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Background: There are limited data on survival prediction models in contemporary inoperable non-small cell lung cancer (NSCLC) patients. The objective of this study was to develop and validate a survival prediction model in a cohort of inoperable stage I-III NSCLC patients treated with radiotherapy., Methods: Data from inoperable stage I-III NSCLC patients diagnosed from 1/1/2016 to 31/12/2017 were collected from three radiation oncology clinics. Patient, tumour and treatment-related variables were selected for model inclusion using univariate and multivariate analysis. Cox proportional hazards regression was used to develop a 2-year overall survival prediction model, the South West Sydney Model (SWSM) in one clinic (n = 117) and validated in the other clinics (n = 144). Model performance, assessed internally and on one independent dataset, was expressed as Harrell's concordance index (c-index)., Results: The SWSM contained five variables: Eastern Cooperative Oncology Group performance status, diffusing capacity of the lung for carbon monoxide, histological diagnosis, tumour lobe and equivalent dose in 2 Gy fractions. The SWSM yielded a c-index of 0.70 on internal validation and 0.72 on external validation. Survival probability could be stratified into three groups using a risk score derived from the model., Conclusions: A 2-year survival model with good discrimination was developed. The model included tumour lobe as a novel variable and has the potential to guide treatment decisions. Further validation is needed in a larger patient cohort., (© 2022. The Author(s).)

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases ( n  = 3,624) and control subjects ( n  = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1 ) individual common variants via logistic regression and 2 ) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele ( P  = 9.60 × 10 -295 ). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

The transition of neutrophils from a resting state to a primed state is an essential requirement for their function as competent immune cells. This transition can be caused not only by chemical signals but also by mechanical perturbation. After cessation of either, these cells gradually revert to a quiescent state over 40 to 120 min. We use two biophysical tools, an optical stretcher and a novel microcirculation mimetic, to effect physiologically relevant mechanical deformations of single nonadherent human neutrophils. We establish quantitative morphological analysis and mechanical phenotyping as label-free markers of neutrophil priming. We show that continued mechanical deformation of primed cells can cause active depolarization, which occurs two orders of magnitude faster than by spontaneous depriming. This work provides a cellular-level mechanism that potentially explains recent clinical studies demonstrating the potential importance, and physiological role, of neutrophil depriming in vivo and the pathophysiological implications when this deactivation is impaired, especially in disorders such as acute lung injury.

Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.

Although cellular mechanical properties are known to alter during stem cell differentiation, understanding of the functional relevance of such alterations is incomplete. Here, we show that during the course of differentiation of human myeloid precursor cells into three different lineages, the cells alter their viscoelastic properties, measured using an optical stretcher, to suit their ultimate fate and function. Myeloid cells circulating in blood have to be advected through constrictions in blood vessels, engendering the need for compliance at short time-scales (minutes), compared to undifferentiated cells. These findings suggest that reduction in steady-state viscosity is a physiological adaptation for enhanced migration through tissues. Our results indicate that the material properties of cells define their function, can be used as a cell differentiation marker and could serve as target for novel therapies.

Objectives: Transport of the critically ill patient to or from the emergency department (ED) is a frequent occurrence. This study was designed to determine whether UK EDs currently have appropriate equipment, monitoring, staff training systems, and processes of care for transportation of the critically ill patient., Methods: A postal questionnaire regarding ED transfer patients was sent to 247 UK EDs, followed by repeat mailing and telephone follow up of non-responders., Results: In total, 139 EDs (56%) responded. An estimated 20-30 critically ill patients are transferred from and <20 are received by each ED annually. Processes of care are poorly developed; only 79 EDs (56%) have transfer guidelines available. Audit of transfers is ongoing in 59 EDs (42%), and critical incident reporting is ongoing in 122 (88%). There is a lack of immediately available transport equipment; for example, 17 EDs (12%) have no transport ventilator, 9 (6%) have no transport monitor, and 9 (6%) have no syringe pump. Transport equipment is invariably not standardised. Anaesthetic staff of specialist registrar (74 doctors; 53%) or senior house officer (36 doctors; 26%) grades carry out the majority of ED transfers accompanied by a D or E grade nurse. Both invariably have no formal transfer training., Conclusions: This study highlights inadequacies in provision of equipment and monitoring during interhospital transfer from the ED. Training and processes of care for transport of the critically ill are also suboptimum. Many departments are currently reviewing these processes to formalize and improve transfer training procedures and protocols.