Miracle-dz/UniFAR-FTUs huggingface dataset:
Do tertiary paediatric hospitals deal with the same spectrum of paediatric pulmonary hypertension as multicentre registries?

To the Editor: Although national [1–5] and international paediatric registries for pulmonary hypertension (PH) [6, 7] have been published recently, inclusion criteria and, therefore, the distribution of aetiologies and severity of cases have not always been comparable [8]. In order to determine possible differences between registries, we have compared the aetiologies of confirmed PH of prevalent versus incident cases of PH in our own large database (in a tertiary paediatric hospital), and compared these to recently reported large multinational registries. According to pre-specified protocols, any children with clinical symptoms or at risk of PH at our centre were referred for echocardiography. If tricuspid regurgitation velocity was >2.8 m·s−1, right heart catheterisation was performed and the diagnosis of PH was confirmed if mean pulmonary artery pressure was ≥25 mmHg. The Dana Point classification was used [1, 9]. A standardised diagnostic work-up was used in PH cases: thoracic computed tomography scan, hepatic echography, lung function tests, genetic screening, screening for systemic diseases, and HIV serology were used when appropriate. At the beginning of our study, our database included 86 prevalent PH patients. Over the next 3 yrs, 126 incident PH patients were referred. Median age at inclusion was 2.4 yrs (range 0.5–15 …
Lung deposition of inhaled α1-proteinase inhibitor in cystic fibrosis and α1-antitrypsin deficiency

Individuals with α1-antitrypsin (AAT) deficiency and cystic fibrosis (CF) have a protease–antiprotease imbalance in their lungs, which leads to early onset progressive lung disease. Inhalation of AAT may restore protective levels in the lungs. This study aimed to determine the efficiency of delivering AAT using a novel inhalation device in subjects with AAT deficiency and CF compared with healthy subjects. In total, 20 subjects (six healthy, seven with AAT deficiency and seven with CF) inhaled ∼70 mg of radiolabelled active AAT, with controlled breathing patterns adjusted to lung function. Post-inhalation, total and regional lung deposition and extrathoracic deposition of radiolabelled AAT were measured. Total lung deposition of AAT was ∼70% of the filling dose. The magnitude of deposition was similar in all treatment groups, with no adverse effect on lung function or any influence of disease severity on total lung deposition. Inhalation with controlled breathing patterns using the AKITA2 device (lung function adapted) leads to high total lung deposition regardless of the degree of lung function impairment. Delivery of large amounts of AAT was achieved in a short period of time. This device may be an ideal option for aerosol therapy.
Effects of emergency department expansion on emergency department patient flow.

OBJECTIVES Emergency department (ED) crowding is an increasing problem associated with adverse patient outcomes. ED expansion is one method advocated to reduce ED crowding. The objective of this analysis was to determine the effect of ED expansion on measures of ED crowding. METHODS This was a retrospective study using administrative data from two 11-month periods before and after the expansion of an ED from 33 to 53 adult beds in an academic medical center. ED volume, staffing, and hospital admission and occupancy data were obtained either from the electronic health record (EHR) or from administrative records. The primary outcome was the rate of patients who left without being treated (LWBT), and the secondary outcome was total ED boarding time for admitted patients. A multivariable robust linear regression model was used to determine whether ED expansion was associated with the outcome measures. RESULTS The mean (±SD) daily adult volume was 128 (±14) patients before expansion and 145 (±17) patients after. The percentage of patients who LWBT was unchanged: 9.0% before expansion versus 8.3% after expansion (difference = 0.6%, 95% confidence interval [CI] = -0.16% to 1.4%). Total ED boarding time increased from 160 to 180 hours/day (difference = 20 hours, 95% CI = 8 to 32 hours). After daily ED volume, low-acuity area volume, daily wait time, daily boarding hours, and nurse staffing were adjusted for, the percentage of patients who LWBT was not independently associated with ED expansion (p = 0.053). After ED admissions, ED intensive care unit (ICU) admissions, elective surgical admissions, hospital occupancy rate, ICU occupancy rate, and number of operational ICU beds were adjusted for, the increase in ED boarding hours was independently associated with the ED expansion (p = 0.005). CONCLUSIONS An increase in ED bed capacity was associated with no significant change in the percentage of patients who LWBT, but had an unintended consequence of an increase in ED boarding hours. ED expansion alone does not appear to be an adequate solution to ED crowding.
Diffusion capacity and BMPR2 mutations in pulmonary arterial hypertension

To the Editor: Pulmonary arterial hypertension (PAH) is a disease in which remodelling of the small pulmonary arteries leads to an increase in pulmonary artery pressure (PAP). The most important genetic predisposing factor related to PAH is a mutation in the bone morphogenetic protein receptor type 2 gene ( BMPR2 ) [1, 2]. BMPR2 mutation carriers are known to present with disease at an earlier age and with worse haemodynamics [3]. We recently showed in a cohort of patients with idiopathic and hereditary PAH that a very low diffusion capacity for carbon monoxide ( D LCO) is exclusively found in some of the patients without identified BMPR2 mutations, whereas BMPR2 mutation carriers have a relatively preserved D LCO [4]. D LCO is a noninvasive marker of the quality of the alveolar capillary structure [5] and the observed difference in D LCO supports the hypothesis that distinct vascular disease processes are at play in BMPR2 mutation-related PAH and non BMPR2 mutation-related idiopathic PAH. Until recently, insufficient availability of lung samples has prohibited the performance of a detailed comparison of the pulmonary vascular pathologies in these two disease groups [6]. Therefore, we sought, in the present study, to confirm the previously found influence of BMPR2 mutations on diffusion capacity in a much larger multinational patient cohort. We performed a retrospective collaborative study at the VU University Medical Center in Amsterdam, the Netherlands and the Universite Paris-Sud, Assistance Publique Hopitaux de Paris, Le Kremlin-Bicetre, France. Patients were eligible for this study when classified in the database with idiopathic or familial PAH, and when the results from BMPR2 mutation analysis and D LCO measurements were available. Patients were diagnosed with idiopathic …
Diagnostic yields, charges, and radiation dose of chest imaging in blunt trauma evaluations.

BACKGROUND Chest radiography (CXR) is the most common imaging in adult blunt trauma patient evaluation. Knowledge of the yields, attendant costs, and radiation doses delivered may guide effective chest imaging utilization. OBJECTIVES The objectives were to determine the diagnostic yields of blunt trauma chest imaging (CXR and chest computed tomography [CT]), to estimate charges and radiation exposure per injury identified, and to delineate assessment points in blunt trauma evaluation at which decision instruments for selective chest imaging would have the greatest effect. METHODS From December 2009 to January 2012, we enrolled patients older than 14 years who received CXR during blunt trauma evaluations at nine U.S. Level I trauma centers in this prospective, observational study. Thoracic injury seen on chest imaging and clinical significance of the injury were defined by a trauma expert panel. Yields of imaging were calculated, as well as mean charges and effective radiation dose (ERD) per injury. RESULTS Of 9,905 enrolled patients, 55.4% had CXR alone, 42.0% had both CXR and CT, and 2.6% had CT alone. The yields for detecting thoracic injury were CXR 8.4% (95% confidence intervals [CIs]) = 7.8% to 8.9%), chest CT 28.8% (95% CI = 27.5% to 30.2%), and chest CT after normal CXR 15.0% (95% CI = 13.9% to 16.2%). The mean charges and ERD (millisievert [mSv]) per injury diagnosis of CXR, chest CT, and chest CT after normal CXR were $3,845 (0.24 mSv), $10,597 (30.9 mSv), and $20,347 (59.3 mSv), respectively. The mean charges and ERD per clinically major thoracic injury diagnosis on chest CT after normal CXR were $203,467 and 593 mSv. CONCLUSIONS Despite greater diagnostic yield, chest CT entails substantially higher charges and radiation dose per injury diagnosed, especially when performed after a normal CXR. Selective chest imaging decision instruments should identify patients who require no chest imaging and patients who may benefit from chest CT after a normal CXR.
Antigen-specific multifunctional T-cells in sarcoidosis patients with Löfgren’s syndrome

Sarcoidosis is a granulomatous disease of unknown aetiology, mainly affecting the lungs. Recently, T-cell responses towards a specific mycobacterial protein, catalase–peroxidase (mKatG), were observed in sarcoidosis patients. Bronchoalveolar lavage (BAL) fluid and peripheral blood were obtained from a total of 23 sarcoidosis patients, of whom 13 had Löfgren’s syndrome and lung accumulations of T-cell receptor AV2S3+ T-cells. Using six-colour flow cytometry in combination with intracellular cytokine staining, T-cell subsets were studied with regard to interferon (IFN)-&ggr;, tumour necrosis factor (TNF) and interleukin-2 production, after stimulation with mKatG or Mycobacterium tuberculosis purified protein derivate (PPD). Stimulation with mKatG resulted in higher simultaneous IFN-&ggr; and TNF production, but less single IFN-&ggr; production, from total BAL fluid CD4+ T-cells of Löfgren’s syndrome patients, when compared with non-Löfgren’s patients. In contrast, PPD stimulation gave rise to largely similar cytokine responses in both patient subgroups. Furthermore, mKatG stimulated higher IFN-&ggr; production in BAL fluid and blood AV2S3+ T-cells than AV2S3- T-cells, whereas the opposite was seen in BAL fluid with PPD stimulation. Our finding that patients with Löfgren’s syndrome exhibited a more pronounced multifunctional cytokine profile (simultaneous IFN-&ggr; and TNF production) towards the mycobacterial protein mKatG may help to explain the distinct disease presentation in this patient subgroup.
Vitamin D counteracts fibrogenic TGF-β signalling in human hepatic stellate cells both receptor-dependently and independently

Objective Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity and constitutes part of the metabolic syndrome, which have been associated with low serum vitamin D (VD). Due to known crosstalk between VD and transforming growth factor (TGF)-β signalling, VD has been proposed as an antifibrotic treatment. Design We evaluated the association between VD, the vitamin D receptor (VDR) and liver fibrosis in primary human hepatic stellate cells (phHSC) and 106 morbidly obese patients with NAFLD. Results Treating phHSC with VD ameliorated TGF-β-induced fibrogenesis via both VDR-dependent and VDR-independent mechanisms. Reduction of fibrogenic response was abolished in cells homozygous for GG at the A1012G single nucleotide polymorphisms within the VDR gene. Compared with healthy livers, NAFLD livers expressed higher levels of VDR mRNA and VDR fragments. VDR mRNA was lower in patients homozygous for GG at A1012G and expression of pro-fibrogenic genes was higher in patients carrying the G allele. Conclusions VD may be an antifibrotic treatment option early in the onset of fibrosis in specific genotypes for VDR. Known polymorphisms of the VDR may influence the response to VD treatment.
Hallmarks of the ageing lung

Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, “dysregulation of the extracellular matrix”, which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF http://ow.ly/HeM2n
CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis

Objective Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined. Design We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis. Results Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5neg or low cell population but was distinct from typical antral Lgr5high stem cells. Treatment with progastrin interconverts Lgr5neg or low CCK2R+ cells into Lgr5high cells, increases CCK2R+ cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis. Conclusions CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy.
Blood eosinophil count and risk of pneumonia hospitalisations in individuals with COPD

Blood eosinophil count in chronic obstructive pulmonary disease (COPD) is associated with higher exacerbation rate and favourable response to corticosteroids; however, frequent exacerbations and use of inhaled corticosteroids could elevate pneumonia risk. We tested the hypothesis that high blood eosinophil counts are associated with high risk of pneumonia in individuals with severe COPD from the general population. We included 7180 individuals with COPD from the Copenhagen General Population Study, including 643 with forced expiratory volume in 1 s (FEV1) <50% predicted between 2003 and 2011. All primary discharge diagnoses of pneumonia during follow-up were recorded. Among individuals with COPD and FEV1 <50% pred, the multivariable adjusted incidence rate ratio was 2.17 (95% CI 1.31–3.58) for pneumonia comparing individuals with blood eosinophil counts ≥0.34×109 cells·L−1 versus <0.34×109 cells·L−1. In individuals with clinical COPD, defined by recent exacerbation, ≥10 pack-years of smoking and FEV1 <70% pred, the corresponding risk was 4.52 (2.11–9.72). Risk of pneumonia did not differ by blood eosinophil count in individuals with COPD and FEV1 ≥50% pred. In individuals with COPD and FEV1 <50% pred, blood eosinophil count ≥0.34×109 cells·L−1 was associated with high risk of hospitalisation due to pneumonia. Eosinophilic COPD with severely impaired lung function is associated with high risk of pneumonia hospitalisations http://ow.ly/Tyl130jsi1D
Shortened multidrug-resistant tuberculosis regimens overcome low-level fluoroquinolone resistance

We read the research letter by Javaid et al. [1] with great interest. The recommendations from the World Health Organization (WHO) on the use of shortened multidrug-resistant tuberculosis (MDR-TB) regimens controversially indicated that “shortened MDR-TB regimens should not be used in patients who have documented or likely resistance to medicines in the regimen” [2], leading to the concept that MDR-TB patients with additional resistance to not only fluoroquinolones (FQs) or second-line injectables (SLIs), but also ethambutol (EMB), prothionamide (Pto) and pyrazinamide (PZA) would not be eligible for the regimens [3]. This is a highly conservative approach that will greatly limit the applicability of shortened MDR-TB regimens and deprive many MDR-TB patients in high-burden countries of short and highly effective regimens. The 9-month MDR-TB regimen piloted in Bangladesh comprised high-dose gatifloxacin (hGfx), clofazimine (Cfz), EMB and PZA throughout, supplemented by kanamycin (Km), Pto and high-dose isoniazid (hINH) during an intensive phase [4]. The regimen was initially designed to be used in settings with limited resources, where drug susceptibility testing was not available in a timely manner. It was designed as a standardised regimen, using clofazimine and first-line drugs to replace toxic and less effective second-line drugs such as cycloserine and para-aminosalicylic acid. The drugs that are crucial in achieving sputum conversion are hGfx and Km, and those crucial in shortening the duration of treatment are hGfx, Cfz and PZA [5]. Other drugs, in combination, play a supportive role and full susceptibility to these drugs was not expected in the original design. Most patients treated with shortened MDR-TB regimens in Bangladesh [4] and other countries [6] have been exposed to EMB for a prolonged period. Those with resistance to EMB were not excluded and replacement of EMB by another drug was not performed. hINH and Pto were combined complimentarily to address cross-resistance to Pto in inhA-mutant strains of Mycobacterium tuberculosis, since the serum level of hINH will exceed the minimum inhibitory concentration (MIC) of strains with inhA mutation by a wide margin, ensuring that at least one of hINH and Pto will be effective in most cases. Resistance to Pto was not associated with an unfavourable outcome [4] and hINH may also be able to suppress a substantial proportion of bacilli with katG mutation. Shortened unmodified MDR-TB regimens using high-dose gatifloxacin overcome low-level fluoroquinolone resistance http://ow.ly/VCHF30bt4kA
Definition and taxonomy of interval colorectal cancers: a proposal for standardising nomenclature

Objective Interval colorectal cancers (interval CRCs), that is, cancers occurring after a negative screening test or examination, are an important indicator of the quality and effectiveness of CRC screening and surveillance. In order to compare incidence rates of interval CRCs across screening programmes, a standardised definition is required. Our goal was to develop an internationally applicable definition and taxonomy for reporting on interval CRCs. Design Using a modified Delphi process to achieve consensus, the Expert Working Group on interval CRC of the Colorectal Cancer Screening Committee of the World Endoscopy Organization developed a nomenclature for defining and characterising interval CRCs. Results We define an interval CRC as a “colorectal cancer diagnosed after a screening or surveillance exam in which no cancer is detected, and before the date of the next recommended exam”. Guidelines and principles for describing and reporting on interval CRCs are provided, and clinical scenarios to demonstrate the practical application of the nomenclature are presented. Conclusions The Working Group on interval CRC of the World Endoscopy Organization endorses adoption of this standardised nomenclature. A standardised nomenclature will facilitate benchmarking and comparison of interval CRC rates across programmes and regions.
The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice

Background and aims Gata6 is required to complete and maintain acinar differentiation in the mouse pancreas. Pancreas-specific Gata6 ablation during development causes extensive and persistent acinar-ductal metaplasia, which is considered an initial step of mutant KRas-driven carcinogenesis. Therefore, the Gata6-null pancreas might represent a tumour-prone environment. We investigated whether Gata6 plays a role during pancreatic tumorigenesis. Design We analysed genetically engineered mouse models and human pancreatic ductal adenocarcinoma (PDAC) cell lines, using a combination of histopathological studies, genome-wide expression and chromatin immunoprecipitation experiments to understand the role of Gata6 in the initiation and progression of KRasG12V-driven tumours Results We show that Gata6 maintains the acinar differentiation programme, both directly and indirectly, and it concomitantly suppresses ectopic programmes in the pancreas. Gata6 ablation renders acinar cells more sensitive to KRasG12V, thereby accelerating tumour development. Gata6 expression is spontaneously lost in a mouse model of KRasG12V-driven PDAC, in association with altered cell differentiation. Using a combination of ChIP-Seq and RNA-Seq, we show that Gata6 exerts its tumour-suppressive effect through the promotion of cell differentiation, the suppression of inflammatory pathways, and the direct repression of cancer-related pathways. Among them is the epidermal growth factor receptor (EGFR) pathway, the activity of which is upregulated in the normal and preneoplastic Gata6-null pancreas. Accordingly, GATA6-silencing in human PDAC cells leads to an upregulation of EGFR. Conclusions We propose that, in the pancreas, Gata6 acts as a tumour suppressor by enforcing acinar cell differentiation, by directly and indirectly repressing ectopic differentiation programmes, and by regulating crucial cancer-related gene expression pathways.
Correlates of Delay in Seeking Treatment for Endometrial Cancer

In endometrial cancer, early detection is usually facilitated by the onset of abnormal bleeding: Despite this, patients at times evidence considerable delay between onset of abnormal bleeding and seeking medical care. The current study of 37 endometrial cancer patients used semi-structured interviews and questionnaires to evaluate physical, interpersonal, and psychological factors which might be associated with delay in seeking care. Results indicated that women typically delayed between 1 and 4 months before seeking medical care. They generally attributed the causes of the abnormal bleeding to 1 of 3 factors: the menopause, benign bodily dysfunctions, or unusual and alarming processes, including cancer. Those who blamed menopause delayed significantly longer in seeking treatment, while those who reported being alarmed by early symptoms were significantly more likely to seek immediate care. Marital dissatisfaction and a lack of unconditionally positive emotional support was also significantly related to d.