Solution NMR goes big: Atomic resolution studies of protein components of molecular machines and phase-separated condensates.

The tools of structural biology have undergone remarkable advances in the past decade. These include new computational and experimental approaches that have enabled studies at a level of detail - and ease - that were not previously possible. Yet, significant deficiencies in our understanding of biomolecular function remain and new challenges must be overcome to go beyond static pictures towards a description of function in terms of structural dynamics.

Methods and Practical Considerations for Conducting Budget Impact Analysis for Non-Pharmaceutical Interventions.

Background: Health technology assessment (HTA) can be conducted at the national, provincial, or hospital level. Although provincial and hospital-based HTAs often focus on non-pharmaceutical interventions, budget impact analysis (BIA) methods for non-pharmaceutical interventions have received less attention in the literature.

Methods: We reviewed HTAs of non-pharmaceutical interventions published since 2015 by a Canadian provincial HTA agency, evaluating the characteristics and challenges of conducting a BIA.

Mapping TcdB interactions with host cell-surface and intracellular factors using proximity-dependent biotinylation labeling.

Many bacterial toxins exert their cytotoxic effects by enzymatically inactivating one or more cytosolic targets in host cells. To reach their intracellular targets, these toxins possess functional domains or subdomains that interact with and exploit various host factors and biological processes. Despite great progress in identifying many of the key host factors involved in the uptake of toxins, significant knowledge gaps remain as to how partially characterized and newly discovered microbial toxins exploit host factors or processes to intoxicate target cells.

Target-agnostic identification of human antibodies to sexual forms reveals cross-stage recognition of glutamate-rich repeats.

Circulating sexual stages of ) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies can efficiently block parasite transmission. In search for naturally acquired antibodies targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of in the form of gametes and gametocyte extracts.

Combining theory and usability testing to inform optimization and implementation of an online primary care depression management tool.

Background: The 'Ottawa Depression Algorithm' is an evidence-based online tool developed to support primary care professionals care for adults with depression. Uptake of such tools require provider behaviour change. Identifying issues which may impact use of an innovation in routine practice (i.

Glycogen synthase GYS1 overactivation contributes to glycogen insolubility and malto-oligoglucan-associated neurodegenerative disease.

Polyglucosans are glycogen molecules with overlong chains, which are hyperphosphorylated in the neurodegenerative Lafora disease (LD). Brain polyglucosan bodies (PBs) cause fatal neurodegenerative diseases including Lafora disease and adult polyglucosan body disease (ABPD), for which treatments, biomarkers, and good understanding of their pathogenesis are currently missing. Mutations in the genes for the phosphatase laforin or the E3 ubiquitin ligase malin can cause LD.

The association between self-reported total gestational weight gain by pre-pregnancy body mass index and moderate to late preterm birth.

Background: Inadequate and excessive gestational weight gain (GWG) defined by the Institute of Medicine (IOM) has been associated with preterm birth. However, studies demonstrate inconsistent associations.

Objectives: We examined the associations between categorical and continuous total GWG and moderate to late preterm birth (32-<37 weeks), and evaluated differences in these associations by pre-pregnancy BMI.

Initial Effectiveness of mRNA-1273 Against SARS-CoV-2 Infection and Hospitalization in Young Children.

Background: Data on mRNA-1273 (Moderna) vaccine effectiveness (VE) in children aged 6 months to 5 years are limited. The objectives of this study were to assess mRNA-1273 vaccine effectiveness against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19)-related hospitalization among children aged 6 months to 5 years during the initial 5 months of the vaccination campaign rollout, as well as to determine whether VE varied by age group (6 months to <2 years vs 2 to 5 years).

Methods: We used a test-negative study with linked health administrative data in Ontario, Canada, to evaluate vaccine effectiveness of mRNA-1273 against symptomatic SARS-CoV-2 infection and COVID-19-related hospitalization from July 28 to December 31, 2022.

The brain selectively allocates energy to functional brain networks under cognitive control.

Network energy has been conceptualized based on structural balance theory in the physics of complex networks. We utilized this framework to assess the energy of functional brain networks under cognitive control and to understand how energy is allocated across canonical functional networks during various cognitive control tasks. We extracted network energy from functional connectivity patterns of subjects who underwent fMRI scans during cognitive tasks involving working memory, inhibitory control, and cognitive flexibility, in addition to task-free scans.

Optimizing Drug Selection in Children with Multiple Sclerosis: What Do We Know and What Remains Unanswered?

Pediatric-onset multiple sclerosis (POMS) refers to multiple sclerosis with onset before 18 years of age. It is characterized by a more inflammatory course, more frequent clinical relapses, and a greater number of magnetic resonance imaging (MRI) lesions compared with adult-onset MS (AOMS), leading to significant impacts on both disability progression and cognitive outcomes in affected individuals. Managing POMS presents distinct challenges due to the unique needs of pediatric patients and the limited number of disease-modifying therapies (DMTs) approved for pediatric use.

Randomized controlled trials - The what, when, how and why.

Randomized controlled trials (RCTs) are at the top of the pyramid of evidence as they offer the best answer on the efficacy of a new treatment. RCTs are true experiments in which participants are randomly allocated to receive a certain intervention (experimental group) or a different intervention (comparison group), or no treatment at all (control or placebo group). Randomization, along with other methodological features such as blinding and allocation concealment, safeguard against biases.

A general system for targeting MHC class II-antigen complex via a single adaptable loop.

Major histocompatibility complex class II (MHCII) bound to a peptide antigen mediates interactions between CD4 T cells and antigen-presenting cells. Targeting peptide-MHCII with T cell antigen receptors (TCRs) and TCR-like antibodies has shown promise for autoimmune diseases and microbiome tolerance. To develop a general targeting approach, we introduce targeted recognition of antigen-MHC complex reporter for MHCII (TRACeR-II) for the rapid development of peptide-specific MHCII binders.

COVID-19 vaccine effectiveness against severe omicron-related outcomes in children aged 5 to 11 years in Ontario: A Canadian immunization research network (CIRN) study.

Background: Understanding how the efficacy of COVID-19 vaccines translates from clinical trials to real-world settings is critical to inform evolving vaccination policies. The objective of this study was to assess COVID-19 vaccine effectiveness (VE) against severe COVID-19-related outcomes in children aged 5-11 years, including COVID-19-related hospital admissions and multisystem inflammatory syndrome in children (MIS-C).

Methods: We conducted a retrospective, population-based cohort study using linked health administrative data in the first year following the emergence of the Omicron variant (January 2 to December 31, 2022) in Ontario, Canada.

Automated classification of cerebral arteries and veins in the neonate using ultrafast doppler spectrogram.

Cerebral arterial and venous flow (A/V) classification is a key parameter for understanding dynamic changes in neonatal brain perfusion. Currently, transfontanellar ultrasound Doppler imaging is the reference clinical technique able to discriminate between A/V using vascular indices such as resistivity index (RI) or pulsatility index (PI). However, under conditions of slow arterial and venular flow, small signal fluctuations can lead to potential misclassifications of vessels.

Multi-gene duplication removal in an engineered human cellular MECP2 duplication syndrome model with an duplication.

Recent progress in genome editing technologies has catalyzed the generation of sophisticated cell models; however, the precise modeling of copy-number variation (CNV) diseases remains a significant challenge despite their substantial prevalence in the human population. To overcome this barrier, we have explored the utility of HAP1 cells for the accurate modeling of disease genomes with large structural variants. As an example, this study details the strategy to generate a novel cell line that serves as a model for the neurological disorder methyl CpG binding protein 2 (MECP2) duplication syndrome (MDS), featuring the critical duplication of both the and genes.

Dexamethasone regime and clinical outcomes in children hospitalized with croup: A cohort study.

Background: High-quality trial evidence supports the use of one dose of dexamethasone in the outpatient management of croup; however, there are no inpatient trials, and the optimal treatment regimen for the inpatient management of croup remains uncertain. Significant practice variability exists in the corticosteroid treatment of children hospitalized for croup.

Objective: To evaluate the association of dexamethasone treatment regimen (1 vs.

Structural Plasticity as a Driver of the Maturation of Pro-Interleukin-18.

Dynamics are often critical for biomolecular function. Herein we explore the role of motion in driving the maturation process of pro-IL-18, a potent pro-inflammatory cytokine that is cleaved by caspases-1 and -4 to generate the mature form of the protein. An NMR dynamics study of pro-IL-18, probing time scales over 12 orders of magnitude and focusing on H, C, and N spin probes along the protein backbone and amino-acid side chains, reveals a plastic structure, with millisecond time scale dynamics occurring in a pair of β-strands, β1 and β*, that show large structural variations in a comparison of caspase-free and bound pro-IL-18 states.

Review of clinical trials and guidelines for children and youth with mucopolysaccharidosis: outcome selection and measurement.

Background: To inform the development of a core outcome set (COS) for children and youth with mucopolysaccharidoses (MPS), we aimed to identify all outcomes and associated outcome measurement instruments that are reported in recent clinical trials and recommended as measurements in clinical management guidelines.

Methods: To identify English-language clinical trials and guidelines pertaining to MPS published between 2011 and mid-2021, we applied a comprehensive peer-reviewed search strategy to relevant databases and registers on May 16, 2021. Two reviewers independently screened retrieved citations and then full-text articles to determine eligibility for inclusion.