Recovery support services as part of the continuum of care for alcohol or drug use disorders.

Background: The definition of 'recovery' has evolved beyond merely control of problem substance use to include other aspects of health and wellbeing (known as 'recovery capital') which are important to prevent relapse to problematic alcohol or other drug (AOD) use. Developing a Recovery Oriented System of Care (ROSC) requires consideration of interventions or services (Recovery Support Services, RSS) designed to build recovery capital which are often delivered alongside established treatment structures. Lived experience and its application to the process of engaging people, changing behaviour and relapse prevention is an essential part of these services.

Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion.

The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals.

Tracheostomy as a Management Option After Listing for Pediatric Cardiac Transplantation.

Background: Children with end-stage heart failure listed for cardiac transplantation may require mechanical ventilation and/or circulatory support whilst awaiting transplantation. A subgroup of these patients is unable to wean off mechanical ventilator support and undergo tracheostomy to enhance quality of life and allow de-escalation of intensive care. There is limited evidence of the use of tracheostomy associated with pediatric cardiac transplantation.

Variations and Asymmetry in Sacral Ventral Rami Contributions to the Bladder.

We have demonstrated in human cadavers and canines that nerve transfer to bladder vesical nerve branches is technically feasible for bladder reinnervation after nerve injury. We further clarify here that sacral (S) ventral rami contribute to these vesical branches in 36 pelvic sides (in 22 human cadavers). Gross post-mortem visualization and open anterior abdominal approaches were used, as was micro-CT of sacral nerve bundles, for further confirmation when needed.

Insights into conformational ensembles of compositionally identical disordered peptidomimetics.

While the conformational ensembles of disordered peptides and peptidomimetics are complex and challenging to characterize, they are a critical component in the paradigm connecting macromolecule sequence, structure, and function. In molecules that do not adopt a single predominant conformation, the conformational ensemble contains rich structural information that, if accessible, can provide a fundamental understanding related to desirable functions such as cell penetration of a therapeutic or the generation of tunable enzyme-mimetic architecture. To address the fundamental challenge of describing broad conformational ensembles, we developed a model system of peptidomimetics comprised of polar glycine and hydrophobic -butylglycine to characterize using a suite of analytical techniques.

Antibody/siRNA Nanocarriers Against Wnt Signaling Suppress Oncogenic and Stem-Like Behavior in Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is infamous for its aggressive phenotype and poorer prognosis when compared to other breast cancer subtypes. One factor contributing to this poor prognosis is that TNBC lacks expression of the receptors that available hormonal or molecular-oriented therapies attack. New treatments that exploit biological targets specific to TNBC are desperately needed to improve patient outcomes.

Conjugation of Antibodies and siRNA Duplexes to Polymer Nanoparticles via Maleimide-Thiol Chemistry.

Polymeric nanoparticles (NPs) have shown great promise as highly modifiable platforms that can be applied across many different disease states. They are advantageous because they can encapsulate a range of hydrophobic and hydrophilic cargoes while having customizable surface properties. Depending on the desired biointerfacing capabilities, the surface of polymeric NPs can be modified with moieties, such as antibodies, peptides, nucleic acids, and more.

A High-Throughput Workflow to Analyze Sequence-Conformation Relationships and Explore Hydrophobic Patterning in Disordered Peptoids.

Understanding how a macromolecule's primary sequence governs its conformational landscape is crucial for elucidating its function, yet these design principles are still emerging for macromolecules with intrinsic disorder. Herein, we introduce a high-throughput workflow that implements a practical colorimetric conformational assay, introduces a semi-automated sequencing protocol using MALDI-MS/MS, and develops a generalizable sequence-structure algorithm. Using a model system of 20mer peptidomimetics containing polar glycine and hydrophobic -butylglycine residues, we identified nine classifications of conformational disorder and isolated 122 unique sequences across varied compositions and conformations.

Prrx1-driven LINC complex disruption in vivo reduces osteoid deposition but not bone quality after voluntary wheel running.

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex serves to connect the nuclear envelope and the cytoskeleton, influencing cellular processes such as nuclear arrangement, architecture, and mechanotransduction. The role LINC plays in mechanotransduction pathways in bone progenitor cells has been well studied; however, the mechanisms by which LINC complexes govern in vivo bone formation remain less clear. To bridge this knowledge gap, we established a murine model disrupting LINC using transgenic Prx-Cre mice and floxed Tg(CAG-LacZ/EGFP-KASH2) mice.

Rhythmic IL-17 production by γδ T cells maintains adipose de novo lipogenesis.

The circadian rhythm of the immune system helps to protect against pathogens; however, the role of circadian rhythms in immune homeostasis is less well understood. Innate T cells are tissue-resident lymphocytes with key roles in tissue homeostasis. Here we use single-cell RNA sequencing, a molecular-clock reporter and genetic manipulations to show that innate IL-17-producing T cells-including γδ T cells, invariant natural killer T cells and mucosal-associated invariant T cells-are enriched for molecular-clock genes compared with their IFNγ-producing counterparts.

Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.

Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1.

Exploring Estimation Procedures for Reducing Dimensionality in Psychological Network Modeling.

To understand psychological data, it is crucial to examine the structure and dimensions of variables. In this study, we examined alternative estimation algorithms to the conventional GLASSO-based exploratory graph analysis (EGA) in network psychometric models to assess the dimensionality structure of the data. The study applied Bayesian conjugate or Jeffreys' priors to estimate the graphical structure and then used the Louvain community detection algorithm to partition and identify groups of nodes, which allowed the detection of the multi- and unidimensional factor structures.

Development of a centralised national AED (automated external defibrillator) network across all ambulance services in the United Kingdom.

Background: Early cardiopulmonary resuscitation and defibrillation is key to increasing survival following an out-of-hospital-cardiac-arrest (OHCA). However, automated external defibrillators (AEDs) are used in a very small percentage of cases. Despite large numbers of AEDs in the community, the absence of a unified system for registering their locations across the UK's ambulance services may have resulted in missed opportunities to save lives.

The relative importance of affect variability and mean levels of affect in predicting complex task performance.

Although research indicates affect variability-the extent to which an individual's emotions fluctuate-is associated with behavioral outcomes related to adjustment and adaptability, it is unclear to what extent findings make important contributions to the literature when past research has failed to account for the role of mean levels of emotion. Accordingly, we conducted a repeated-measures laboratory study of college students ( = 253) learning to perform a complex computer task to examine the relative importance of affect variability indices (i.e.

IL-1 Signal Inhibition in Alcohol-Related Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial of Canakinumab.

Background And Aims: Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1β has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1β, in the treatment of patients with AH.

Renal cell carcinoma.

The landscape of the management of renal cell carcinoma has evolved substantially in the last decade, leading to improved survival in localised and advanced disease. We review the epidemiology, pathology, and diagnosis of renal cell carcinoma and discuss the evidence for current management strategies from localised to metastatic disease. Developments in adjuvant therapies are discussed, including use of pembrolizumab-the first therapy to achieve overall survival benefit in the adjuvant setting.

Antibody and siRNA Nanocarriers to Suppress Wnt Signaling, Tumor Growth, and Lung Metastasis in Triple-Negative Breast Cancer.

The paucity of targeted therapies for triple-negative breast cancer (TNBC) causes patients with this aggressive disease to suffer a poor clinical prognosis. A promising target for therapeutic intervention is the Wnt signaling pathway, which is activated in TNBC cells when extracellular Wnt ligands bind overexpressed Frizzled7 (FZD7) transmembrane receptors. This stabilizes intracellular β-catenin proteins that in turn promote transcription of oncogenes that drive tumor growth and metastasis.

Anatomical Location of the Vesical Branches of the Inferior Hypogastric Plexus in Human Cadavers.

We have demonstrated in canines that somatic nerve transfer to vesical branches of the inferior hypogastric plexus (IHP) can be used for bladder reinnervation after spinal root injury. Yet, the complex anatomy of the IHP hinders the clinical application of this repair strategy. Here, using human cadavers, we clarify the spatial relationships of the vesical branches of the IHP and nearby pelvic ganglia, with the ureteral orifice of the bladder.

FZD7-Targeted Nanoparticles to Enhance Doxorubicin Treatment of Triple-Negative Breast Cancer.

Doxorubicin (DOX) is a chemotherapy agent commonly used to treat triple-negative breast cancer (TNBC), but it has insufficient efficacy against the disease and considerable toxicity due to its off-target delivery. To improve the specificity of DOX for TNBC, we encapsulated it in poly(lactic--glycolic acid) (PLGA) nanoparticles (NPs) coated with antibodies against Frizzled7 (FZD7), a receptor that is overexpressed on TNBC cells and which is a key activator of the Wnt signaling pathway. In vitro studies show that DOX encapsulation does not hinder its ability to localize to the nucleus in human TNBC cell cultures and that DOX delivered via NPs induces apoptosis and DNA damage via H2A.

Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans.

Metformin, a widely used first-line treatment for type 2 diabetes (T2D), is known to reduce blood glucose levels and suppress appetite. Here we report a significant elevation of the appetite-suppressing metabolite N-lactoyl phenylalanine (Lac-Phe) in the blood of individuals treated with metformin across seven observational and interventional studies. Furthermore, Lac-Phe levels were found to rise in response to acute metformin administration and post-prandially in patients with T2D or in metabolically healthy volunteers.

The UK National Recovery Survey: nationally representative survey of people overcoming a drug or alcohol problem.

Background: Alcohol or drug (AOD) problems are a significant health burden in the UK population, and understanding pathways to remission is important.

Aims: To determine the UK population prevalence of overcoming an AOD problem and the prevalence and correlates of 'assisted' pathways to problem resolution.

Method: Stage 1: a screening question was administered in a national telephone survey to provide (a) an estimate of the UK prevalence of AOD problem resolution; and (b) a demographic profile of those reporting problem resolution.