Large-scale evaluation of outcomes after a genetic diagnosis in children with severe developmental disorders.

Purpose: We sought to evaluate outcomes for clinical management after a genetic diagnosis from the Deciphering Developmental Disorders study.

Methods: Individuals in the Deciphering Developmental Disorders study who had a pathogenic/likely pathogenic genotype in the DECIPHER database were selected for inclusion ( = 5010). Clinical notes from regional clinical genetics services notes were reviewed to assess predefined clinical outcomes relating to interventions, prenatal choices, and information provision.

Formal Dearomative Hydroamination of 2-Arylphenols.

An acid-promoted dearomative rearrangement of -arylhydroxylamines affords 2-aminocyclohexadien-1-ones, which can in turn be reductively quenched for the synthesis of -aminoalcohols on a cyclohexadiene core. This method serves as an efficient entry to the pharmaceutically relevant 1-arylcyclohexylamine scaffold in two steps (one purification) from commercially available or readily prepared 2-arylphenols.

Clinical Effectiveness of Continuous Infusion Flucloxacillin in the Outpatient Parenteral Antimicrobial Therapy (OPAT) Setting in a UK Hospital: A Service Evaluation.

The availability of stability data for the use of continuous intravenous flucloxacillin in an elastomeric device has enabled the treatment of serious Methicillin Sensitive (MSSA) in the outpatient parenteral antimicrobial therapy (OPAT) setting. This service review aimed to evaluate current standard of care to establish the clinical effectiveness and complication rates associated with its use since its introduction at our institution. A retrospective review of clinical outcomes and adverse events/complications, was undertaken for all patients who received continuous infusion flucloxacillin for complicated MSSA infection between January 2019 and July 2022 via our OPAT service.

Deletion of a conserved genomic region associated with adolescent idiopathic scoliosis leads to vertebral rotation in mice.

Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis, in which spinal curvature develops in adolescence, and 90% of patients are female. Scoliosis is a debilitating disease that often requires bracing or surgery in severe cases. AIS affects 2%-5.

Novel prognostic nomogram for predicting recurrence-free survival in medullary thyroid carcinoma.

Aims: Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC.

Control intervention design for preclinical and clinical trials: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings.

Control intervention design for preclinical and clinical trials: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings.

A Detailed Histologic and Molecular Assessment of the Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma.

Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAF mutation but common RET gene rearrangements. Using strict criteria, we studied 43 DS-PTCs (1.

Organ Donation Organization Architecture: Recommendations From an International Consensus Forum.

Unlabelled: This report contains recommendations from 1 of 7 domains of the International Donation and Transplantation Legislative and Policy Forum (the Forum). The purpose is to provide expert guidance on the structure and function of Organ and Tissue Donation and Transplantation (OTDT) systems. The intended audience is OTDT stakeholders working to establish or improve existing systems.

A national pilot of donation after circulatory death (DCD) heart transplantation within the United Kingdom.

Background: The United Kingdom (UK) was one of the first countries to pioneer heart transplantation from donation after circulatory death (DCD) donors. To facilitate equity of access to DCD hearts by all UK heart transplant centers and expand the retrieval zone nationwide, a Joint Innovation Fund (JIF) pilot was provided by NHS Blood and Transplant (NHSBT) and NHS England (NHSE). The activity and outcomes of this national DCD heart pilot program are reported.

N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection.

Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation of ionotropic glutamate receptors. Although dysregulation of proteolytic signaling networks is critical for excitotoxicity, the identity of affected proteins and mechanisms by which they induce neuronal cell death remain unclear. To address this, we used quantitative N-terminomics to identify proteins modified by proteolysis in neurons undergoing excitotoxic cell death.

The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα.

Ca/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a major contributor to physiological and pathological glutamate-mediated Ca signals, and its involvement in various critical cellular pathways demands specific pharmacological strategies. We recently presented γ-hydroxybutyrate (GHB) ligands as the first small molecules selectively targeting and stabilizing the CaMKIIα hub domain. Here, we report that the cyclic GHB analogue 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA), improves sensorimotor function after experimental stroke in mice when administered at a clinically relevant time and in combination with alteplase.

Optimization of thermoresponsive chitosan/β-glycerophosphate hydrogels for injectable neural tissue engineering application.

Regeneration of neural tissue and recovery of lost functions following an accident or disease to the central nervous system remains a major challenge worldwide, with limited treatment options available. The main reason for the failure of conventional therapeutic techniques to regenerate neural tissue is the presence of blood-brain barrier separating nervous system from systemic circulation and the limited capacity of self-regeneration of the nervous system. Injectable hydrogels have shown great promise for neural tissue engineering given their suitability for minimally invasive in situ delivery and tunable mechanical and biological properties.

Hydrogels and Nanoscaffolds for Long-Term Intraparenchymal Therapeutic Delivery After Stroke.

Stroke remains a leading cause of adult disability with treatments limited to thrombolytic therapies that are severely limited by a narrow therapeutic window. The potential of hundreds of other therapeutic agents cannot be evaluated due to their poor ability to cross the blood-brain barrier. Recently, biopolymer hydrogels have shown promise at overcoming these obstacles via the delivering of therapeutic molecules (pharmacological, mRNA, stem cells, etc.

The Presence of Typical "BRAFV600E-Like" Atypia in Papillary Thyroid Carcinoma is Highly Specific for the Presence of the BRAFV600E Mutation.

Papillary thyroid carcinomas (PTCs) are driven by a variety of molecular abnormalities including BRAF, RAS, ALK, RET, and NTRK alterations. PTCs driven by the BRAFV600E mutation, or tumours which demonstrate a similar gene expression profile to PTCs driven by this mutation, have been reported to demonstrate specific morphological features sometimes termed "BRAFV600E-like" atypia. BRAFV600E-like atypia is characterised by a well-developed papillary architecture, infiltrative growth, marked nuclear clearing, prominent intranuclear pseudoinclusions, abundant eosinophilic cytoplasm, and scattered psammoma bodies.

Green Synthesis of Carbon Nanoparticles (CNPs) from Biomass for Biomedical Applications.

In this review, we summarize recent work on the "green synthesis" of carbon nanoparticles (CNPs) and their application with a focus on biomedical applications. Recent developments in the green synthesis of carbon nanoparticles, from renewable precursors and their application for environmental, energy-storage and medicinal applications are discussed. CNPs, especially carbon nanotubes (CNTs), carbon quantum dots (CQDs) and graphene, have demonstrated utility as high-density energy storage media, environmental remediation materials and in biomedical applications.

Non-coding RNAs in stroke pathology, diagnostics, and therapeutics.

Ischemic stroke is a leading cause of death and disability worldwide. Methods to alleviate functional deficits after ischemic stroke focus on restoration of cerebral blood flow to the affected area. However, pharmacological or surgical methods such as thrombolysis and thrombectomy have a narrow effective window.

CaMKIIα as a Promising Drug Target for Ischemic Grey Matter.

Ca/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of Ca-dependent signaling pathways in various cell types throughout the body. Its neuronal isoform CaMKIIα () centrally integrates physiological but also pathological glutamate signals directly downstream of glutamate receptors and has thus emerged as a target for ischemic stroke. Previous studies provided evidence for the involvement of CaMKII activity in ischemic cell death by showing that CaMKII inhibition affords substantial neuroprotection.

Vascular perfusion differs in two distinct PDGFRβ-positive zones within the ischemic core of male mice 2 weeks following photothrombotic stroke.

Stroke therapy has largely focused on preventing damage and encouraging repair outside the ischemic core, as the core is considered irreparable. Recently, several studies have suggested endogenous responses within the core are important for limiting the spread of damage and enhancing recovery, but the role of blood flow and capillary pericytes in this process is unknown. Using the Rose Bengal photothrombotic model of stroke, we illustrate blood vessels are present in the ischemic core and peri-lesional regions 2 weeks post stroke in male mice.