What strategies are used to select patients for direct admission under acute medicine services? A protocol paper for a systematic review of the literature.

Introduction: Despite unprecedented pressures on urgent and emergency care services, there is no clear consensus on how to provide acute medical care delivery in the UK. These pressures can lead to significant delays in care for patients presenting with emergencies when admitted via traditional routes through the emergency department. Historically, a separate pathway has existed where patients are directly admitted to acute medicine services without attending the emergency department.

Development of a NanoBRET Assay Platform to Detect Intracellular Ligands for the Chemokine Receptors CCR6 and CXCR1.

A conserved intracellular allosteric binding site (IABS) was recently identified at several G protein-coupled receptors (GPCRs). This target site allows the binding of allosteric modulators and enables a new mode of GPCR inhibition. Herein, we report the development of a NanoBRET-based assay platform based on the fluorescent ligand LT221 (5), to detect intracellular binding to CCR6 and CXCR1, two chemokine receptors that have been pursued as promising drug targets in inflammation and immuno-oncology.

Vaccination induces broadly neutralizing antibody precursors to HIV gp41.

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display.

Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2.

Herein, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of CXC chemokine receptor 2 (CXCR2), a G protein-coupled receptor (GPCR) that has been pursued as a drug target in oncology and inflammation. Starting from the cocrystallized intracellular CXCR2 antagonist 00767013 (), tetramethylrhodamine (TAMRA)-labeled CXCR2 ligands were designed, synthesized, and tested for their suitability as fluorescent reporters to probe binding to the IABS of CXCR2. By means of these studies, we developed Mz438 () as a high-affinity and selective fluorescent CXCR2 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a nonisotopic and high-throughput manner.

Small Molecule Tools to Study Cellular Target Engagement for the Intracellular Allosteric Binding Site of GPCRs.

A conserved intracellular allosteric binding site (IABS) has recently been identified at several G protein-coupled receptors (GPCRs). Ligands targeting the IABS, so-called intracellular allosteric antagonists, are highly promising compounds for pharmaceutical intervention and currently evaluated in several clinical trials. Beside co-crystal structures that laid the foundation for the structure-based development of intracellular allosteric GPCR antagonists, small molecule tools that enable an unambiguous identification and characterization of intracellular allosteric GPCR ligands are of utmost importance for drug discovery campaigns in this field.

The Advisory Group on Risk Evidence Education for Dementia: Multidisciplinary and Open to All.

The brain changes of Alzheimer's disease and other degenerative dementias begin long before cognitive dysfunction develops, and in people with subtle cognitive complaints, clinicians often struggle to predict who will develop dementia. The public increasingly sees benefits to accessing dementia risk evidence (DRE) such as biomarkers, predictive algorithms, and genetic information, particularly as this information moves from research to demonstrated usefulness in guiding diagnosis and clinical management. For example, the knowledge that one has high levels of amyloid in the brain may lead one to seek amyloid reducing medications, plan for disability, or engage in health promoting behaviors to fight cognitive decline.

Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR2.

Fluorescently labeled ligands are versatile molecular tools to study G protein-coupled receptors (GPCRs) and can be used for a range of different applications, including bioluminescence resonance energy transfer (BRET) assays. Here, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of the CC chemokine receptor 2 (CCR2), a class A GPCR that has been pursued as a drug target in oncology and inflammation. Starting from previously reported intracellular CCR2 antagonists, several tetramethylrhodamine (TAMRA)-labeled CCR2 ligands were designed, synthesized, and tested for their suitability as fluorescent reporters to probe binding to the IABS of CCR2.

The lived experience of haemodialysis patients managed with transmission-based precautions for MDRO colonisation: A qualitative study.

Background: Patients undergoing haemodialysis colonised with multi-drug resistant organisms (MDROs) are commonly managed with transmission-based precautions (TBP) to prevent nosocomial transmission. TBP have been linked to mixed effects on patient psychological well-being and clinical care. This study was designed to report the lived experience of dialysis patients managed with TBP.

A Chemical Biology Toolbox Targeting the Intracellular Binding Site of CCR9: Fluorescent Ligands, New Drug Leads and PROTACs.

A conserved intracellular allosteric binding site (IABS) has recently been identified at several G protein-coupled receptors (GPCRs). Starting from vercirnon, an intracellular C-C chemokine receptor type 9 (CCR9) antagonist and previous phase III clinical candidate for the treatment of Crohn's disease, we developed a chemical biology toolbox targeting the IABS of CCR9. We first synthesized a fluorescent ligand enabling equilibrium and kinetic binding studies via NanoBRET as well as fluorescence microscopy.

Vaccine genetics of IGHV1-2 VRC01-class broadly neutralizing antibody precursor naïve human B cells.

A successful HIV vaccine eliciting broadly neutralizing antibodies (bnAbs) must overcome the hurdle of being able to activate naive precursor B cells encoding features within their germline B cell receptors (BCR) that allow recognition of broadly neutralizing epitopes. Knowledge of whether bnAb precursor B cells are circulating at sufficient frequencies within individuals in communities heavily impacted by HIV may be important. Using a germline-targeting eOD-GT8 immunogen and high-throughput droplet-based single-cell BCR sequencing, we demonstrate that large numbers of paired BCR sequences from multiple donors can be efficiently screened to elucidate precursor frequencies of rare, naive VRC01-class B cells.

A Modified 2-Stage Treatment for AO/OTA 43-C1 Pilon Fractures Accompanied by Distal Fibular and Posterior Lip of the Distal Tibia Fracture.

The management of pilon fractures remains challenging owing to the high-energy axial loading mechanism that produces comminution of the articular surface, displacement of tibia metaphysis, and severe soft tissue injury. How to preserve the vitality of soft tissue and achieve anatomic reduction has become a timely issue. We report and evaluate the effect of a modified staging treatment for AO Foundation/Orthopaedic Trauma Association (AO/OTA) 43C1 pilon fracture accompanied by distal fibular and posterior lip of the distal tibia fracture.

A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses.

Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts.

Synthesis of Soluble Metal Organic Framework Composites for Mixed Matrix Membranes.

A general, green, efficient, and easily scalable methodology has been developed to more effectively incorporate (disperse) metal-organic frameworks (MOFs) into polymer technologies via solid state synthesis of any MOF nanocrystals within soluble mesoporous polymers. The resulting solid hybrid materials (pellets) can be directly transformed into colloidal MOF polymeric suspensions (inks) by simple dissolution in organic solvents. The straightforward use of novel colloidal MOF polymeric inks as ultimate additive for mixed matrix membranes resulted in unprecedented snakeskin microstructure exhibiting outstanding selectivity for CO over N (>100) from post-combustion flue gas at very low and well-dispersed MOF nanocrystal concentrations ranging from 1 to 7 wt %.

Are Disease Modifying Treatments Enough? Improving Quality of Life in Late-Stage Patients.

The potential for successful disease modifying treatments for Alzheimer's disease (AD) opens up the possibility that there will be a large cohort of patients living with late-stage dementia and poor quality of life. There must thus be a parallel effort to leverage restorative therapies that improve quality of life in these patients. With the potential for stopping the onset of AD in new patients must come a commitment to those patients living with this chronic disability for many more years than first thought.

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen.

Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells.

You're so vein: bundle sheath physiology, phylogeny and evolution in C3 and C4 plants.

Bundle sheath (BS) anatomy is found in most C4 lineages, associated with low inter-veinal distances (IVD) and high BS:mesophyll ratio (BS:MC). The origins, function and selective advantages of the BS in C3 lineages are relevant for understanding the environmental, molecular and phylogenetic determinants of C4 evolution. Suggested functions for BS have included structural support, hydraulic isolation, storage for water, ions, and carbohydrates, and photorespiratory carbon metabolism; we propose a central role for cavitation repair, consistent with the BS as a control centre on regulating stem and leaf hydraulic continuity.

Evidence-based review of silver dressing use on chronic wounds.

Purpose: Use of silver containing dressings has become prevalent in clinical practice to manage chronic wounds at risk for infections. This literature review examines the evidence for the efficacy of using silver dressings in the chronic wound management.

Data Sources: Relevant in vitro articles on antimicrobial activity of silver dressings, relevant randomized controlled studies (RCTs), and one retrospective cohort study were selected to assess the effectiveness of silver dressings on human chronic wounds.

A patient's journey. Mesothelioma.

Professor Kieran Sweeney was diagnosed with malignant mesothelioma at age 57. He describes here his thoughts on his interactions with the health professionals who care for him.

Plasticization-enhanced hydrogen purification using polymeric membranes.

Polymer membranes are attractive for molecular-scale separations such as hydrogen purification because of inherently low energy requirements. However, membrane materials with outstanding hydrogen separation performance in feed streams containing high-pressure carbon dioxide and impurities such as hydrogen sulfide and water are not available. We report highly permeable, reverse-selective membrane materials for hydrogen purification, as exemplified by molecularly engineered, highly branched, cross-linked poly(ethylene oxide).

Evidence for a genetic defect in oral tolerance induction in inflammatory bowel disease.

Background: Previous studies have suggested that there may be a defect in the control of immune responses locally in the intestines of patients with inflammatory bowel disease (IBD). Recently, we documented a failure to induce oral tolerance to a fed soluble protein antigen, keyhole limpet hemocyanin (KLH), in IBD patients. Both Crohn's disease (CD) and ulcerative colitis (UC) appear to be multigenic disorders with evidence of familial segregation.

How much do we understand about the effects of ageing on healing?

Poor experimental design has contributed to a perceived association of ageing with delayed wound healing. Continuing research on the influence of ageing will allow more focused therapeutic strategies.

Failure to induce oral tolerance in Crohn's and ulcerative colitis patients: possible genetic risk.

It has been proposed that defective activation of suppressor or regulatory T cells is one mechanism involved in the uncontrolled inflammatory process seen in inflammatory bowel disease (IBD). Because suppressor/regulatory T cells are thought to play a role in the promotion of oral tolerance, we attempted to induce oral tolerance in normal controls (n = 21) and patients with either Crohn's disease (CD; n = 12) or ulcerative colitis (UC; n = 13). In the first study, subjects were fed the neoantigen keyhole limpet hemocyanin (KLH) on days 1 to 5 and 11 to 15.