bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous targeting of XPO1 and BCL2 as an effective treatment strategy for double-hit lymphoma
Authors: Liu Yuanhui , Azizian Nancy G. , Dou Yaling , Pham Lan V. , Li Yulin 
Published: November 2019

AbstractDouble-hit lymphoma (DHL) is among the most aggressive and chemoresistant lymphoma subtypes. DHLs carry genomic abnormalities in MYC, BCL2, and/or BCL6 oncogenes. Due to the simultaneous overexpression of these driver oncogenes, DHLs are highly resistant to frontline therapies. Most DHLs overexpress both MYC and BCL2 driver oncogenes concurrently. We reasoned that simultaneous suppression of the two driver oncogenes would be more effective in eradicating DHLs than inactivation of single oncogene. XPO1 is a receptor for nuclear cytoplasmic transport of protein and RNA species. Recently, XPO1 inhibition was shown to downregulate MYC expression in several cancer cell lines. We therefore examined the role of XPO1 as a therapeutic target in suppressing MYC function and the potential synergistic effects of simultaneous suppression of XPO1 and BCL2 in the treatment of DHL. Here, we demonstrate that XPO1 inhibition abrogates MYC protein expression and induces massive tumor cell apoptosis. Combined use of XPO1 and BCL2 inhibitors is highly effective in eradicating DHL cells in cell culture. Notably, in a mouse model of DHL bearing primary tumor cells derived from lymphoma patients, combined treatment with XPO1 and BCL2 inhibitors blocks tumor progression, prevents brain metastasis, and extends host survival. Thus, our study confirms the simultaneous targeting of MYC and BCL2 driver oncogenes through the combined use of XPO1 and BCL2 inhibitors as a unique approach for the treatment of DHLs.
Effects of inspiratory flow on lung stress, pendelluft, and ventilation heterogeneity in ARDS: a physiological study
Authors: Santini Alessandro , Mauri Tommaso , Dalla Corte Francesca , Spinelli Elena , Pesenti Antonio 
Published: November 2019

AbstractBackgroundHigh inspiratory flow might damage the lungs by mechanisms not fully understood yet. We hypothesized that increasing inspiratory flow would increase lung stress, ventilation heterogeneity, and pendelluft in ARDS patients undergoing volume-controlled ventilation with constant tidal volume and that higher PEEP levels would reduce this phenomenon.MethodsTen ARDS patients were studied during protective volume-controlled ventilation. Three inspiratory flows (400, 800, and 1200 ml/s) and two PEEP levels (5 and 15 cmH2O) were applied in random order to each patient. Airway and esophageal pressures were recorded, end-inspiratory and end-expiratory holds were performed, and ventilation distribution was measured with electrical impedance tomography. Peak and plateau airway and transpulmonary pressures were recorded, together with the airway and transpulmonary pressure corresponding to the first point of zero end-inspiratory flow (P1). Ventilation heterogeneity was measured by the EIT-based global inhomogeneity (GI) index. Pendelluft was measured as the absolute difference between pixel-level inflation measured at plateau pressure minus P1.ResultsPlateau airway and transpulmonary pressure was not affected by inspiratory flow, while P1 increased at increasing inspiratory flow. The difference between P1 and plateau pressure was higher at higher flows at both PEEP levels (p < 0.001). While higher PEEP reduced heterogeneity of ventilation, higher inspiratory flow increased GI (p = 0.05), irrespective of the PEEP level. Finally, gas volume undergoing pendelluft was larger at higher inspiratory flow (p < 0.001), while PEEP had no effect.ConclusionsThe present exploratory analysis suggests that higher inspiratory flow increases additional inspiratory pressure, heterogeneity of ventilation, and pendelluft while PEEP has negligible effects on these flow-dependent phenomena. The clinical significance of these findings needs to be further clarified.
Outcomes of Stenotrophomonas maltophilia hospital-acquired pneumonia in intensive care unit: a nationwide retrospective study
Authors:   AZUREA research network, Guerci Philippe , Bellut Hugo , Mokhtari Mokhtar , Gaudefroy Julie , Mongardon Nicolas , Charpentier Claire , Louis Guillaume , Tashk Parvine , Dubost Clément , Ledochowski Stanislas , Kimmoun Antoine , Godet Thomas , Pottecher Julien , Lalot Jean-Marc , Novy Emmanuel , Hajage David , Bouglé Adrien 
Published: November 2019

Abstract
Background
There is little descriptive data on Stenotrophomonas maltophilia hospital-acquired pneumonia (HAP) in critically ill patients. The optimal modalities of antimicrobial therapy remain to be determined. Our objective was to describe the epidemiology and prognostic factors associated with S. maltophilia pneumonia, focusing on antimicrobial therapy.

Methods
This nationwide retrospective study included all patients admitted to 25 French mixed intensive care units between 2012 and 2017 with hospital-acquired S. maltophilia HAP during intensive care unit stay. Primary endpoint was time to in-hospital death. Secondary endpoints included microbiologic effectiveness and antimicrobial therapeutic modalities such as delay to appropriate antimicrobial treatment, mono versus combination therapy, and duration of antimicrobial therapy.

Results
Of the 282 patients included, 84% were intubated at S. maltophilia HAP diagnosis for duration of 11 [5–18] days. The Simplified Acute Physiology Score II was 47 [36–63], and the in-hospital mortality was 49.7%. Underlying chronic pulmonary comorbidities were present in 14.1% of cases. Empirical antimicrobial therapy was considered effective on S. maltophilia according to susceptibility patterns in only 30% of cases. Delay to appropriate antimicrobial treatment had, however, no significant impact on the primary endpoint. Survival analysis did not show any benefit from combination antimicrobial therapy (HR = 1.27, 95%CI [0.88; 1.83], p = 0.20) or prolonged antimicrobial therapy for more than 7 days (HR = 1.06, 95%CI [0.6; 1.86], p = 0.84). No differences were noted in in-hospital death irrespective of an appropriate and timely empiric antimicrobial therapy between mono- versus polymicrobial S. maltophilia HAP (p = 0.273). The duration of ventilation prior to S. maltophilia HAP diagnosis and ICU length of stay were shorter in patients with monomicrobial S. maltophilia HAP (p = 0.031 and p = 0.034 respectively).

Conclusions
S. maltophilia HAP occurred in severe, long-stay intensive care patients who mainly required prolonged invasive ventilation. Empirical antimicrobial therapy was barely effective while antimicrobial treatment modalities had no significant impact on hospital survival.

Trial registration
clinicaltrials.gov, NCT03506191
Respective contribution of intensive care unit-acquired limb muscle and severe diaphragm weakness on weaning outcome and mortality: a post hoc analysis of two cohorts
Authors: Dres Martin , Jung Boris , Molinari Nicolas , Manna Federico , Dubé Bruno-Pierre , Chanques Gerald , Similowski Thomas , Jaber Samir , Demoule Alexandre 
Published: November 2019

Abstract
Background
Intensive care unit (ICU)-acquired weakness (ICU-AW) and ICU-acquired diaphragm dysfunction (ICU-DD) occur frequently in mechanically ventilated (MV) patients. It is unknown whether they have different risk factors and different impacts on outcome. This study was designed to (1) describe the respective risk factors associated with ICU-AW and severe ICU-DD and (2) evaluate the respective impact of ICU-AW and severe ICU-DD on outcome.

Methods
Post hoc analysis of two prospective cohort studies conducted in two ICUs. In patients mechanically ventilated for at least 24 h undergoing a first spontaneous breathing trial, severe ICU-DD was defined as diaphragm twitch pressure < 7 cmH2O and ICU-AW was defined as Medical Research Council Score < 48.

Results
One hundred sixteen patients were assessed. Factors independently associated with severe ICU-DD were age, longer duration of MV, and exposure to sufentanil, and those factors associated with ICU-AW were longer duration of MV and exposure to norepinephrine. Severe ICU-DD (OR 3.56, p = 0.008), but not ICU-AW, was independently associated with weaning failure (59%). ICU-AW (OR 4.30, p = 0.033), but not severe ICU-DD, was associated with ICU mortality. Weaning failure and mortality rate were higher in patients with both severe ICU-DD and ICU-AW (86% and 39%, respectively) than in patients with either severe ICU-DD (64% and 0%) or ICU-AW (63% and 13%).

Conclusion
Severe ICU-DD and ICU-AW have different risk factors and different impacts on weaning failure and mortality. The impact of the combination of ICU-DD and ICU-AW is more pronounced than their individual impact.
Host factors associated with Giardia duodenalis infection in dogs across multiple diagnostic tests
Authors: Uiterwijk Mathilde , Nijsse Rolf , Kooyman Frans N. J. , Wagenaar Jaap A. , Mughini-Gras Lapo , Ploeger Harm W. 
Published: November 2019

Abstract
Background
The aim of this study was to assess potential associations between Giardia duodenalis infection in dogs, as determined by three diagnostic tests, and dog’s group of origin, fecal consistency, age, sex, neuter status, and co-infections with other gastrointestinal parasites.

Methods
Fecal samples from 1291 dogs from four groups (household, shelter, hunting and clinical dogs) were tested with qPCR, rapid enzyme immunochromatographic assay (IDEXX SNAP®Giardia), and direct immunofluorescence (DFA, Merifluor) for presence of G. duodenalis. Moreover, fecal samples were tested with centrifugation sedimentation flotation (CSF) coproscopical analysis for presence of gastrointestinal parasites. Associations were expressed as odds ratios (ORs).

Results
Several significant associations were found, of which a few were consistent for all three tests and Giardia positivity in general (positive with at least one of these tests). Dogs older than one year were significantly less likely to test positive for Giardia than younger dogs. Group-housed dogs, especially hunting dogs, were significantly more likely to test positive for Giardia compared to household and clinical dogs. A consistently significant association with Trichuris appeared to be driven by the high prevalence in hunting dogs. Although there was no significant association between loose stool and Giardia infection in the overall population, household dogs were significantly more likely to test Giardia-positive when having loose stool. Overall, Giardia-positive dogs with loose stool shed significantly more cysts, both determined semi-quantitatively with CSF and quantitatively by qPCR, than positive dogs with no loose stool. When other gastrointestinal parasites were present, significantly fewer cysts were detected with CSF, but this was not confirmed with qPCR.

Conclusion
Giardia is the most common gastrointestinal parasite in Dutch dogs, except for hunting dogs, in which Trichuris and strongyle-type eggs (hookworms) prevailed. Giardia infection was not significantly associated with loose stool, except for household dogs. Young dogs and group-housed dogs were significantly more often Giardia-positive. These associations were consistent across diagnostic tests. Young dogs, clinical dogs and dogs with loose stool shed Giardia cysts in the highest numbers. If another gastrointestinal parasite was present lower numbers of cysts were observed by microscope (CSF), but not with a molecular method (qPCR).
Is ‘likely pathogenic’ really 90% likely? Reclassification data in ClinVar
Authors: Harrison Steven M. , Rehm Heidi L. 
Published: November 2019

AbstractIn 2015, professional guidelines defined the term ‘likely pathogenic’ to mean with a 90% chance of pathogenicity. To determine whether current practice reflects this definition, ClinVar classifications were tracked from 2016 to 2019. During that period, between 83.8 and 99.1% of likely pathogenic classifications were reclassified as pathogenic, depending on whether LP to VUS reclassifications are included and on how these classifications are categorized.
Physical, behavioral and sociodemographic determinants of hypertension among the adult population in Nekemte town, western Ethiopia: community based study
Authors: Geleta Gemechis Teshome , Cheme Melese Chego , Roro Elias Merdassa 
Published: November 2019

Abstract
Objectives
Hypertension is a growing public health problem in many developing countries. However, there is an insufficiency of scientific evidence on the prevalence of hypertension (HTN) at a community level in the study area. The aim of the study was exploring the prevalence and associated factors of hypertension among adults in Nekemte town, Ethiopia. A community-based cross-sectional study was conducted on 711 adults who were selected by the multistage sampling procedure. Height, weight, blood pressure and waist circumference were measured with standard procedures. Data were analyzed by statistical package for social sciences (SPSS) version 20, and multiple logistic regression model was used to determine the independent risk factors for hypertension.

Result
The overall prevalence of hypertension was 34.9% among the adult population. Of them, only 52.7% know their status, and 22.4% were on antihypertensive medication. The prevalence of hypertension was higher among the older aged; AOR 5.85 (95% CI 1.74–20), Obese and over-weighted; (AOR 1.71 (95% CI 1.09–2.67)), Khat chewers in the past year; AOR 2.44 (95% CI 1.05–5.68), and with higher formal education (college and above); AOR 2.75 (95% CI 1.26–6.03) than their respective counterparts. Community-level prevention and treatment of hypertension should get due attention.
Measles outbreak investigation in Artuma Fursi Woreda, Oromia Zone, Amhara Region, Ethiopia, 2018: a case control study
Authors: Tariku Mengistie Kassahun , Misikir Sewnet Wongiel 
Published: November 2019

Abstract
Objective
To confirm the existence of Outbreak, describe cases in person, place and time, and identify determinants of the outbreak. Unmatched case control study in the ratio of 1:4 (38 cases and 152 controls) was conducted in Artuma Fursi Woreda from July 13 to August 1/2018. Data were collected with standard questionnaires. Collected data were entered into Epi Info version 7 and exported to Statistical package for social science (SPSS) version 23 for analysis.

Results
A total of 38 cases and 1 death with attack rate and case fatality rate 11.8/100,000 and 2.6%, respectively. All study participants had not vaccination history. Females and age group 5–14 were more affected. Being 5–14 years old versus (vs) ≥ 15 years [adjusted odd ratio (AOR) = 3.53; 95% CI 1.52–8.45)], contact with cases vs no contact with cases [AOR = 2.78; 95% CI 1.23–8.67] and travel history 7–18 days prior onset of illness vs no travel history [AOR = 2.53; 95% CI 1.31–7.24] were significantly associated with contracting measles. Routine and supplement immunization should be strengthened to reduce future occurrence of outbreak.
Genetic variants in humanin nuclear isoform gene regions show no association with coronary artery disease
Authors: Eltermaa Mall , Jakobson Maili , Utt Meeme , Kõks Sulev , Mägi Reedik , Starkopf Joel 
Published: November 2019

Abstract
Objective
Coronary artery disease contributes to noncommunicable disease deaths worldwide. In order to make preventive methods more accurate, we need to know more about the development and progress of this pathology, including the genetic aspects. Humanin is a small peptide known for its cytoprotective and anti-apoptotic properties. Our study looked for genomic associations between humanin-like nuclear isoform genes and coronary artery disease using CARDIoGRAMplusC4D Consortium data.

Results
Lookup from meta-analysis datasets gave single nucleotide polymorphisms in all 13 humanin-like nuclear isoform genes with the lowest P value for rs6151662 from the MTRNR2L2 gene including the 50 kb flanking region in both directions (P-value = 0.0037). Within the gene region alone the top variant was rs78083998 from the MTRNR2L13 region (meta-analysis P-value = 0.042). None of the found associations were statistically significant after correction for multiple testing. Lookup for expression trait loci in these gene regions gave no statistically significant variants.
Whole blood vs PBMC: compartmental differences in gene expression profiling exemplified in asthma
Authors: He Daniel , Yang Chen Xi , Sahin Basak , Singh Amrit , Shannon Casey P. , Oliveria John-Paul , Gauvreau Gail M. , Tebbutt Scott J. 
Published: November 2019

Abstract
Background
Blood has proven to be a useful resource for molecular analysis in numerous biomedical studies, with peripheral blood mononuclear cells (PBMCs) and whole blood being the major specimen types. However, comparative analyses between these two major compartments (PBMCs and whole blood) are few and far between. In this study, we compared gene expression profiles of PBMCs and whole blood samples obtained from research subjects with or without mild allergic asthma.

Methods
Whole blood (PAXgene) and PBMC samples were obtained from 5 mild allergic asthmatics and 5 healthy controls. RNA from both sample types was measured for expression of 730 immune-related genes using the NanoString nCounter platform.

Results
We identified 64 uniquely expressed transcripts in whole blood that reflected a variety of innate, humoral, and adaptive immune processes, and 13 uniquely expressed transcripts in PBMCs which were representative of T-cell and monocyte-mediated processes. Furthermore, analysis of mild allergic asthmatics versus non-asthmatics revealed 47 differentially expressed transcripts in whole blood compared to 1 differentially expressed transcript in PBMCs (FDR < 0.25). Finally, through simultaneous measurement of PBMC proteins on the nCounter assay, we identified CD28 and OX40 (TNFRSF4), both of which are critical co-stimulatory molecules during T-cell activation, as significantly upregulated in asthmatics.

Conclusions
Whole blood RNA preserved in PAXgene tubes is excellent for producing gene expression data with minimal variability and good sensitivity, suggesting its utility in multi-centre studies requiring measurement of blood gene expression.
A novel mutation in NCF2 resulting in very-early-onset colitis and juvenile idiopathic arthritis in a patient with chronic granulomatous disease
Authors: AlKhater Suzan 
Published: November 2019

AbstractBackgroundChronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease primarily presents with recurrent infections, and patients may also present with inflammatory conditions, including noninfectious colitis, and an increased frequency of autoimmunity. We report here a patient with CGD in whom the presentation, unlike the classical presentation of CGD, was predominantly of an inflammatory and autoimmune phenotype.Case presentationA 3-year-old Pakistani female presented with bloody diarrhea since the age of 7 days, followed by the development of perianal abscesses and fistula. There was no other history of recurrent infections. The patient subsequently developed joint pain and stiffness with persistently elevated inflammatory markers and elevated anti-cyclic citrullinate peptide (anti-CCP) antibody titer. She was diagnosed with oligoarticular juvenile idiopathic arthritis and colitis. The diagnosis of CGD was later made and was based on the absence of NADPH oxidase activity in the patient’s neutrophils upon phorbol myristate acetate (PMA) stimulation using the dihydrorhodamine-1,2,3 (DHR) flow cytometry test. Targeted next-generation sequencing revealed an unreported deletion mutation in exon 10 as a homozygous loss-of-function variant of the human neutrophil oxidase factor 2 (NCF2) (NCF2: NM_001190789, nucleotide change: c.855_856del:p.T285fs). The gene encodes a protein subunit, p67phox, in the NADPH enzyme complex.ConclusionsThe case emphasizes the importance of maintaining high clinical suspicion of immunodeficiency and CGD in patients with very-early-onset colitis and autoimmune disorders. This case is important due to its rarity and because it might represent a previously undiscovered mutation, which is possibly more common in the patient’s ethnic group. Other mutations inNCF2have been linked to inflammatory bowel disease and autoimmunity, but without CGD, suggesting similarities in the pathogenesis.
Association between methylation in nasal epithelial TSLP gene and chronic rhinosinusitis with nasal polyps
Authors: Li Jingyun , Jiao Jian , Gao Yunbo , Zhang Yuan , Zhang Luo 
Published: November 2019

Abstract
Background
This study was performed to determine whether there was any association between abnormal DNA methylation of a thymic stromal lymphopoietin (TSLP) locus and pathogenesis of chronic rhinosinusitis (CRS).

Methods
A total of 48 CRS patients with nasal polyps (CRSwNP), 28 CRS patients without nasal polyps (CRSsNP) and 21 control subjects were enrolled into the study; and evaluated for serum total IgE level, olfactory score and nasal resistance. Samples were obtained from nasal polyps of CRSwNP patients, ethmoid mucosae of CRSsNP patients and inferior turbinate (IT) mucosa of control subjects during surgery, and used to isolate purified primary human nasal epithelial cells (HNECs). Genomic DNA was extracted from purified primary HNECs of each subject and DNA methylation ratios for a selected region of the TSLP gene were screened the using MassARRAY EpiTYPER.

Results
A total of 17 CpG units were analyzed; of which two CpG units (CpG3 and 22:23:24) had increased methylation ratios in the CRSwNP patients compared to the CRSsNP and control subjects after correction for false discovery rate (FDR) (Q < 0.1). The methylation ratios at both CpG3 and CpG22:23:24 units were positively correlated with olfactory score (r = 0.41, P = 0.0001; r = 0.25, P = 0.021) and unilateral nasal resistance at 75 Pa (r = 0.24, P = 0.04; r = 0.24, P = 0.036) and 150 Pa (r = 0.34, P = 0.004; r = 0.25, P = 0.031). Total nasal resistance at 75 Pa/150 Pa or serum total IgE levels were not correlated with the methylation ratios at either CpG unit.

Conclusions
Increased DNA methylation at the TSLP locus is likely to be associated with CRSwNP pathogenesis; however these findings need to be confirmed in larger multicentre group studies.
lncRNAs: function and mechanism in cartilage development, degeneration, and regeneration
Authors: Zhu Jian , Yu Wei , Wang Yitian , Xia Kaishun , Huang Yuluan , Xu Ankai , Chen Qixin , Liu Bing , Tao Huimin , Li Fangcai , Liang Chengzhen 
Published: November 2019

AbstractWith the increasing incidence of cartilage-related diseases such as osteoarthritis (OA) and intervertebral disc degeneration (IDD), heavier financial and social burdens need to be faced. Unfortunately, there is no satisfactory clinical method to target the pathophysiology of cartilage-related diseases. Many gene expressions, signaling pathways, and biomechanical dysregulations were involved in cartilage development, degeneration, and regeneration. However, the underlying mechanism was not clearly understood. Recently, lots of long non-coding RNAs (lncRNAs) were identified in the biological processes, including cartilage development, degeneration, and regeneration. It is clear that lncRNAs were important in regulating gene expression and maintaining chondrocyte phenotypes and homeostasis. In this review, we summarize the recent researches studying lncRNAs’ expression and function in cartilage development, degeneration, and regeneration and illustrate the potential mechanism of how they act in the pathologic process. With continued efforts, regulating lncRNA expression in the cartilage regeneration may be a promising biological treatment approach.