Klebsiella pneumoniae emerging anti-immunology paradigms: from stealth to evasion.

Klebsiella pneumoniae (KP) is a global threat to human health due to the isolation of multidrug-resistant strains. Despite advancements in understanding KP's population structure, antibiotic resistance mechanisms, and transmission patterns, a gap remains in how KP evades defenses, allowing the pathogen to flourish in tissues despite an activated immune system. KP infection biology has been shaped by the notion that the pathogen has evolved to shield from defenses more than actively suppress them.

Role of inflammasomes in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is present in >10% of all people admitted to critical care and is associated with severe morbidity and mortality. Despite more than half a century since its first description, no efficacious pharmacological therapies have been developed, and little progress has been made in improving clinical outcomes. Neutrophils are the principal drivers of ARDS, with their priming and subsequent aberrant downstream functions, including interleukin (IL) 1β and IL-18 secretion, central to the disease pathogenesis.

Xanthomatous hypophysitis relapsing and remitting over two decades.

Inflammation of the pituitary gland can be primary (without another underlying cause) or secondary (associated with a systemic inflammatory condition). Primary hypophysitis is very rare, among which xanthomatous hypophysitis as a histological type is extremely unusual. A woman in her late 50s presented with recurrent pituitary lesions over 20 years.

Oral tranexamic acid for immediate use in major trauma: implications for mass casualty events.

The early administration of tranexamic acid is recognised as significantly reducing mortality in traumatically injured patients with major haemorrhage, typically given via intravenous or intramuscular routes. In the context of mass casualty events, there may exist multiple traumatically injured casualties that would benefit from tranexamic acid, however, it's administration may be delayed through the need to establish intravenous access. Additionally, if the initial assessment of the traumatically injured casualty is undertaken by an individual who cannot administer intravenous or intramuscular medications, time to administration will be further delayed.

Risk factors for visual loss after excision of orbital cavernous venous malformations: a systematic review.

Background: Orbital cavernous venous malformations (OCVMs) are the most common primary orbital mass lesion and presenting symptoms are usually secondary to a mass effect. Surgical excision presents unique challenges and vision loss is a rare, but devastating, complication. This review aims to identify risk factors for vision loss with excision of OCVMs.

Real-world application of physiologically based pharmacokinetic models in drug discovery.

The utility of physiologically based pharmacokinetic (PBPK) models in support of drug development has been well documented. During the discovery stage, PBPK modeling has increasingly been applied for early risk assessment, prediction of human dose, toxicokinetic dose projection, and early formulation assessment. Previous review articles have proposed model-building and application strategies for PBPK-based first-in-human predictions with comprehensive descriptions of the individual components of PBPK models.

Absolute membrane protein abundance of P-glycoprotein, breast cancer resistance protein, and multidrug resistance proteins in term human placenta tissue and commonly used cell systems: Application in physiologically based pharmacokinetic modeling of placental drug disposition.

The placenta acts as a barrier, excluding noxious substances while actively transferring nutrients to the fetus, mediated by various transporters. This study quantified the expression of key placental transporters in term human placenta (n = 5) and BeWo, BeWo b30, and JEG-3 placenta cell lines. Combining these results with pregnancy physiologically based pharmacokinetic (PBPK) modeling, we demonstrate the utility of proteomic analysis for predicting placental drug disposition and fetal exposure.

A Phase I/IIa Clinical Trial to Evaluate Safety and Adrenal Uptake of Para-Chloro-2-[F]Fluoroethyletomidate in Healthy Volunteers and Patients with Primary Aldosteronism.

Primary aldosteronism (PA) is a common, potentially reversible, cause of hypertension. Distinguishing unilateral from bilateral PA is critical when deciding who should be offered surgery (unilateral adrenalectomy). Recent studies have shown that PET/CT with [C]metomidate can accurately identify unilateral PA, with localization of the causative aldosterone-producing adenoma (APA).

Accelerated epigenetic aging worsens survival and mediates environmental stressors in fibrotic interstitial lung disease.

Background: The role of epigenetic aging in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter ≤2.5 μm (PM) and neighbourhood disadvantage exposures are associated with accelerated epigenetic aging, and whether epigenetic age is associated with adverse clinical outcomes in patients with fILD.

Efficacy and safety of the activin signalling inhibitor, sotatercept, in a pooled analysis of PULSAR and STELLAR studies.

Introduction: Pulmonary arterial hypertension (PAH) is a progressive disease associated with significant morbidity and mortality. Sotatercept is a first-in-class activin signalling inhibitor that acts to restore the balance between the growth-promoting and growth-inhibiting signalling pathways.

Methods: This post-hoc, exploratory, pooled analysis combines data from the double-blind placebo periods of the phase 2 PULSAR (NCT03496207) and phase 3 STELLAR (NCT04576988) studies.

Enhancing nanopore adaptive sampling for PromethION using readfish at scale.

A unique feature of Oxford Nanopore Technologies sequencers, adaptive sampling, allows precise DNA molecule selection from sequencing libraries. Here we present enhancements to our tool, readfish, enabling all features for the industrial scale PromethION sequencer, including standard and "barcode-aware" adaptive sampling. We demonstrate effective coverage enrichment and assessment of multiple human genomes for copy number and structural variation on a single PromethION flow cell.

Subdermal contraceptive implant migration to pulmonary artery branch.

Subdermal contraceptive implants are now commonly used throughout the world. One of the rare complications of these implants is migration to the lungs due to misplacement of the implant during insertion, with only a limited number of cases documented. Here, we present a case where a subdermal contraceptive implant embolised in the subsegmental branch of the pulmonary artery within the anterobasal segment of the left lower lobe.

Complex high-risk indicated PCI (CHIP-PCI): is it safe to let fellows-in-training perform it as primary operators?

Background: Training in complex high-risk indicated percutaneous coronary intervention (CHIP-PCI) has frequently been reserved for established operators (consultants/attending) with trainees (fellows-in-training or FIT) being often discouraged from carrying out such procedures as a primary operator due to their high-risk nature. Whether the outcomes of these cases differ if the primary operator is a supervised FIT compared with a consultant is unknown.

Methods: Using multicentre PCI data from three cardiac centres in South Wales, UK (2018-2022), we identified 2295 CHIP-PCI cases with a UK-BCIS CHIP Score of 3 or more.

Safety and efficacy of filgotinib in patients with rheumatoid arthritis: final results of the DARWIN 3 long-term extension study.

Objectives: DARWIN 3 (ClinicalTrials.gov: NCT02065700) assessed the safety and efficacy of filgotinib in a long-term extension (LTE) of two phase II randomised controlled rheumatoid arthritis (RA) trials.

Methods: Eligible patients completing the 24-week DARWIN 1 (filgotinib plus methotrexate) and DARWIN 2 (filgotinib monotherapy) trials could enrol.

Systematic literature review on Calcium Pyrophosphate Deposition (CPPD) nomenclature: condition elements and clinical states- A Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus project.

Objectives: The Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) has developed a calcium pyrophosphate deposition (CPPD) nomenclature project. This systematic literature review constituted its first step and aimed to provide a state-of-the-art analysis of the medical literature of the last 20 years.

Methods: A systematic literature search was undertaken in the , and databases between 2000 and 2022, restricted to studies on humans and in the English language.

Implications of conflict on vaccination in the Sahel region.

The Sahel region is a geographical belt in Africa that stretches from the Atlantic Ocean to the Red Sea, between the Sahara Desert in the north and the Savannah in the south. It is characterised by challenging environmental crises and conflicts. This analysis highlights the potential implications of conflict on vaccination across five Sahel countries, including Burkina Faso, Chad, Mali, Niger and Sudan, from 2019 to 2023.

Impact of introducing transnasal endoscopy on expanding diagnostic endoscopy services.

Introduction: Demand for endoscopic services is outstripping capacity in the UK. Transnasal endoscopy (TNE) utilises a narrow calibre endoscope to pass through the nasal passages, thereby reducing retching and discomfort. It is better tolerated compared with standard transoral endoscopy (TOE) but is still rarely used as a diagnostic modality.

Qualitative study exploring the views and perceptions of parents/carers of young children with CF regarding the introduction of CFTR modulator therapy (The REVEAL study; PaRents pErspectiVEs of KAftrio in chiLdren aged 2-5).

Background: Cystic fibrosis (CF) is associated with a historically high treatment burden which causes anxiety and exhaustion for parents of children with CF, especially in the early years of a child's life. Recently, a new medication, elexacaftor/tezacaftor/ivacaftor (ETI), has become available to some people with CF, which has had a significant impact on the quality of life of older children and adults. This medication will soon be available for children ages 2-5 in the UK.

Cross-National Validation of the WHO-5 Well-Being Index Within Adolescent Populations: Findings From 43 Countries.

The five-item World Health Organization Well-Being Index (WHO-5) is among the most frequently used brief standard measures to assess hedonic well-being. Numerous studies have investigated different facets of its psychometric properties in adult populations. However, whether these results apply to adolescents is uncertain, and only few psychometric studies employed adolescent populations.