigate the prognostic role of body mass index (BMI) on survival from head and neck cancer (HNC). We performed a pooled analysis of studies included in the International Head and Neck Cancer Epidemiology consortium. We used Cox proportional hazards models to estimate the adjusted hazard ratios (HR) for overall survival and HNC-specific survival, and we stratified the results according to cancer site.

Characterizing the SARS-CoV-2 antibody response and associations with patient factors: Serological profiling of participants enrolled in the GENCOV study.

Introduction: The GENCOV study sought to evaluate serological differences between individuals with differing COVID-19 severity and outcomes. We assessed the SARS-CoV-2 antibody response of GENCOV participants cross-sectionally 1-, 6-, and 12-months following COVID-19 diagnosis to identify patient factors associated with more robust and durable humoral immune responses.

Materials And Methods: COVID-19 patients and a control cohort of vaccinated infection-naïve participants were recruited at hospital sites across the Greater Toronto Area in Ontario, Canada.

A missense variant effect map for the human tumor-suppressor protein CHK2.

The tumor suppressor CHEK2 encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair, and inducing apoptosis. CHK2 phosphorylation of the tumor suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell-cycle checkpoint role, both germline and somatic variants in CHEK2 have been linked to breast and other cancers.

Sympathetic Response to 1-Leg Cycling Exercise Predicts Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction.

Background: In heart failure, sympathetic excess and exercise intolerance impair quality of life. In heart failure with reduced ejection fraction, exercise stimulates a reflex increase in muscle sympathetic nerve activity (MSNA) that relates inversely to peak oxygen uptake (V̇O). Whether similar sympathoexcitatory responses are present in heart failure with preserved EF (HFpEF) and relate to V̇O are unknown.

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).

A-I-D for cascades: an application of the Behaviour Change Wheel to design a theory-based intervention for addressing prescribing cascades in primary care.

Background: Prescribing cascades, which occur when a medication is used to treat the side effect of another medication, are important contributors to polypharmacy. There is an absence of studies that evaluate interventions to address them. We describe an application of the Behaviour Change Wheel (BCW) to design theory-informed interventions for addressing prescribing cascades within interprofessional primary care teams.

Treating sleep disordered breathing for cardiovascular outcomes: observational and randomised trial evidence.

Sleep disordered breathing (SDB) is considered a risk factor for cardiovascular disease (CVD). Obstructive sleep apnoea (OSA) can be treated with continuous positive airway pressure (CPAP), and central sleep apnoea (CSA), in patients with heart failure with reduced ejection fraction (HFrEF), by peak flow-triggered adaptive servo-ventilation. Presently, there is equipoise as to whether treating SDB prevents cardiovascular events.

Impact of a national dementia research consortium: The Canadian Consortium on Neurodegeneration in Aging (CCNA).

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014-2019; 2019-2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them.

GSK3β Deficiency Expands Obese Adipose Vasculature to Mitigate Metabolic Disorders.

Background: Maintaining a well-developed vascular system alongside adipose tissue (AT) expansion significantly reduces the risk of metabolic complications. Although GSK3β (glycogen synthase kinase-3 beta) is known for its role in various cellular processes, its specific functions in AT and regulation of body homeostasis have not been reported.

Methods: GSK3β-floxed and GSK3α-floxed mice were crossed with adiponectin-Cre mice to generate GSK3β or GSK3α adipocyte-specific knockout mice (GSK3β and GSK3α).

Synthetic lethal strategies for the development of cancer therapeutics.

Synthetic lethality is a genetic phenomenon whereby the simultaneous presence of two different genetic alterations impairs cellular viability. Importantly, targeting synthetic lethal interactions offers potential therapeutic strategies for cancers with alterations in pathways that might otherwise be considered undruggable. High-throughput screening methods based on modern CRISPR-Cas9 technologies have emerged and become crucial for identifying novel synthetic lethal interactions with the potential for translation into biologically rational cancer therapeutic strategies as well as associated predictive biomarkers of response capable of guiding patient selection.

Comparison of a SARS-CoV-2 mRNA booster immunization containing additional antigens to a spike-based mRNA vaccine against Omicron BA.5 infection in hACE2 mice.

The emergence of SARS-CoV-2 variants presents challenges to vaccine effectiveness, underlining the necessity for next-generation vaccines with multiple antigens beyond the spike protein. Here, we investigated a multiantigenic booster containing spike and a chimeric construct composed of nucleoprotein (N) and membrane (M) proteins, comparing its efficacy to a spike-only booster against Omicron BA.5 in K18-hACE2 mice.

The clinical perspective of circular RNAs in neurodegenerative diseases: potential diagnostic tools and therapeutic targets.

Neurodegenerative diseases (NDDs) mostly occur in older demographics. With the average lifespan increasing over time, NDDs are becoming one of the major adverse factors affecting human health and the quality of life. Currently, there are no specific diagnostic methods for NDDs and they are usually diagnosed based on nonspecific clinical symptoms and occasionally by biomarkers, such as -amyloid (Aβ) for Alzheimer's disease (AD) and a-synuclein (-syn) for Parkinson's disease, etc.

Activating Mechanisms Through Employee-Driven Innovation Comment on "Employee-Driven Innovation in Health Organizations: Insights From a Scoping Review".

Caddedu and colleagues' paper "Employee-Driven Innovation in Health Organizations: Insights From a Scoping Review," presents findings regarding the state of the literature around employee-driven innovation (EDI). In uncovering the who, what, and how of EDI in healthcare organizations the authors suggest that embracing EDI at an organizational level may be a key to supporting larger system transformation efforts. This commentary builds on this contention suggesting that to help realize that broader vision, attention should be paid to the overlapping implementation mechanisms around empowerment, adaptability, learning, and meaning and value that drive both processes.

Long-term potentiation in the hippocampus: From magnesium to memory.

Long-term potentiation (LTP) is a widely studied phenomenon since the underlying molecular mechanisms are widely believed to be critical for learning and memory and their dysregulation has been implicated in many brain disorders affecting cognitive functions. Central to the induction of LTP, in most pathways that have been studied in the mammalian CNS, is the N-methyl-D-aspartate receptor (NMDAR). Philippe Ascher discovered that the NMDAR is subject to a rapid, highly voltage-dependent block by Mg.

Specific loss of GIPR signaling in GABAergic neurons enhances GLP-1R agonist-induced body weight loss.

Objectives: Dual incretin agonists are among the most effective pharmaceutical treatments for obesity and type 2 diabetes to date. Such therapeutics can target two receptors, such as the glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor in the case of tirzepatide, to improve glycemia and reduce body weight. Regarding body weight effects, GIPR signaling is thought to involve at least two relevant mechanisms: the enhancement of food intake reduction and the attenuation of aversive effects caused by GLP-1R agonists.

Combination of Haloperidol With UNC9994, β-arrestin-Biased Analog of Aripiprazole, Ameliorates Schizophrenia-Related Phenotypes Induced by NMDAR Deficit in Mice.

Background: Glutamatergic system dysfunction contributes to a full spectrum of schizophrenia-like symptoms, including the cognitive and negative symptoms that are resistant to treatment with antipsychotic drugs (APDs). Aripiprazole, an atypical APD, acts as a dopamine partial agonist, and its combination with haloperidol (a typical APD) has been suggested as a potential strategy to improve schizophrenia. Recently, an analog of aripiprazole, UNC9994, was developed.

Role of the liver in the sustained normalisation of A1c over 2 years following short-term insulin therapy in early type 2 diabetes.

Aims: When administered in early type 2 diabetes (T2DM), the strategy of 'induction' with short-term intensive insulin therapy (IIT) followed by 'maintenance' with metformin thereafter can yield outstanding glycaemic control, with some patients achieving A1c in the normal range of its assay. We thus sought to identify determinants of sustained normalisation of A1c in response to this treatment strategy.

Materials And Methods: In this study, adults with T2DM of mean duration 1.