Elective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors.

Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma.

Integrative genomic analysis of DLBCL identifies immune environments associated with bispecific antibody response.

Most diffuse large B-cell lymphoma (DLBCL) patients treated with immunotherapies such as bispecific antibodies (BsAb) or chimeric antigen receptor (CAR) T cells fail to achieve durable treatment responses, underscoring the need for a deeper understanding of mechanisms that regulate the immune environment and response to treatment. Here, an integrative, multi-omic approach was applied to multiple large independent datasets in order to characterize DLBCL immune environments, and to define their association with tumor cell-intrinsic genomic alterations and outcomes to CD19-directed CAR T-cell and CD20 x CD3 BsAb therapies. This approach effectively segregated DLBCLs into four immune quadrants (IQ) defined by cell-of-origin and immune-related gene set expression scores.

Automating the practice of science: Opportunities, challenges, and implications.

Automation transformed various aspects of our human civilization, revolutionizing industries and streamlining processes. In the domain of scientific inquiry, automated approaches emerged as powerful tools, holding promise for accelerating discovery, enhancing reproducibility, and overcoming the traditional impediments to scientific progress. This article evaluates the scope of automation within scientific practice and assesses recent approaches.

Is Ockham's razor losing its edge? New perspectives on the principle of model parsimony.

The preference for simple explanations, known as the parsimony principle, has long guided the development of scientific theories, hypotheses, and models. Yet recent years have seen a number of successes in employing highly complex models for scientific inquiry (e.g.

Bubble coalescence principle in saline water.

Bubbles present in saline water typically exhibit a prolonged lifetime, making them attractive for various engineering processes. Herein, we unveil a transition from delayed bubble coalescence to rapid bursting within about one millisecond in salty solutions. The key aspect in understanding this transition lies in the combined influences of surface deformation and ion surface excess instead of characterizing the ions alone.

Effects of femoral neck width and hip Axis length on incident hip fracture risk: a registry-based cohort study.

Bone mineral density (BMD) measured with dual-energy X-ray absorptiometry (DXA) is widely used in clinical practice to assess fracture risk and guide management. DXA can also assess hip geometry, including femoral neck width (FNW) and hip axis length (HAL), which have both been associated with increased risk for hip fracture independently from BMD. Our objective was to assess if FNW predicts hip fracture independently from other factors including HAL.

Power assist add-ons for adult manual wheelchair users: A scoping review.

Manual wheelchairs can promote independence among users. However, the user's level of disability, strength, stamina, and the environmental conditions within which the wheelchair is used may limit manual wheelchair functionality. The use of power assist add-ons may mitigate these limitations and help individuals to age in place.

Responsivity research: Informing psychological services for justice systems that work.

Public service psychologists engage their research competencies to explore the psychological health needs of underserved populations and the justice systems that deliver them psychological services. In late June 2023. the Criminal Justice Section of Division 18 of the American Psychological Association cosponsored the Fifth North American Correctional and Criminal Justice Psychology Conference: Towards a Justice System That Works, Toronto, Canada.

The development and implementation of an innovative community-based intervention to strengthen community capacity for HIV prevention and care among Canadians of African Caribbean and Black (ACB) women in Ontario: a research protocol.

African, Caribbean, and Black (ACB) women are overrepresented among new HIV diagnoses due to social and structural factors. This study seeks to create, implement, and evaluate a community-based peer-led intervention to improve access to HIV prevention and care for ACB women in Canada. This multisite, five-year project, using community-based participatory research, implementation science and evaluation frameworks, will be implemented in five non-iterative phases.

Specificity and tunability of efflux pumps: A new role for the proton gradient?

Efflux pumps that transport antibacterial drugs out of bacterial cells have broad specificity, commonly leading to broad spectrum resistance and limiting treatment strategies for infections. It remains unclear how efflux pumps can maintain this broad spectrum specificity to diverse drug molecules while limiting the efflux of other cytoplasmic content. We have investigated the origins of this broad specificity using theoretical models informed by the experimentally determined structural and kinetic properties of efflux pumps.

Supraspinal facilitation of painful stimuli by glutamatergic innervation from the retrosplenial to the anterior cingulate cortex.

The anterior cingulate cortex (ACC) is recognized as a pivotal cortical region involved in the perception of pain. The retrosplenial cortex (RSC), located posterior to the ACC, is known to play a significant role in navigation and memory processes. Although the projections from the RSC to the ACC have been found, the specifics of the synaptic connections and the functional implications of the RSC-ACC projections remain less understood.

Suppressing Tymovirus replication in plants using a variant of ubiquitin.

RNA viruses have evolved numerous strategies to overcome host resistance and immunity, including the use of multifunctional proteases that not only cleave viral polyproteins during virus replication but also deubiquitinate cellular proteins to suppress ubiquitin (Ub)-mediated antiviral mechanisms. Here, we report an approach to attenuate the infection of Arabidopsis thaliana by Turnip Yellow Mosaic Virus (TYMV) by suppressing the polyprotein cleavage and deubiquitination activities of the TYMV protease (PRO). Performing selections using a library of phage-displayed Ub variants (UbVs) for binding to recombinant PRO yielded several UbVs that bound the viral protease with nanomolar affinities and blocked its function.

Trithorax regulates long-term memory in Drosophila through epigenetic maintenance of mushroom body metabolic state and translation capacity.

The role of epigenetics and chromatin in the maintenance of postmitotic neuronal cell identities is not well understood. Here, we show that the histone methyltransferase Trithorax (Trx) is required in postmitotic memory neurons of the Drosophila mushroom body (MB) to enable their capacity for long-term memory (LTM), but not short-term memory (STM). Using MB-specific RNA-, ChIP-, and ATAC-sequencing, we find that Trx maintains homeostatic expression of several non-canonical MB-enriched transcripts, including the orphan nuclear receptor Hr51, and the metabolic enzyme lactate dehydrogenase (Ldh).

From impact metrics and open science to communicating research: Journalists' awareness of academic controversies.

This study sheds light on how journalists respond to evolving debates within academia around topics including research integrity, improper use of metrics to measure research quality and impact, and the risks and benefits of the open science movement. It does so through a codebook thematic analysis of semi-structured interviews with 19 health and science journalists from the Global North. We find that journalists' perceptions of these academic controversies vary widely, with some displaying a highly critical and nuanced understanding and others presenting a more limited awareness.

Impact of Chlorella vulgaris and probiotic supplementation on performance, immunity and intestinal microbiota of broiler chickens.

Chlorella vulgaris has antioxidant, antimicrobial, and anti-inflammatory properties, as well as the probiotic that is important for keeping the intestinal microbiota balanced. The objective was to test the impact of supplementation with microalgae and/or probiotics on broiler chickens' performance, immunity, and intestinal microbiota. The experimental design was in randomized blocks in a 4x2 factorial scheme, with four levels of inclusion of C.

Intramolecular Fluoroacylation Enabled by TrBF-Catalyzed Fluoride Recycling.

Alkyne- and alkene-tethered acyl fluorides undergo intramolecular carbofluorination via fluoride recycling using catalytic TrBF. Excellent stereoselectivity is observed for the alkyne addition, enabling access to novel fluorinated indan-2-ones (all ≥95:5 /) and cyclopentan-2-ones (85:15 /). Fluorinated chroman-2-ones and tertiary alkyl fluorides can also be synthesized using this method, comparing favorably to previously reported protocols that employ expensive metal catalysts under harsher conditions.

Transient shear wave elastometry using a portable magnetic resonance sensor.

Purpose: Magnetic resonance elastography (MRE) provides detailed maps of tissue stiffness, helping to diagnose various health conditions, but requires the use of expensive clinical MRI scanners. Our approach utilizes compact, cost-effective portable MR sensors that offer bulk characterization of material properties in a region of interest close to the surface (within 1-2 cm). This accessible instrument could enable routine monitoring and prevention of diseases not readily evaluated with conventional tools.

White matter connections within the central sulcus subserving the somato-cognitive action network.

The somato-cognitive action network (SCAN) consists of three nodes interspersed within Penfield's motor effector regions. The configuration of the somato-cognitive action network nodes resembles the one of the 'plis de passage' of the central sulcus: small gyri bridging the precentral and postcentral gyri. Thus, we hypothesize that these may provide a structural substrate of the somato-cognitive action network.

Immune checkpoint inhibitors in pediatric patients with melanoma: a systematic literature review.

This study summarized the existing evidence on the outcomes and safety of anti-PD-1s, anti-PD-L1s and anti-CTLA-4s in pediatric patients with melanoma. MEDLINE and Embase were searched from database inception to 01-12-2023. Of 1537 records identified, 27 studies (k) of 64 patients were included.

New Oral Selective Estrogen Receptor Degraders Redefine Management of Estrogen Receptor-Positive Breast Cancer.

Oral selective estrogen receptor degraders (SERDs) are pure estrogen receptor antagonists that have the potential to overcome common resistance mechanisms to endocrine therapy in estrogen receptor-positive breast cancer. There are currently five oral SERDs in published and ongoing clinical trials-elacestrant, camizestrant, giredestrant, imlunestrant, and amcenestrant-with more in development. They offer a reasonably well-tolerated oral therapy option with low discontinuation rates in studies.

Long-Term Risks of Living Kidney Donation: State of the Evidence and Strategies to Resolve Knowledge Gaps.

Living-donor kidney transplantation is the preferred treatment for kidney failure. In the United States, rates of living kidney donation have been stagnant, which is partly related to concerns over medical and financial risks. Recent research has better characterized the risks of living kidney donation, although the field is limited by a lack of robust registries.

Factor V Serves as an Early Biomarker for Graft Loss After Liver Transplant: A Prospective Evaluation.

Background: Low post-operative day (POD) 1 Factor V has been retrospectively associated with graft loss after liver transplantation when stratified by a cutoff of 0.36 U/mL. We aimed to validate this prospectively.

Identifying the Views and Needs of Family Physicians on Providing Care to Living Kidney Donors: A Cross-Sectional Survey.

Optimizing the long-term care and follow-up of living kidney donors (LKDs) has been challenging, and prior LKDs have reported suboptimal healthcare experiences. Long-term care of LKDs is largely undertaken by primary care practitioners such as family physicians (FPs). We conducted a cross-sectional survey of Canadian FPs (n = 151).