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Abstract The SP/KLF family of transcription factors harbour three C-terminal C2H2 zinc fingers interspersed by two linkers which confers DNA-binding to a 9-10 bp motif. Mutations in KLF1, the founding member of the family, are common. Missense mutations in linker two result in a mild phenotype. However, when co-inherited with loss-of-function mutations, they result in severe non-spherocytic hemolytic anemia. We generate a mouse model of this disease by crossing Klf1 +/− mice with Klf1 H350R/+ mice that harbour a missense mutation in linker-2. Klf1 H350R/− mice exhibit severe hemolysis without thalassemia. RNA-seq demonstrate loss of expression of genes encoding transmembrane and cytoskeletal proteins, but not globins. ChIP-seq show no change in DNA-binding specificity, but a global reduction in affinity, which is confirmed using recombinant proteins and in vitro binding assays. This study provides new insights into how linker mutations in zinc finger transcription factors result in different phenotypes to those caused by loss-of-function mutations.

Impaired respiratory function secondary to acute or chronic respiratory disease poses a significant clinical and healthcare burden. Intrapulmonary percussive ventilation (IPV) is used in various clinical settings to treat excessive airway secretions, pulmonary atelectasis, and impaired gas exchange. Despite IPV’s wide use, there is a lack of clinical guidance on IPV application which may lead to inconsistency in clinical practice. This scoping review aimed to summarise the clinical application methods and dosage of IPV used by clinicians and researchers to provide guidance. A two-staged systematic search was conducted to retrieve studies that used IPV in inpatient and outpatient settings. MEDLINE, EMBASE, CINAHL, Scopus, and Google scholar were searched from January 1979 till 2022. Studies with patients aged ≥16 years and published in any language were included. Two reviewers independently screened the title and abstract, reviewed full text articles, and extracted data. Search yielded 514 studies. After removing duplicates and irrelevant studies, 25 studies with 905 participants met the inclusion criteria. This is the first scoping review to summarise IPV application methods and dosages from the available studies in intensive care unit (ICU), acute inpatient (non-ICU), and outpatient settings. Some variations in clinical applications and prescribed dosages of IPV were noted. Despite variations, common trends in clinical application and prescription of IPV dosages were observed and summarised to assist clinicians with IPV intervention. Although an evidence-based clinical guideline could not be provided, this review provides detailed information on IPV application and dosages in order to provide clinical guidance and lays a foundation towards developing a clinical practice guideline in the future.

Abstract Background Right ventricular (RV) function is tightly coupled to afterload, yet echocardiographic indices of RV function are frequently assessed in isolation. Normalizing RV function for afterload (RV-PA coupling) using a simplified ratio of tricuspid annular plane systolic excursion (TAPSE)/ tricuspid regurgitant velocity (TRV) could help to identify RV decompensation and improve risk stratification in critically ill patients. This is the first study to explore the distribution of TAPSE/TRV ratio and its prognostic relevance in a large general critical care cohort. Methods We undertook retrospective analysis of echocardiographic, clinical, and mortality data of intensive care unit (ICU) patients between January 2012 and May 2017. A total of 1077 patients were included and stratified into tertile groups based on TAPSE/TRV ratio: low (