Real-life prevalence of progressive fibrosing interstitial lung diseases.

The concept of progressive fibrosing interstitial lung disease (PF-ILD) has recently emerged. However, real-life proportion of PF-ILDs outside IPF is still hard to evaluate. Therefore, we sought to estimate the proportion of PF-ILD in our ILD cohort. We also determined the proportion of ILD subtypes within PF-ILD and investigated factors associated with PF-ILDs. Finally, we quantified interobserver agreement between radiologists for the assessment of fibrosis. We reviewed the files of ILD patients discussed in multidisciplinary discussion between January 1st 2017 and December 31st 2019. Clinical data, pulmonary function tests (PFTs) and high-resolution computed tomography (HRCTs) were centrally reviewed. Fibrosis was defined as the presence of traction bronchiectasis, reticulations with/out honeycombing. Progression was defined as a relative forced vital capacity (FVC) decline of ≥ 10% in ≤ 24 months or 5% < FVC decline < 10% and progression of fibrosis on HRCT in ≤ 24 months. 464 consecutive ILD patients were included. 105 had a diagnosis of IPF (23%). Most frequent non-IPF ILD were connective tissue disease (CTD)-associated ILD (22%), hypersensitivity pneumonitis (13%), unclassifiable ILD (10%) and sarcoidosis (8%). Features of fibrosis were common (82% of CTD-ILD, 81% of HP, 95% of uILD). After review of HRCTs and PFTs, 68 patients (19% of non-IPF ILD) had a PF-ILD according to our criteria. Interobserver agreement for fibrosis between radiologists was excellent (Cohen's kappa 0.86). The main diagnosis among PF-ILD were CTD-ILD (36%), HP (22%) and uILD (20%). PF-ILD patients were significantly older than non-F-ILD (P = 0.0005). PF-ILDs represent about 20% of ILDs outside IPF. This provides an estimation of the proportion of patients who might benefit from antifibrotics. Interobserver agreement between radiologists for the diagnosis of fibrotic ILD is excellent.

Integrative respiratory follow-up of severe COVID-19 reveals common functional and lung imaging sequelae.

BACKGROUND: COVID-19 pandemic resulted in an unprecedented number of hospitalizations in general wards and intensive care units (ICU). Severe and critical COVID-19 patients suffer from extensive pneumonia; therefore, long-term respiratory sequelae may be expected. RESEARCH QUESTION: We conducted a cohort study to determine respiratory sequelae in patients with severe and critical COVID-19. We aimed at evaluating the proportion of patients with persisting respiratory symptoms and/or abnormalities in pulmonary function tests (PFT) or in lung imaging. STUDY DESIGN: and methods: This is a single center cohort study including COVID-19 survivors who underwent a three-month follow-up with clinical evaluation, PFT and lung high-resolution computed tomography (HRCT). All clinical, functional, and radiological data were centrally reviewed. Multiple linear regression analysis was performed to identify factors associated with residual lesions on HRCT. RESULTS: Full clinical evaluation, PFT and lung HRCT were available for central review in 126, 122 and 107 patients, respectively. At follow-up, 25% of patients complained from dyspnea and 35% from fatigue, lung diffusion capacity (DLCO) was decreased in 45%, 17% had HRCT abnormalities affecting more than 5% of their lung parenchyma while signs of fibrosis were found in 21%. In multiple linear regression model, number of days in ICU were related to the extent of persisting lesions on HRCT, while intubation was associated with signs of fibrosis at follow-up (P = 0.0005, Fisher's exact test). In contrast, the severity of lung imaging or PFT changes were not predictive of fatigue and dyspnea. INTERPRETATION: Although most hospitalized COVID-19 patients recover, a substantial proportion complains from persisting dyspnea and fatigue. Impairment of DLCO and signs suggestive of fibrosis are common but are not strictly related to long-lasting symptoms.

Short telomeres increase the risk of severe COVID-19.

Telomeres are non-coding DNA sequences that protect chromosome ends and shorten with age. Short telomere length (TL) is associated with chronic diseases and immunosenescence. The main risk factor for mortality of coronavirus disease 2019 (COVID-19) is older age, but outcome is very heterogeneous among individuals of the same age group. Therefore, we hypothesized that TL influences COVID-19-related outcomes. In a prospective study, we measured TL by Flow-FISH in 70 hospitalized COVID-19 patients and compared TL distribution with our reference cohort of 491 healthy volunteers. We also correlated TL with baseline clinical and biological parameters. We stained autopsy lung tissue from six non-survivor COVID-19 patients to detect senescence-associated ß-galactosidase activity, a marker of cellular aging. We found a significantly higher proportion of patients with short telomeres (<10th percentile) in the COVID-19 patients as compared to the reference cohort (P<0.001). Short telomeres were associated with a higher risk of critical disease, defined as admission to intensive care unit (ICU) or death without ICU. TL was negatively correlated with C-reactive protein and neutrophil-to-lymphocyte ratio. Finally, lung tissue from patients with very short telomeres exhibit signs of senescence in structural and immune cells. Our results suggest that TL influences the severity of the disease.

Multidisciplinary management of interstitial lung diseases: A real-life study.

BACKGROUND: The guidelines on idiopathic pulmonary fibrosis (IPF) diagnosis established the crucial role of multidisciplinary discussion (MDD) in the diagnosis of interstitial lung diseases (ILD). However, real-life evaluation of MDD remains scarce. Our aim was to study the impact of a well-structured MDD on etiological assessment, diagnosis, and management of ILD. METHODS: We collected and analysed all relevant data on patients concerning diagnosis and treatment before and after MDD during the year 2017. RESULTS: One hundred fifty patients were included in the analysis. MDD had a significant impact on management: 42% of diagnoses were revised and the number of unclassifiable ILD was significantly reduced. Lung biopsy was performed in 26 patients (12 cryobiopsies and 14 surgical biopsies). The most prevalent diagnoses were connective-tissue disease associated ILD (32%), idiopathic pulmonary fibrosis (23%), hypersensitivity pneumonitis (13%) and granulomatous ILD (7%). MDD led to a change or initiation of treatment in 55% of cases. Nine patients were evaluated for transplantation, 23 patients were screened for academic or sponsored clinical trials and an 8-fold increase in rehabilitation inclusion was observed. CONCLUSION: Our results confirm the benefits of MDD on ILD management and diagnosis. MDD also facilitates access to non-pharmacological therapies and clinical trials.

Inositol(1,4,5)P3 3-kinase isoenzymes: Catalytic properties and importance of targeting to F-actin to understand function.

Inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) 3-kinases (Itpks) catalyze the phosphorylation of inositol(1,4,5)trisphosphate into inositol(1,3,4,5)tetrakisphosphate (Ins(1,3,4,5)P4). Three isoenzymes Itpka/b and c have been identified in human, rat and mouse. They share a catalytic domain relatively well conserved at the C-terminal end and a quite isoenzyme specific regulatory domain at the N-terminal end of the protein. Activity determined in cell homogenates with Ins(1,4,5)P3 and ATP as substrate is generally very low compared to Ins(1,4,5)P3 5-phosphatase, except in a few tissues such as brain, testis, thymus or intestine. Activity is very much Ca(2+) sensitive and increased in the presence of Ca(2+)/calmodulin (CaM) as compared to EGTA alone. When challenged after receptor activation, activity could be further activated several fold, e.g. in rat brain cortical slices stimulated by carbachol or in human astrocytoma cells stimulated by purinergic agonists. Two of the three isoenzymes show an unexpected cytoskeletal localization for Itpka/b or at the leading edge for Itpkb. This is explained by the presence of an F-actin binding site at the N-terminal part of the two isoenzymes. This interaction confers to Itpka the properties of an F-actin bundling protein with two major consequences: i) it can reorganize the cytoskeletal network, particularly in dendritic spines, and ii) can provide an opportunity for Ins(1,3,4,5)P4 to act very locally as second messenger.

Regulation of NGF-driven neurite outgrowth by Ins(1,4,5)P3 kinase is specifically associated with the two isoenzymes Itpka and Itpkb in a model of PC12 cells.

Four inositol phosphate kinases catalyze phosphorylation of the second messenger inositol 1,4,5-trisphosphate [Ins(1,4,5)P3 ] to inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4 ]: these enzymes comprise three isoenzymes of inositol 1,4,5-trisphosphate 3-kinase (Itpk), referred to as Itpka, Itpkb and Itpkc, and the inositol polyphosphate multikinase (IPMK). The four enzymes that act on Ins(1,4,5)P3 are all expressed in rat pheochromocytoma PC12 cells, a model that is used to study neurite outgrowth induced by nerve growth factor (NGF). We compared the effect of over-expression of the four GFP-tagged kinases on NGF-induced neurite outgrowth. Our data show that over-expression of the Itpka and Itpkb isoforms inhibits NGF-induced neurite outgrowth, but over-expression of Itpkc and IPMK does not. Surprisingly, over-expression of the N-terminal F-actin binding domain of Itpka, which lacks catalytic activity, was as effective at inhibiting neurite outgrowth as the full-length enzyme. Neurite length was also significantly decreased in cells over-expressing Itpka and Itpkb but not Itpkc or IPMK. This result did not depend on the over-expression level of any of the kinases. PC12 cells over-expressing GFP-tagged kinase-dead mutants Itpka/b have shorter neurites than GFP control cells. The decrease in neurite length was never as pronounced as observed with wild-type GFP-tagged Itpka/b. Finally, the percentage of neurite-bearing cells was increased in cells over-expressing the membranous type I Ins(1,4,5)P3 5-phosphatase. We conclude that Itpka and Itpkb inhibit neurite outgrowth through both F-actin binding and localized Ins(1,4,5)P3 3-kinase activity. Itpkc and IPMK do not influence neurite outgrowth or neurite length in this model.

School-based practice patterns: a survey of occupational therapists in Colorado.

OBJECTIVE: This purpose of this study was to describe school-based occupational therapy practice for kindergarten through twelfth-grade students in Colorado and to examine occupational therapy practice in light of current education policy and published views of best practice. METHOD: Study data were provided by 105 occupational therapists and occupational therapy assistants who completed a 24-item questionnaire. RESULTS: Occupational therapists carried an average caseload of 43.68 students; most frequently served kindergarten through third-grade students with perceptual or communicative disabilities; and delivered services most often in pullout treatment areas. Practitioners spent most of their work week providing direct services. Remedial or developmental approaches were used 62% of the time and compensatory and educational approaches 37% of the time. Individualized education program goals addressed by occupational therapists were most frequently developed by the occupational therapist and targeted students' sensory or motor impairments. Workshops on autism and sensorimotor intervention techniques were reported as the primary and preferred forms of professional development. CONCLUSION: The strong majority of reported occupational therapy services contrasted with emerging views of best practice. They were, however, consistent with the Colorado Department of Education's guidelines for "motor specialists" that address occupational therapy, physical therapy, and adaptive physical educators working in schools. Study findings are discussed.

BrainMap taxonomy of experimental design: description and evaluation.

Coordinate-based, voxel-wise meta-analysis is an exciting recent addition to the human functional brain mapping literature. In view of the critical importance of selection criteria for any valid meta-analysis, a taxonomy of experimental design should be an important tool for aiding in the design of rigorous meta-analyses. The coding scheme of experimental designs developed for and implemented within the BrainMap database provides a candidate taxonomy. In this study, the BrainMap experimental-design taxonomy is described and evaluated by comparing taxonomy fields to data-filtering choices made by subject-matter experts carrying out meta-analyses of the functional imaging literature. Fifteen publications reporting a total of 46 voxel-wise meta-analyses were included in this assessment. Collectively these 46 meta-analyses pooled data from 351 publications, selected for experimental similarity within each meta-analysis. Filter implementations within BrainMap were graded by ease-of-use (A-C) and by stage-of-use (1-3). Quality filters and content filters were tabulated separately. Quality filters required for data entry into BrainMap were classed as mandatory (five filters), being above the use grading system. All authors spontaneously adopted the five mandatory filters in constructing their meta-analysis, indicating excellent agreement on data quality among authors and between authors and the BrainMap development team. Two non-mandatory quality filters (group size and imaging modality) were applied by all authors; both were Stage 1, Grade A filters. Field-of-view filters were the least-accessible quality filters (Stage 3, Grade C); two field-of-view filters were applied by six and four authors, respectively. Authors made a total of 115 content-filter choices. Of these, 78 (68%) were Stage 1, Grade A filters; 16 (14%) were Stage 2, Grade A; and 21 (18%) were Stage 2, Grade C. No author-applied filter was absent from the taxonomy.