bluuebunny/crossref_metadata_2025_split huggingface dataset:
The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome
Authors: Foskolou Iosifina P. , Barbieri Laura , Vernet Aude , Bargiela David , Cunha Pedro P. , Velica Pedro , Suh Eunyeong , Pietsch Sandra , Matuleviciute Rugile , Rundqvist Helene , McIntyre Dominick , Smith Ken G. C. , Johnson Randall S. 
Published: September 2020

Abstract
Cancer immunotherapy is advancing rapidly and gene-modified T cells expressing chimeric antigen receptors (CARs) show particular promise. A challenge of CAR-T cell therapy is that the ex vivo–generated CAR-T cells become exhausted during expansion in culture, and do not persist when transferred back to patients. It has become clear that naive and memory CD8 T cells perform better than the total CD8 T-cell populations in CAR-T immunotherapy because of better expansion, antitumor activity, and persistence, which are necessary features for therapeutic success and prevention of disease relapse. However, memory CAR-T cells are rarely used in the clinic due to generation challenges. We previously reported that mouse CD8 T cells cultured with the S enantiomer of the immunometabolite 2-hydroxyglutarate (S-2HG) exhibit enhanced antitumor activity. Here, we show that clinical-grade human donor CAR-T cells can be generated from naive precursors after culture with S-2HG. S-2HG–treated CAR-T cells establish long-term memory cells in vivo and show superior antitumor responses when compared with CAR-T cells generated with standard clinical protocols. This study provides the basis for a phase 1 clinical trial evaluating the activity of S-2HG–treated CD19-CAR-T cells in patients with B-cell malignancies.
Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial
Authors: Edalatifard Maryam , Akhtari Maryam , Salehi Mohammadreza , Naderi Zohre , Jamshidi Ahmadreza , Mostafaei Shayan , Najafizadeh Seyed Reza , Farhadi Elham , Jalili Nooshin , Esfahani Masoud , Rahimi Besharat , Kazemzadeh Hossein , Mahmoodi Aliabadi Maedeh , Ghazanfari Tooba , Sattarian Mohammadreza , Ebrahimi Louyeh Hourvash , Raeeskarami Seyed Reza , Jamalimoghadamsiahkali Saeidreza , Khajavirad Nasim , Mahmoudi Mahdi , Rostamian Abdolrahman 
Published: September 2020

IntroductionThere are no determined treatment agents for severe COVID-19. It is suggested that methylprednisolone, as an immunosuppressive treatment, can reduce the inflammation of the respiratory system in COVID-19 patients.MethodsWe conducted a single-blind, randomised controlled clinical trial involving severe hospitalised patients with confirmed COVID-19 at the early pulmonary phase of the illness in Iran. The patients were randomly allocated in a 1:1 ratio by the block randomisation method to receive standard care with methylprednisolone pulse (intravenous injection, 250 mg·day−1for 3 days) or standard care alone. The study end-point was the time of clinical improvement or death, whichever came first. Primary and safety analysis was done in the intention-to-treat (ITT) population.Results68 eligible patients underwent randomisation (34 patients in each group) from April 20, 2020 to June 20, 2020. In the standard care group, six patients received corticosteroids by the attending physician before the treatment and were excluded from the overall analysis. The percentage of improved patients was higher in the methylprednisolone group than in the standard care group (94.1%versus57.1%) and the mortality rate was significantly lower in the methylprednisolone group (5.9%versus42.9%; p<0.001). We demonstrated that patients in the methylprednisolone group had a significantly increased survival time compared with patients in the standard care group (log-rank test: p<0.001; hazard ratio 0.293, 95% CI 0.154–0.556). Two patients (5.8%) in the methylprednisolone group and two patients (7.1%) in the standard care group showed severe adverse events between initiation of treatment and the end of the study.ConclusionsOur results suggest that methylprednisolone pulse could be an efficient therapeutic agent for hospitalised severe COVID-19 patients at the pulmonary phase.
Dexmedetomidine sedation for endobronchial ultrasound-guided transbronchial needle aspiration, a randomised controlled trial
Authors: Lin Ting-Yu , Huang Yu-Chen , Kuo Chih-Hsi , Chung Fu-Tsai , Lin Yu-Ting , Wang Tsai-Yu , Lin Shu-Min , Lo Yu-Lun 
Published: September 2020

Background and aimAppropriate sedation is important to the success of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Dexmedetomidine is a sedative agent that operatesviathe α2 adrenergic agonist, which provides sleep-like sedation with little respiratory suppression. This study compared the efficacy and safety of dexmedetomidine sedation with propofol in cases of EBUS-TBNA.MethodsPatients requiring EBUS-TBNA were randomly assigned dexmedetomidine sedation (D, n=25) or propofol sedation (P, n=25). Vital signs, diagnostic yield and the bispectral index (BIS) were recorded throughout the bronchoscopic procedure and recovery period. The tolerance and cooperation of the patients were evaluated using questionnaires.Measurements and resultsThe lowest mean arterial blood pressure in group D (79.2±9.9versus72.5±12.9 mmHg, p=0.049) exceeded that in group P, the lowest heart rate was lower (60.9±10.2versus71.4±11.8 beats·min−1, p=0.006) and the mean BIS during sedation was significantly higher (84.1±8.3versus73.6±5.7, p<0.001). Patients in group D were more likely to report perceiving procedure-related symptoms and express an unwillingness to undergo the bronchoscopy again, if indicated (41.1versus83.3%, p=0.007). One subject in group D aborted EBUS-TBNA due to intolerance. Many of the variables in the two groups were similar, including the proportion of hypoxaemic events, recovery times, patient cooperation and diagnostic yield.ConclusionsThe effects of dexmedetomidine on haemodynamics were in line with its pharmacodynamic features. Patients who received dexmedetomidine were more likely than those who received propofol to perceive the procedures. Overall, dexmedetomidine did not prove inferior to propofol sedation in terms of patient cooperation or diagnostic yield.
Home invasive mechanical ventilation in Finland in 2015–2019
Authors: Kotanen Petra , Kreivi Hanna-Riikka , Vainionpää Aki , Laaksovirta Hannu , Brander Pirkko , Siirala Waltteri 
Published: September 2020

IntroductionThe prevalence of long-term invasive mechanical ventilationviatracheostomy in chronic respiratory insufficiency is largely unknown. We aimed to clarify prevalence and aetiology of the use of home invasive mechanical ventilation (HIMV) in Finland in 2015–2019.MethodsInformation on HIMV patients was collected yearly from all Finnish Hospital District patient registries between 1 January 2015 and 1 January 2019. Data included underlying diagnosis, time from diagnosis to HIMV initiation, treatment length, mortality and basic sociodemographic data.ResultsIn 2015, we had 107 HIMV patients. During the follow-up we received 34 new patients (24.1%) and 46 patients (32.6%) died. In 2019, we had 95 HIMV patients and the prevalence in Finland was 2.0 in 100 000. The most common diagnoses were motor neurone disease (29.1%) and spinal cord injuries (19.9%). Mean duration of HIMV among all patients on 1 January 2019 was 12.3 years and among deceased patients, 11.2 years. Treatment durations ranged from 7.7 years for motor neurone disease patients to 47.3 years for post-polio syndrome patients. Most patients (81.6%) used HIMV 24 h·day−1.ConclusionsHIMV is a rare, long-lasting treatment, most often used in chronic hypoventilation caused by chronic neurological disease. Based on our 4 year follow-up the prevalence of HIMV seems to be diminishing in Finland. Treatment duration and survival vary greatly depending on the underlying diagnosis. Most of the patients were totally dependent on HIMV, requiring 24-h care.
Moulds andStaphylococcus aureusenterotoxins are relevant allergens to affect Type 2 inflammation and clinical outcomes in chronic rhinosinusitis patients
Authors: Kanemitsu Yoshihiro , Fukumitsu Kensuke , Kurokawa Ryota , Takeda Norihisa , Ozawa Yoshiyuki , Masaki Ayako , Ono Junya , Izuhara Kenji , Yap Jennifer Maries , Nishiyama Hirono , Fukuda Satoshi , Uemura Takehiro , Tajiri Tomoko , Ohkubo Hirotsugu , Maeno Ken , Ito Yutaka , Oguri Tetsuya , Takemura Masaya , Suzuki Motohiko , Niimi Akio 
Published: September 2020

BackgroundSensitisation to moulds andStaphylococcus aureusenterotoxins (SEs) is associated with the pathophysiology of both asthma and chronic rhinosinusitis (CRS). The purpose of this study was to clarify the contribution of sensitisation to these allergens to Type 2 inflammation in the blood, nose and the lower airways, and clinical outcomes in CRS patients.MethodsWe prospectively enrolled 56 CRS patients who underwent endoscopic sinus surgery (ESS) (20 with comorbid asthma) and 28 healthy controls between October 2015 and December 2017. CRS patients were followed up for 12 months after surgery. Type 2 inflammation-related biomarkers were analysed using blood, resected tissue samples and sputum. 10 allergens includingAlternaria,Aspergillusand SEs were measured. Type 2 inflammation-related biomarkers and clinical outcomes were compared in the stratification with the presence or absence of allergen sensitisation.ResultsSensitisation rate to moulds and SEs in asthmatic patients was increased when changing the cut-off value of specific IgE titre from 0.35 UA·mL−1to 0.10 UA·mL−1(1.7- and 4.5-fold, respectively). Moulds and SEs affected the prevalence of asthma and eosinophilic CRS by interacting with each other. All Type 2 inflammation-related biomarkers except for eosinophils in sinus tissue were significantly higher in patients with mould or SE (mould/SE) sensitisation (≥0.10 UA·mL−1) (n=19) than in those without (n=37) and healthy subjects (all p<0.05). Meanwhile, mould/SE sensitisation did not affect longitudinal changes in clinical outcomes after ESS. Changes in serum mould/SE-IgE levels after ESS remained unclear.ConclusionMould/SE sensitisation (≥0.10 UA·mL−1) may affect the development of Type 2 inflammation and clinical outcomes in CRS patients.
Applying a Standardized Approach to Strengthen Performances of GeneXpert Networks programme: lessons learned from Burkina Faso, 2019
Authors: Alagna Riccardo , Sawadogo T. Léon , Tagliani Elisa , Combary Adjima , Cirillo Daniela Maria 
Published: September 2020

GeneXpert scale-up is a historic step in the process of tuberculosis (TB) elimination. However, the global roll-out of the test has highlighted gaps that have limited its impact on the TB care cascade. Here we report the description of an innovative GeneXpert network strengthening tool called Applying a Standardized Approach to Strengthen Performances of GeneXpert Networks (ASAP-GxNet) and highlight results and challenges during implementation of the pilot in Burkina Faso.ASAP-GxNet is a 6-month competency-based programme involving an innovative GeneXpert assessment tool as well as a series of short courses and projects designed to qualitatively improve the network while strengthening the capacity of the national GeneXpert focal point to oversee the network. Progress of the GeneXpert network is measured before and at the end of the programme and is rated using a star system (0 to 4 stars).In Burkina Faso, implementation of the ASAP-GxNet programme resulted in improved management of the national GeneXpert network with a 21% increase in points from the start to the end of the programme.To our knowledge, ASAP-GxNet is the first programme to give an overall picture of the quality of GeneXpert networks and to investigate performance in terms of management behaviour. ASAP-GxNet has been developed to help national TB programmes coordinate efforts and needs and highlights the expected achievements of the GeneXpert network.
Treatable traits qualifying for nonpharmacological interventions in COPD patients upon first referral to a pulmonologist: the COPD sTRAITosphere
Authors: van ’t Hul Alex J. , Koolen Eleonore H. , Antons Jeanine C. , de Man Marianne , Djamin Remco S. , in ’t Veen Johannes C.C.M. , Simons Sami O. , van den Heuvel Michel , van den Borst Bram , Spruit Martijn A. 
Published: September 2020

IntroductionThe present study assessed the prevalence of nine treatable traits (TTs) pinpointing nonpharmacological interventions in patients with COPD upon first referral to a pulmonologist, how these TTs co-occurred and whether and to what extent the TTs increased the odds having a severely impaired health status.MethodsData were collected from a sample of 402 COPD patients. A second sample of 381 patients with COPD was used for validation. Nine TTs were assessed: current smoking status, activity-related dyspnoea, frequent exacerbations <12 months, severe fatigue, depressed mood, poor physical capacity, low physical activity, poor nutritional status and a low level of self-management activation. For each TT the odds ratio (OR) of having a severe health status impairment was calculated. Furthermore, a graphic representation was created, the COPD sTRAITosphere, to visualise TTs prevalence and OR.ResultsOn average 3.9±2.0 TTs per patient were observed. These TTs occurred relatively independently of each other and coexisted in 151 unique combinations. A significant positive correlation was found between the number of TTs and Clinical COPD Questionnaire total score (r=0.58; p<0.001). Patients with severe fatigue (OR: 8.8), severe activity-related dyspnoea (OR: 5.8) or depressed mood (OR: 4.2) had the highest likelihood of having a severely impaired health status. The validation sample corroborated these findings.ConclusionsUpon first referral to a pulmonologist, COPD patients show multiple TTs indicating them to several nonpharmacological interventions. These TTs coexist in many different combinations, are relatively independent and increase the likelihood of having a severely impaired health status.
Short-term survival of acute respiratory distress syndrome patients due to influenza virus infection alone: a cohort study
Authors: Gacouin Arnaud , Lesouhaitier Mathieu , Reizine Florian , Pronier Charlotte , Grégoire Murielle , Painvin Benoit , Maamar Adel , Thibault Vincent , Le Tulzo Yves , Tadié Jean Marc 
Published: September 2020

BackgroundInfluenza virus (IV)-related pathophysiology suggests that the prognosis of acute respiratory distress syndrome (ARDS) due to IV could be different from the prognosis of ARDS due to other causes. However, the impact of IV infection alone on the prognosis of ARDS patients compared to that of patients with other causes of ARDS has been poorly assessed.MethodsWe compared the 28-day survival from the diagnosis of ARDS with an arterial oxygen tension/inspiratory oxygen fraction ratio ≤150 mmHg between patients with and without IV infection alone. Data were collected prospectively and analysed retrospectively. We first performed survival analysis on the whole population; second, patients with IV infection alone were compared with matched pairs using propensity score matching.ResultsThe cohort admitted from October 2009 to March 2020 consisted of 572 patients, including 73 patients (13%) with IV alone. On the first 3 days of mechanical ventilation, nonpulmonary Sequential Organ Failure Assessment scores were significantly lower in patients with IV infection than in the other patients. After the adjusted analysis, IV infection alone remained independently associated with lower mortality at day 28 (hazard ratio 0.51, 95% CI 0.26–0.99, p=0.047). Mortality at day 28 was significantly lower in patients with IV infection alone than in other patients when propensity score matching was used (20%versus38%, p=0.02).ConclusionsOur results suggest that patients with ARDS following IV infection alone have a significantly better prognosis at day 28 and less severe nonpulmonary organ dysfunction than do those with ARDS from causes other than IV infection alone.
Genetic profiling of primary and secondary tumors from patients with lung adenocarcinoma and bone metastases reveals targeted therapy options
Authors: Huang Long , Jiang Xiao-Liu , Liang Hong-Bin , Li Jian-Cheng , Chin Li-Han , Wei Jian-Ping , Wang Rui-Ru , Cai Jing , Xiong Qiang , Wang Lien-Tu , Cram David S. , Liu An-Wen 
Published: September 2020

Abstract
Background
Patients newly diagnosed with lung adenocarcinoma with bone metastases (LABM) have poor survival rates after treatment with conventional therapies. To improve outcomes, we retrospectively investigated whether the application of a more comprehensive genetic test of tumor biopsies samples from LABM patients could provide the basis for treatment with more effective tyrosine kinase inhibitors (TKIs) regimens.

Methods
Fine needle biopsies were taken from the primary tumor (PT) and a secondary bone metastasis (BM) of 17 LABM patients before treatment. Simple genetic profiles for selecting therapies were initially obtained using an ARMS-PCR test for EGFR and ALK fusion mutations. More detailed genetic profiles of somatic exon SNVs and CNVs in 457 cancer-related genes were retrospectively derived using capture single molecule amplification and resequencing technology (capSMART).

Results
ARMS-PCR identified 14 EGFR positive, 3 EGFR negative and 1 ALK fusion positive patient. A therapy regimen incorporating TKIs Gefitinib and Crizotinib was offered to the EGFR and ALK fusion positive patients, respectively. With the exception of two patients, molecular profiling of matching PT and BM biopsies identified a highly shared somatic variant fingerprint, although the BMs exhibited additional genomic instability. In six of 13 EGFR positive patients and in all three EGFR negative patients, examination of the genetic profiles identified additional clinically significant mutations that are known or experimental drug targets for treatment of lung cancer.

Conclusion
Our findings firstly suggest that treatment regimens based on comprehensive genetic assessment of newly diagnosed LABM patients should target both the PT and secondary BMs, including rogue clones with potential to form new BMs. Second, the additional information gained should allow clinicians to design and implement more personalized treatment regimens and potentially improve outcomes for LABM patients.
Prediction of hot spots in protein–DNA binding interfaces based on supervised isometric feature mapping and extreme gradient boosting
Authors: Li Ke , Zhang Sijia , Yan Di , Bin Yannan , Xia Junfeng 
Published: September 2020

Abstract
Background
Identification of hot spots in protein-DNA interfaces provides crucial information for the research on protein-DNA interaction and drug design. As experimental methods for determining hot spots are time-consuming, labor-intensive and expensive, there is a need for developing reliable computational method to predict hot spots on a large scale.

Results
Here, we proposed a new method named sxPDH based on supervised isometric feature mapping (S-ISOMAP) and extreme gradient boosting (XGBoost) to predict hot spots in protein-DNA complexes. We obtained 114 features from a combination of the protein sequence, structure, network and solvent accessible information, and systematically assessed various feature selection methods and feature dimensionality reduction methods based on manifold learning. The results show that the S-ISOMAP method is superior to other feature selection or manifold learning methods. XGBoost was then used to develop hot spots prediction model sxPDH based on the three dimensionality-reduced features obtained from S-ISOMAP.

Conclusion
Our method sxPDH boosts prediction performance using S-ISOMAP and XGBoost. The AUC of the model is 0.773, and the F1 score is 0.713. Experimental results on benchmark dataset indicate that sxPDH can achieve generally better performance in predicting hot spots compared to the state-of-the-art methods.
Meiotic recombination in the offspring of Microbotryum hybrids and its impact on pathogenicity
Authors: Bueker Britta , Guerreiro Marco Alexandre , Hood Michael E. , Brachmann Andreas , Rahmann Sven , Begerow Dominik 
Published: September 2020

Abstract
Background
Hybridization is a central mechanism in evolution, producing new species or introducing important genetic variation into existing species. In plant-pathogenic fungi, adaptation and specialization to exploit a host species are key determinants of evolutionary success. Here, we performed experimental crosses between the two pathogenic Microbotryum species, M. lychnidis-dioicae and M. silenes-acaulis that are specialized to different hosts. The resulting offspring were analyzed on phenotypic and genomic levels to describe genomic characteristics of hybrid offspring and genetic factors likely involved in host-specialization.

Results
Genomic analyses of interspecific fungal hybrids revealed that individuals were most viable if the majority of loci were inherited from one species. Interestingly, species-specific loci were strictly controlled by the species’ origin of the mating type locus. Moreover we detected signs of crossing over and chromosome duplications in the genomes of the analyzed hybrids. In Microbotryum, mitochondrial DNA was found to be uniparentally inherited from the a2 mating type. Genome comparison revealed that most gene families are shared and the majority of genes are conserved between the two species, indicating very similar biological features, including infection and pathogenicity processes. Moreover, we detected 211 candidate genes that were retained under host-driven selection of backcrossed lines. These genes and might therefore either play a crucial role in host specialization or be linked to genes that are essential for specialization.

Conclusion
The combination of genome analyses with experimental selection and hybridization is a promising way to investigate host-pathogen interactions. This study manifests genetic factors of host specialization that are required for successful biotrophic infection of the post-zygotic stage, but also demonstrates the strong influence of intra-genomic conflicts or instabilities on the viability of hybrids in the haploid host-independent stage.