bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alpha-1 antitrypsin deficiency: clarifying the role of the putative protective threshold
Authors: Franciosi Alessandro N. , Fraughen Daniel , Carroll Tomás P. , McElvaney Noel G. 
Published: June 2021

Alpha-1 antitrypsin deficiency (AATD) is the only readily identifiable monogenic cause of COPD. To date the only condition-specific treatment for AATD-associated COPD is weekly administration of intravenous plasma-purified human alpha-1 antitrypsin (IV-AAT). Uncertainties regarding which AATD genotypes should benefit from IV-AAT persist. IV-AAT is costly and involves weekly administration of a plasma product. Much of the risk stratification has been centred around the long-accepted hypothesis of a “putative protective threshold” of 11 µM (0.57 g·L−1) AAT in serum. This hypothesis has become central to the paradigm of AATD care, although its derivation and accuracy for defining risk of disease remain unclear.We reviewed the literature and examined the association between the 11 µM threshold and clinical outcomes to provide context and insight into the issues surrounding this topic.We found no data demonstrating an increased risk of COPD dependent on the 11 µM threshold. Moreover, an abundance of recent clinical data examining this threshold refutes the hypothesis. Conversely, the use of 11 µM as a treatment target in appropriate ZZ individuals is supported by clinical evidence, although more refined dosing regimens are being explored.Continued use of the 11 µM threshold as a determinant of clinical risk is questionable, perpetuates inappropriate AAT-augmentation practices, may drive increased healthcare expenditure and should not be used as an indicator for commencing treatment.Genotype represents a more proven indicator of risk, with ZZ and rare ZZ-equivalent genotypes independently associated with COPD. New and better risk assessment models are needed to provide individuals diagnosed with AATD with reliable risk estimation and optimised treatment goals.
Prognostic factors for adverse outcomes in patients with COVID-19: a field-wide systematic review and meta-analysis
Authors: Bellou Vanesa , Tzoulaki Ioanna , van Smeden Maarten , Moons Karel G.M. , Evangelou Evangelos , Belbasis Lazaros 
Published: June 2021

IntroductionThe individual prognostic factors for coronavirus disease 2019 (COVID-19) are unclear. For this reason, we aimed to present a state-of-the-art systematic review and meta-analysis on the prognostic factors for adverse outcomes in COVID-19 patients.MethodsWe systematically reviewed PubMed from 1 January 2020 to 26 July 2020 to identify non-overlapping studies examining the association of any prognostic factor with any adverse outcome in patients with COVID-19. Random-effects meta-analysis was performed, and between-study heterogeneity was quantified using I2statistic. Presence of small-study effects was assessed by applying the Egger's regression test.ResultsWe identified 428 eligible articles, which were used in a total of 263 meta-analyses examining the association of 91 unique prognostic factors with 11 outcomes. Angiotensin-converting enzyme inhibitors, obstructive sleep apnoea, pharyngalgia, history of venous thromboembolism, sex, coronary heart disease, cancer, chronic liver disease, COPD, dementia, any immunosuppressive medication, peripheral arterial disease, rheumatological disease and smoking were associated with at least one outcome and had >1000 events, p<0.005, I2<50%, 95% prediction interval excluding the null value, and absence of small-study effects in the respective meta-analysis. The risk of bias assessment using the Quality in Prognosis Studies tool indicated high risk of bias in 302 out of 428 articles for study participation, 389 articles for adjustment for other prognostic factors and 396 articles for statistical analysis and reporting.ConclusionsOur findings could be used for prognostic model building and guide patient selection for randomised clinical trials.
Diffusing capacity of the lung for carbon monoxide: association with long-term outcomes after lung transplantation in a 20-year longitudinal study
Authors: Darley David Ross , Ma Jin , Huszti Ella , Ghany Rasheed , Hutcheon Michael , Chow Chung-Wai , Tikkanen Jussi , Keshavjee Shaf , Singer Lianne Gail , Martinu Tereza 
Published: June 2021

RationaleThe diffusing capacity of the lung for carbon monoxide corrected for haemoglobin (DLCOcor) measures gas movement across the alveolar–capillary interface. We hypothesised thatDLCOcoris a sensitive measure of injurious allograft processes disrupting this interface.ObjectivesTo determine the prognostic significance of theDLCOcortrajectory on chronic lung allograft dysfunction (CLAD) and survival.MethodsA retrospective analysis was conducted of all bilateral lung transplant recipients at a single centre, between January 1998 and January 2018, with one or moreDLCOcormeasurements. Low baselineDLCOcorwas defined as the failure to achieve aDLCOcor>75% predicted. Drops inDLCOcorwere defined as >15% below recent baseline.Results1259 out of 1492 lung transplant recipients were included. The median (range) time to peakDLCOcorwas 354 (181–737) days and the mean±sdDLCOcorwas 80.2±21.2% pred. Multivariable analysis demonstrated that low baselineDLCOcorwas significantly associated with death (hazrd ratio (HR) 1.68, 95% CI 1.27–2.20; p<0.001). Low baselineDLCOcorwas not independently associated with CLAD after adjustment for low baseline forced expiratory volume in 1 s or forced vital capacity. AnyDLCOcordeclines ≥15% were significantly associated with death, independent of concurrent spirometric decline. Lower percentage predictedDLCOcorvalues at CLAD onset were associated with shorter post-CLAD survival (HR 0.75 per 10%-unit change, p<0.01).ConclusionLow baselineDLCOcorand post-transplant declines inDLCOcorwere significantly associated with survival, independent of spirometric measurements. We propose thatDLCOcortesting may allow identification of a subphenotype of baseline and chronic allograft dysfunction not captured by spirometry. There may be benefit in routine monitoring ofDLCOcorafter lung transplantation to identify patients at risk of poor outcomes.
Genetically increased circulating FUT3 level leads to reduced risk of idiopathic pulmonary fibrosis: a Mendelian randomisation study
Authors: Nakanishi Tomoko , Cerani Agustin , Forgetta Vincenzo , Zhou Sirui , Allen Richard J. , Leavy Olivia C. , Koido Masaru , Assayag Deborah , Jenkins R. Gisli , Wain Louise V. , Yang Ivana V. , Lathrop G. Mark , Wolters Paul J. , Schwartz David A. , Richards J. Brent 
Published: June 2021

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF.MethodsTo identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments, we used genetic determinants of circulating proteins which residecisto the encoded gene (cis-single nucleotide polymorphisms (SNPs)), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalisation analyses to ensure that both the circulating proteins and IPF shared a common genetic signal.ResultsMR analyses of 834 proteins found that a 1 sdincrease in circulating galactoside 3(4)-l-fucosyltransferase (FUT3) and α-(1,3)-fucosyltransferase 5 (FUT5) was associated with a reduced risk of IPF (OR 0.81, 95% CI 0.74–0.88; p=6.3×10−7and OR 0.76, 95% CI 0.68–0.86; p=1.1×10−5, respectively). Sensitivity analyses including multiplecis-SNPs provided similar estimates both for FUT3 (inverse variance weighted (IVW) OR 0.84, 95% CI 0.78–0.91; p=9.8×10−6and MR-Egger OR 0.69, 95% CI 0.50–0.97; p=0.03) and FUT5 (IVW OR 0.84, 95% CI 0.77–0.92; p=1.4×10−4and MR-Egger OR 0.59, 95% CI 0.38–0.90; p=0.01). FUT3 and FUT5 signals colocalised with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%, respectively. Further transcriptomic investigations supported the protective effects ofFUT3for IPF.ConclusionsAn efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.
Lung function trajectory and biomarkers in the Tasmanian Longitudinal Health Study
Authors: Bui Dinh S. , Agusti Alvar , Walters Haydn , Lodge Caroline , Perret Jennifer L. , Lowe Adrian , Bowatte Gayan , Cassim Raisa , Hamilton Garun S. , Frith Peter , James Alan , Thomas Paul S. , Jarvis Debbie , Abramson Michael J. , Faner Rosa , Dharmage Shyamali C. 
Published: June 2021

Background and objectiveDifferent lung function trajectories through life can lead to COPD in adulthood. This study investigated whether circulating levels of biomarkers can differentiate those with accelerated (AD) from normal decline (ND) trajectories.MethodsThe Tasmanian Longitudinal Health Study (TAHS) is a general population study that measured spirometry and followed up participants from ages 7 to 53 years. Based on their forced expiratory volume in 1 s (FEV1) trajectories from age 7 to 53 years, this analysis included those with COPD at age 53 years (60 with AD and 94 with ND) and controls (n=720) defined as never-smokers with an average FEV1trajectory. Circulating levels of selected biomarkers determined at 53 and 45 years of age were compared between trajectories.ResultsResults showed that CC16 levels (an anti-inflammatory protein) were lower and C-reactive protein (CRP) (a pro-inflammatory marker) higher in the AD than in the ND trajectory. Higher CC16 levels were associated with a decreased risk of belonging to the AD trajectory (OR=0.79 (0.63–0.98) per unit increase) relative to ND trajectory. Higher CRP levels were associated with an increased risk of belonging to the AD trajectory (OR=1.07, 95% CI: 1.00–1.13, per unit increase). Levels of CC16 (area under the curve (AUC)=0.69, 95% CI: 0.56–0.81, p=0.002), CRP (AUC=0.63, 95% CI: 0.53–0.72, p=0.01) and the combination of both (AUC=0.72, 95% CI: 0.60–0.83, p<0.001) were able to discriminate between the AD and ND trajectories. Other quantified biomarkers (interleukin (IL)-4, IL-5, IL-6, IL-10 and tumour necrosis factor-α (TNF-α)) were not significantly different between AD, ND and controls.ConclusionsCirculating levels of CRP and CC16 measured in late adulthood identify different lung function trajectories (ADversusND) leading to COPD at age 53 years.
Upper airway symptoms associate with the eosinophilic phenotype of COPD
Authors: Obling Nicolai , Backer Vibeke , Hurst John R. , Bodtger Uffe 
Published: June 2021

BackgroundThere is growing evidence that upper airway symptoms coexist with lower airway symptoms in COPD. Still, the prevalence and impact of upper airway disease on the nature and course of COPD remain unclear. We aimed to describe this in a cross-sectional study.MethodsWe examined a cohort of COPD patients with pulmonary function tests, induced sputum, blood eosinophils, atopy tests and computed tomography (CT) of the paranasal sinuses. Lower airway symptoms were assessed using the COPD Assessment Test (CAT), and upper airway symptoms were assessed using the nasal subdomain of the 22-item Sino Nasal Outcome Test (SNOT22nasal). We recruited patients from five sites in Denmark and Sweden. We excluded patients with a history of asthma.FindingsIn total, 180 patients (female 55%, age 67±8 years, forced expiratory volume in 1 s (FEV1%) 52.4±16.6, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage: A: 18%, B: 54%, C: 3%, D: 25%) were included in the study. Seventy-four patients (41%) reported high upper airway symptoms (UAS, defined as SNOT22nasal≥6) with a median score of 10 (IQR 8–13). Patients with high UAS reported higher CAT scores (17.4±7.5versus14.9±6.6, p<0.05) and displayed higher fractions of eosinophils in blood (median 3.0% (IQR 1.6–4.2%)versus2.3% (IQR 1.4–3.1%), p<0.05) and in induced sputum (median 1.8% (IQR 0.3–7.1%)versusmedian 0.5% (IQR 0–1.7%), p<0.05). No differences in atopy, CT findings or exacerbation rates were observed.ConclusionCOPD patients with upper airway disease showed increased evidence of eosinophilic disease and increased lower airway symptom burden.
Lung diffusing capacity for nitric oxide measured by two commercial devices: a randomised crossover comparison in healthy adults
Authors: Radtke Thomas , de Groot Quintin , Haile Sarah R. , Maggi Marion , Hsia Connie C.W. , Dressel Holger 
Published: June 2021

In Europe, two commercial devices are available to measure combined single-breath diffusing capacity of the lung for nitric oxide (DLNO) and carbon monoxide (DLCO) in one manoeuvre. Reference values were derived by pooling datasets from both devices, but agreement between devices has not been established.We conducted a randomised crossover trial in 35 healthy adults (age 40.0±15.5 years, 51% female) to compareDLNO(primary end-point) between MasterScreen™ (Vyaire Medical, Mettawa, IL, USA) and HypAir (Medisoft, Dinant, Belgium) devices during a single visit under controlled conditions. Linear mixed models were used adjusting for device and period as fixed effects and random intercept for each participant.Difference inDLNObetween HypAir and MasterScreen was 24.0 mL·min−1·mmHg−1(95% CI 21.7–26.3). There was no difference inDLCO(−0.03 mL·min−1·mmHg−1, 95% CI −0.57–0.12) between devices while alveolar volume (VA) was higher on HypAir compared to MasterScreen™ (0.48 L, 95% CI 0.45–0.52). Disparity in the estimation ofVAand the rate of NO uptake (KNO=DLNO/VA) could explain the discrepancy inDLNObetween devices. Disparity in the estimation ofVAand the rate of CO uptake (KCO=DLCO/VA) per unit ofVAoffset each other resulting in negligible discrepancy inDLCObetween devices. Differences in methods of expiratory gas sampling and sensor specifications between devices likely explain these observations.These findings have important implications for derivation ofDLNOreference values and comparison of results across studies. Until this issue is resolved, reference values, established on the respective devices, should be used for test interpretation.
Protocol for long-term effect of pulmonary rehabilitation under nintedanib in idiopathic pulmonary fibrosis
Authors: Nishiyama Osamu , Kataoka Kensuke , Ando Masahiko , Arizono Shinichi , Morino Akira , Nishimura Koichi , Ogawa Tomoya , Shiraki Akira , Watanabe Fumiko , Kozu Ryo , Ogura Takashi , Kondoh Yasuhiro 
Published: June 2021

BackgroundPulmonary rehabilitation causes short-term improvement in exercise capacity, dyspnoea and health-related quality of life in idiopathic pulmonary fibrosis (IPF); however, long-term maintenance of the improvement is difficult. Nintedanib, an antifibrotic drug, has been shown to delay the worsening of pulmonary function in IPF. Therefore, the concomitant use of nintedanib with pulmonary rehabilitation is anticipated to contribute to the long-term maintenance of the pulmonary rehabilitation effects. The long-term effect of pulmonary rehabilitation under nintedanib treatment in IPF (FITNESS) study is a multicenter, randomised, prospective, parallel-group, open-label trial.MethodsThe study will enrol 84 patients with IPF who have been treated with nintedanib. Patients in the pulmonary rehabilitation group will receive a programmed short-term induction pulmonary rehabilitation programme, followed by a maintenance home-based pulmonary rehabilitation programme, while patients in the control group will receive usual outpatient care. Patients in both groups will continue to receive nintedanib treatment throughout the study period. The primary end-point of the study is to compare the change in the 6-min walk distance from the baseline to 12 months between the pulmonary rehabilitation and control groups. The main secondary end-point is endurance exercise time, measured using a bicycle ergometer.DiscussionFITNESS is the first randomised controlled study to evaluate the long-term effects of pulmonary rehabilitation in IPF treated with nintedanib. This study will address the hypothesis that concomitant use of nintedanib contributes to the maintenance of long-term effects of pulmonary rehabilitation, thus leading to a comprehensive therapeutic approach of “nintedanib and pulmonary rehabilitation” in the antifibrotic era.
Clinical relevance of depressed kynurenine pathway in episodic migraine patients: potential prognostic markers in the peripheral plasma during the interictal period
Authors: Tuka Bernadett , Nyári Aliz , Cseh Edina Katalin , Körtési Tamás , Veréb Dániel , Tömösi Ferenc , Kecskeméti Gábor , Janáky Tamás , Tajti János , Vécsei László 
Published: June 2021

AbstractBackgroundAltered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism. Previously, we confirmed that kynurenic acid, an endogenous glutamatergic antagonist, was able to decrease the expression of pituitary adenylate cyclase-activating polypeptide 1–38, a neuropeptide with known migraine-inducing properties. Hence, our aim was to reveal the role of the peripheral kynurenine pathway (KP) in episodic migraineurs. We focused on the complete tryptophan (Trp) catabolism, which comprises the serotonin and melatonin routes in addition to kynurenine metabolites. We investigated the relationship between metabolic alterations and clinical characteristics of migraine patients.MethodsFemale migraine patients aged between 25 and 50 years (n = 50) and healthy control subjects (n = 34) participated in this study. Blood samples were collected from the cubital veins of subjects (during both the interictal/ictal periods in migraineurs,n = 47/12, respectively). 12 metabolites of Trp pathway were determined by neurochemical measurements (UHPLC-MS/MS).ResultsPlasma concentrations of the most Trp metabolites were remarkably decreased in the interictal period of migraineurs compared to healthy control subjects, especially in the migraine without aura (MWoA) subgroup: Trp (p < 0.025), L-kynurenine (p < 0.001), kynurenic acid (p < 0.016), anthranilic acid (p < 0.007), picolinic acid (p < 0.03), 5-hydroxy-indoleaceticacid (p < 0.025) and melatonin (p < 0.023). Several metabolites showed a tendency to elevate during the ictal phase, but this was significant only in the cases of anthranilic acid, 5-hydroxy-indoleaceticacid and melatonin in MWoA patients. In the same subgroup, higher interictal kynurenic acid levels were identified in patients whose headache was severe and not related to their menstruation cycle. Negative linear correlation was detected between the interictal levels of xanthurenic acid/melatonin and attack frequency. Positive associations were found between the ictal 3-hydroxykynurenine levels and the beginning of attacks, just as between ictal picolinic acid levels and last attack before ictal sampling.ConclusionsOur results suggest that there is a widespread metabolic imbalance in migraineurs, which manifests in a completely depressed peripheral Trp catabolism during the interictal period. It might act as trigger for the migraine attack, contributing to glutamate excess induced neurotoxicity and generalised hyperexcitability. This data can draw attention to the clinical relevance of KP in migraine.
A two-way rectification method for identifying differentially expressed genes by maximizing the co-function relationship
Authors: Chen Bolin , Gao Li , Shang Xuequn 
Published: June 2021

Abstract
Background
The identification of differentially expressed genes (DEGs) is an important task in many biological studies. The currently widely used methods often calculate a score for each gene by estimating the significance level in terms of the differential expression. However, biological experiments often have only three duplications, plus plenty of noises contain in gene expression datasets, which brings a great challenge to statistical analysis methods. Moreover, the abundance of gene expression levels are not evenly distributed. Thus, those low expressed genes are more easily to be detected by fold-change based methods, which may results in high false positives among the DEG list. Since phenotypical changes result from DEGs should be strongly related to several distinct cellular functions, a more robust method should be designed to increase the true positive rate of the functional related DEGs.

Results
In this study, we propose a two-way rectification method for identifying DEGs by maximizing the co-function relationships between genes and their enriched cellular pathways. An iteration strategy is employed to sequentially narrow down the group of identified DEGs and their associated biological functions. Functional analyses reveal that the identified DEGs are well organized in the form of functional modules, and the enriched pathways are very significant with lower p-value and larger gene count.

Conclusions
An integrative rectification method was proposed to identify key DEGs and their related functions simultaneously. The experimental validations demonstrate that the method has high interpretability and feasibility. It performs very well in terms of the identification of remarkable functional related genes.
The impact of tube replacement timing during LCIG therapy on PEG-J associated adverse events: a retrospective multicenter observational study
Authors: Yamashita Kanefumi , Yube Yukinori , Yamazaki Yukinao , Fukuchi Takehide , Kato Masaki , Koike Tomoyuki , Uehara Takeshi , Ikeda Yoshiou , Furune Satoshi , Murakami Hidehiro , Kubota Eiji , Fujioka Shinsuke , Sato Yoshinori , Jin Xiaoyi , Suzuki Tomohiko , Furukawa Kazuhiro , Tsuboi Yoshio 
Published: June 2021

Abstract
Background
Levodopa–carbidopa intestinal gel (LCIG) treatment, a unique drug delivery system for patients with advanced Parkinson’s disease (PD), is covered by health insurance in Japan since September 2016. Various LCIG procedure/device-associated adverse events (AEs) have been reported; however, reports on their treatment have been limited. This is the first multicenter study to clarify the frequency and timing of device-related AEs.

Methods
Between September 2016 and December 2018, 104 patients introduced to the LCIG treatment for advanced PD in 11 hospitals were included. The patients’ characteristics, AEs incidence, AEs time, and tube exchange time were investigated.

Results
The median follow-up period was 21.5 months. Minor AE cases were 29.4%, whereas major AE cases were 43.1%. Majority of major AEs (n = 55, 94.8%) were managed with endoscopic treatment, such as tube exchange. Few severe AEs required surgical treatment (n =3, 5.2%). The mean (range) exposure to percutaneous endoscopic gastrojejunostomy (PEG-J) was 14.7 (0–33) months. One year after the LCIG treatment introduction, 55 patients (54.0%) retained the original PEG-J tube. The mean PEG-J tube exchange time was 10.8 ± 7.0 months in all patients, 11.6 ± 4.7 and 10.5 ± 7.7 months in patients with scheduled exchange and who underwent exchange due to AEs, respectively.

Conclusions
Some device-related AEs occurred during the LCIG treatment; however, only few were serious, most of which could be treated with simple procedures or tube replacement with endoscopy. Therefore, the LCIG treatment is feasible and safe and is a unique treatment option for PD, requiring endoscopists’ understanding and cooperation.