The effect of triple CFTR modulator therapy and azithromycin on ion channels and inflammation in cystic fibrosis.

Background: Inflammation in cystic fibrosis (CF) airways is difficult to treat with well-established regimens often including azithromycin (AZ) as an immunomodulatory drug. As AZ has been reported to require CF transmembrane conductance regulator (CFTR) to be able to reduce interleukin (IL)-8 and given the emergence of highly effective CFTR "triple" modulator therapy (elexacaftor/tezacaftor/ivacaftor; ETI), the aim of this study was to investigate the effect of AZ and ETI, singly and in combination, on ion channel activity and to assess the potential anti-inflammatory effects.

Methods: Electrophysiological assessment of ETI and AZ was performed on three-dimensional cultures of primary CF human bronchial epithelial (HBE) cells using a Multi Trans-Epithelial Current Clamp.

Performance of clinical decision aids (CDA) for the care of young febrile infants: a multicentre prospective cohort study conducted in the UK and Ireland.

Background: Between 1% and 4% of febrile infants, aged from birth to 90 days of age, presenting to hospital will be diagnosed with an invasive bacterial infection (IBI). Traditional teaching has advocated a treat all approach but more recently a number of clinical decision aids (CDA) have been developed to classify febrile infants into lower and higher risk cohorts, with lower risk infants suitable for management without immediate parenteral antibiotics and lumbar puncture. The aim of this study was to apply these CDA to a UK and Irish cohort.

Histone Deacetylase 7-Derived 7-Amino Acid Peptide Increases Skin Wound Healing via Regulating Epidermal Fibroblast Proliferation and Migration.

Due to the complexity of wound healing, how to achieve successful healing is a significant clinical challenge. In this study, we found that the histone deacetylase-7-derived 7-amino acid peptide (7A, MHSPGAD), especially its phosphorylated version 7Ap (MH[pSer]PGAD), increased dermal fibroblast cell HDFα proliferation and migration via elevated delta-catenin (CTNND1) serine phosphorylation-mediated beta-catenin (CTNNB) nuclear translocation and subsequent upregulation of c-Myc and cyclin D1 expression. 7Ap physically interacted with platelet-derived growth factor receptor (PDGFR) and increased PDGFR interaction with cyclin-dependent kinase 6 (CDK6).

The Clinical Approach to Chronic Cough.

Chronic cough remains a significant clinical challenge, affecting approximately 10% of the population and leading to significant impairment in psychological, social, and physical quality of life. In recent years, efforts have intensified to elucidate the mechanisms underlying chronic cough and to focus on investigating and treating refractory chronic cough (RCC). A "treatable trait" approach, which focuses on identifying and addressing the specific associated causes of chronic cough, has gained traction.

Change is in the air: key questions on the 'Treatable Traits' model for chronic airway diseases in primary care.

Despite great advancements in the treatment of chronic airway diseases, improvements in morbidity and mortality have stalled in recent years. Asthma and chronic obstructive pulmonary disease are complex and heterogeneous diseases that require tailored management based on individual patient characteristics and needs. The Treatable Traits (TTs) approach aims to personalise and improve patient care through the identification and targeting of clinically relevant and modifiable pulmonary, extra-pulmonary and behavioural traits.

A clinical score to predict recovery in end-stage kidney disease due to acute kidney injury.

Background: Acute kidney injury (AKI) is a major contributor to end-stage kidney disease (ESKD). About one-third of patients with ESKD due to AKI recover kidney function. However, the inability to accurately predict recovery leads to improper triage of clinical monitoring and impacts the quality of care in ESKD.

Sex Differences in Cardiovascular Outcomes in Patients With Kidney Failure.

Background: Cardiovascular disease is the leading cause of mortality in patients with kidney failure, and their risk of cardiovascular events is 10 to 20 times higher as compared with the general population.

Methods And Results: We evaluated 508 822 patients who initiated dialysis between January 1, 2005 and December 31, 2014 using the United States Renal Data System with linked Medicare claims. We determined hospitalization rates for cardiovascular events, defined by acute coronary syndrome, heart failure, and stroke.

Recovery following discharge from intensive care: What do patients think is helpful and what services are missing?

Background: Recovery following critical illness is complex due to the many challenges patients face which influence their long-term outcomes. We explored patients' views about facilitators of recovery after critical illness which could be used to inform the components and timing of specific rehabilitation interventions.

Aims: To explore the views of patients after discharge from an intensive care unit (ICU) about their recovery and factors that facilitated recovery, and to determine additional services that patients felt were missing during their recovery.

Consensus statement-graft treatment in cardiovascular bypass graft surgery.

Coronary artery bypass grafting (CABG) is and continues to be the preferred revascularization strategy in patients with multivessel disease. Graft selection has been shown to influence the outcomes following CABG. During the last almost 60 years saphenous vein grafts (SVG) together with the internal mammary artery have become the standard of care for patients undergoing CABG surgery.

Conundrums in the Management of Febrile Infants under Three Months of Age and Future Research.

Febrile infants under three months of age pose a diagnostic challenge to clinicians. Unlike in older children, the rates of invasive bacterial infections (IBIs), such as bacteraemia or meningitis, are high. This greater risk of IBI combined with the practical challenges of assessing young infants results in a cautious approach with many febrile infants receiving parenteral antibiotics "just in case".

Artificial intelligence for biomarker discovery in Alzheimer's disease and dementia.

With the increase in large multimodal cohorts and high-throughput technologies, the potential for discovering novel biomarkers is no longer limited by data set size. Artificial intelligence (AI) and machine learning approaches have been developed to detect novel biomarkers and interactions in complex data sets. We discuss exemplar uses and evaluate current applications and limitations of AI to discover novel biomarkers.

Biologically Relevant Murine Models of Chronic Respiratory Infection.

is an opportunistic pathogen and the leading cause of infection in patients with cystic fibrosis (CF). The ability of to evade host responses and develop into chronic infection causes significant morbidity and mortality. Several mouse models have been developed to study chronic respiratory infections induced by , with the bead agar model being the most widely used.

Efficacy and Safety of Eliapixant in Refractory Chronic Cough: The Randomized, Placebo-Controlled Phase 2b PAGANINI Study.

Introduction: The PAGANINI study evaluated the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough (RCC).

Methods: PAGANINI was a randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose-finding, phase 2b study. Adults with RCC lasting ≥ 12 months and cough severity ≥ 40 mm on a visual analog scale at screening were enrolled.

The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial.

Background: P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough.

Methods: Following a crossover design, 23 patients with refractory chronic cough (age: 60.

Impact of HLA Polymorphism on the Immune Response to Bacillus Anthracis Protective Antigen in Vaccination versus Natural Infection.

The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA.

Isolation, cultivation, and application of primary respiratory epithelial cells obtained by nasal brushing, polyp samples, or lung explants.

Here, we present a standardized protocol for isolation, maintenance, and polarization of the respiratory epithelial primary cells from patient samples acquired from nasal brushing, polyp specimens, or lung explants. This protocol generates a clearly defined polarized layer of epithelial cells on filters, with a good number of ciliated cells and a thin layer of mucus. We detail the steps for samples prepared from patients with cystic fibrosis as well as from subjects without cystic fibrosis.

Diagnostic value of mid-regional pro-Adrenomedullin as a biomarker of invasive bacterial infection in children: a systematic review.

Background: Invasive bacterial infections (IBI) in children present a difficult clinical challenge. They are often life-threatening, however in the early stages they can be hard to differentiate from benign viral infections. This leaves clinicians with the risk of missing a serious IBI diagnosis or inappropriately using antimicrobials in a child with a viral infection- contributing to the ongoing development of increased antimicrobial resistance.

A Potential New Role for Zinc in Age-Related Macular Degeneration through Regulation of Endothelial Fenestration.

Age-related macular degeneration (AMD) is a common blinding disease in the western world that is linked to the loss of fenestration in the choriocapillaris that sustains the retinal pigment epithelium and photoreceptors in the back of the eye. Changes in ocular and systemic zinc concentrations have been associated with AMD; therefore, we hypothesized that these changes might be directly involved in fenestrae formation. To test this hypothesis, an endothelial cell (bEND.

Subthreshold Aortic Valve Calcium Scores in Severe Aortic Stenosis and Transthyretin Cardiac Amyloidosis.

We have clinically observed that some patients with transthyretin cardiac amyloidosis and severe aortic stenosis may have lesser degrees of calcification than one might expect. We report a case series of 3 patients with transthyretin cardiac amyloidosis and severe aortic stenosis despite discordant aortic valve calcium scores. ().

A core outcome set for studies evaluating interventions to prevent and/or treat delirium for adults requiring an acute care hospital admission: an international key stakeholder informed consensus study.

Background: Trials of interventions to prevent or treat delirium in adults in an acute hospital setting report heterogeneous outcomes. Our objective was to develop international consensus among key stakeholders for a core outcome set (COS) for future trials of interventions to prevent and/or treat delirium in adults with an acute care hospital admission and not admitted to an intensive care unit.

Methods: A rigorous COS development process was used including a systematic review, qualitative interviews, modified Delphi consensus process, and in-person consensus using nominal group technique (registration http://www.

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study.

Background: ATP acting P2X3 receptors is an important mediator of refractory chronic cough (RCC). This phase 2a double-blinded crossover study assessed the safety, tolerability and efficacy of eliapixant (BAY 1817080), a selective P2X3 receptor antagonist, in adults with RCC attending specialist centres.

Methods: In period A, patients received placebo for 2 weeks then eliapixant 10 mg for 1 week.