bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel insights into surfactant protein C trafficking revealed through the study of a pathogenic mutant
Authors: Dickens Jennifer A. , Rutherford Eimear N. , Abreu Susana , Chambers Joseph E. , Ellis Matthew O. , van Schadewijk Annemarie , Hiemstra Pieter S. , Marciniak Stefan J. 
Published: May 2021

BackgroundAlveolar epithelial cell dysfunction plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), but remains incompletely understood. Some monogenic forms of pulmonary fibrosis are associated with expression of mutant surfactant protein C (SFTPC). The commonest pathogenic mutant, I73T, mislocalises to the alveolar epithelial cell plasma membrane and displays a toxic gain of function. Because the mechanisms explaining the link between this mutant and IPF are incompletely understood, we sought to interrogate SFTPC trafficking in health and disease to understand the functional significance of SFTPC-I73T relocalisation.MethodsWe performed mechanistic analysis of SFTPC trafficking in a cell model that reproduces thein vivophenotype and validated findings in human primary alveolar organoids.ResultsWe show that wild-type SFTPC takes an unexpected indirect trafficking routeviathe plasma membrane and undergoes the first of multiple cleavage events before reaching the multivesicular body (MVB) for further processing. SFTPC-I73T takes this same route, but its progress is retarded both at the cell surface and due to failure of trafficking into the MVB. Unable to undergo onward trafficking, it is recycled to the plasma membrane as a partially cleaved intermediate.ConclusionThese data show for the first time that all SFTPC transits the cell surface during normal trafficking, and the I73T mutation accumulates at the cell surface through both retarded trafficking and active recycling. This understanding of normal SFTPC trafficking and how the I73T mutant disturbs it provides novel insight into SFTPC biology in health and disease, and in the contribution of the SFTPC mutant to IPF development.
A prospective multicentre diagnostic accuracy study for the Truenat tuberculosis assays
Authors: Penn-Nicholson Adam , Gomathi Sivaramakrishnan N. , Ugarte-Gil Cesar , Meaza Abyot , Lavu Evelyn , Patel Pranav , Choudhury Bandana , Rodrigues Camilla , Chadha Sarabjit , Kazi Mubin , Macé Aurélien , Nabeta Pamela , Boehme Catharina , Gangakhedkar Raman R. , Sarin Sanjay , Tesfaye Ephrem , Gotuzzo Eduardo , du Cros Philipp , Tripathy Srikanth , Ruhwald Morten , Singh Manjula , Denkinger Claudia M. , Schumacher Samuel G. ,   the Truenat Trial Consortium
Published: May 2021

BackgroundBringing reliable and accurate tuberculosis (TB) diagnosis closer to patients is a key priority for global TB control. Molbio Diagnostics have developed the Truenat point-of-care molecular assays for detection of TB and rifampicin (RIF) resistance.MethodsWe conducted a prospective multicentre diagnostic accuracy study at 19 primary healthcare centres and seven reference laboratories in Peru, India, Ethiopia and Papua New Guinea to estimate the diagnostic accuracy of the point-of-care Truenat MTB, MTB Plus and MTB-RIF Dx assays for pulmonary TB using culture and phenotypic drug susceptibility testing as the reference standard, compared with Xpert MTB/RIF or Ultra.ResultsOf 1807 enrolled participants with TB signs/symptoms, 24% were culture-positive forMycobacterium tuberculosis, of which 15% were RIF-resistant. In microscopy centres, the pooled sensitivity of Truenat MTB and Truenat MTB Plus was 73% (95% CI 67–78%) and 80% (95% CI 75–84%), respectively. Among smear-negative specimens, sensitivities were 36% (95% CI 27–47%) and 47% (95% CI 37–58%), respectively. Sensitivity of Truenat MTB-RIF was 84% (95% CI 62–95%). Truenat assays showed high specificity. Head-to-head comparison in the central reference laboratories suggested that the Truenat assays have similar performance to Xpert MTB/RIF.ConclusionWe found the performance of Molbio's Truenat MTB, MTB Plus and MTB-RIF Dx assays to be comparable to that of the Xpert MTB/RIF assay. Performing the Truenat tests in primary healthcare centres with very limited infrastructure was feasible. These data supported the development of a World Health Organization policy recommendation of the Molbio assays.
Long-term modulation of airway remodelling in severe asthma following bronchial thermoplasty
Authors: Jendzjowsky Nicholas , Laing Austin , Malig Michelle , Matyas John , de Heuvel Elaine , Dumonceaux Curtis , Dumoulin Elaine , Tremblay Alain , Leigh Richard , Chee Alex , Kelly Margaret M. 
Published: May 2021

RationaleBronchial thermoplasty is a mechanical therapeutic intervention that has been advocated as an effective treatment option for severe asthma. The mechanism is promoted as being related to the attenuation of airway smooth muscle which has been shown to occur in the short-term. However, long-term studies of the effects of bronchial thermoplasty on airway remodelling are few, with only limited assessment of airway remodelling indices.ObjectivesTo evaluate the effect of bronchial thermoplasty on 1) airway epithelial and smooth muscle cells in culture and 2) airway remodelling in patients with severe asthma who have been prescribed bronchial thermoplasty up to 12 months post-treatment.MethodsThe distribution of heat within the airway by bronchial thermoplasty was assessed in a porcine model. Culture of human airway smooth muscle cells and bronchial epithelial cells evaluated the impact of thermal injury. Histological evaluation and morphometric assessment were performed on bronchial biopsies obtained from severe asthma patients at baseline, 6 weeks and 12 months following bronchial thermoplasty.ResultsBronchial thermoplasty resulted in heterogeneous heating of the airway wall. Airway smooth muscle cell cultures sustained thermal injury, whilst bronchial epithelial cells were relatively resistant to heat. Airway smooth muscle and neural bundles were significantly reduced at 6 weeks and 12 months post-treatment. At 6 weeks post-treatment, submucosal collagen was reduced and vessel density increased, with both indices returning to baseline at 12 months. Goblet cell numbers, submucosal gland area and sub-basement membrane thickness were not significantly altered at any time point examined.ConclusionsBronchial thermoplasty primarily affects airway smooth muscle and nerves with the effects still present at 12 months post-treatment.
Shift from high-frequency to low-frequency episodic migraine in patients treated with Galcanezumab: results from two global randomized clinical trials
Authors: Jedynak Jakub , Eross Eric , Gendolla Astrid , Rettiganti Mallikarjuna , Stauffer Virginia L. 
Published: May 2021

Abstract
Background
Patients with episodic migraine (EM) with a higher-frequency of migraine headache days (HFEM: 8–14 migraine headache days/month) have a greater disease burden and a higher risk of progressing to chronic migraine (CM) with associated acute treatment overuse versus those with low-frequency EM (LFEM: 4–7 migraine headache days/month). In this post hoc analysis, we assessed the proportions of patients who shifted from HFEM to LFEM and to very low-frequency EM (VLFEM: 0–3 migraine headache days/month) status following treatment with galcanezumab versus placebo.

Methods
EVOLVE-1 and EVOLVE-2 were double-blind, Phase 3 studies in patients with EM. Patients (18–65 years) were randomized (2:1:1) to subcutaneous monthly injections of placebo, galcanezumab 120 mg (240 mg loading dose) or 240 mg, for up to 6 months. Data were pooled and endpoints were change from baseline in number of migraine headache days/month and patients who shifted from HFEM to LFEM or VLFEM status. Impact of change in HFEM status on migraine headache days/month, quality of life and disability was also assessed.

Results
A total of 66% (1176/1773) patients from EVOLVE studies had HFEM status at baseline and were included in this analysis; placebo: 592, galcanezumab 120 mg: 294 and galcanezumab 240 mg: 290. At each month, both doses of galcanezumab resulted in a higher proportion of patients who shifted to 0–7 monthly headache days/month (VLFEM or LFEM status). Patients who shifted from HFEM at baseline to VLFEM status at Month 3, a relatively larger proportion of patients on galcanezumab 120 mg versus placebo remained at VLFEM status at Months 4–6; Months 4–5 for galcanezumab 240 mg versus placebo. Among the galcanezumab-treated patients who did-not-shift or shifted to LFEM or VLFEM status for ≥3 consecutive months until the end of the study, patients who shifted from HFEM to VLFEM status experienced the largest reduction in migraine headache days/month and the largest clinically meaningful improvements in daily functioning (MSQ-RFR) and disability (MIDAS).

Conclusions
In patients with HFEM, treatment with galcanezumab (120 mg and 240 mg) significantly reduced migraine headache days/month, maintained remission status at subsequent months until the end of the study, and improved patients’ quality of life versus placebo.

Trial registration
ClinicalTrials.gov Identifier: EVOLVE-1, NCT02614183; EVOLVE-2, NCT02614196.
Revisiting Theron’s hypothesis on the origin of fairy circles after four decades: Euphorbias are not the cause
Authors: Getzin Stephan , Nambwandja Ailly , Holch Sönke , Wiegand Kerstin 
Published: May 2021

AbstractBackgroundThe Euphorbia hypothesis on the origin of fairy circles (FCs) in Namibia dates back to 1979. It proposes that the remains of decaying shrubs would induce an allelopathic interaction with the grasses and thereby cause bare-soil FCs. Here, we investigated this hypothesis based on revisiting marked Euphorbias after four decades, comparing the typical size distribution of deadEuphorbia damaranaand FCs, and analyzing the spatial patterns of Euphorbias and FCs within the same drone-mapped study plots in three regions of Namibia.ResultsWe found four dead Euphorbias in the southern Giribes that were marked by G.K. Theron about 40 years ago. Those locations did not develop into FCs over this time span. However, for the four dead Euphorbias, we provide photographic evidence that grass tufts were growing at the metal pins of those decaying shrubs, agreeing with previous research findings that the soil taken from beneath deadE. damaranashrubs was stimulating rather than inhibiting the growth of grasses. In the Giribes, there were very large FCs that ranged in diameter from 13.0 to 19.1 m. By contrast, the measured deadE. damarana, including the largest plants that we could find, ranged in size only between 4.2 and 11.7 m. At Brandberg, we found particularly small FCs with diameters between 2.4 and 2.7 m but the deadE. damarana, including the smallest dead shrubs in the area, ranged in size between 4.1 and 7.2 m. Hence given these size mismatches, the decaying Euphorbias cannot induce such observed FCs in the two regions. Spatial patterns ofE. damaranaand FCs in the two regions Giribes and Brandberg, as well as ofE. gummiferaand FCs near Garub, showed a strong mismatch within the same habitat: in four out of five plots the patterns differed significantly. FCs were regularly distributed while Euphorbias were predominantly clustered.ConclusionsWe reject the Euphorbia hypothesis based on the fact that grass growth was not prevented under decaying shrubs, the size of dead Euphorbias cannot explain the size of observed FCs and the spatial distribution of Euphorbias cannot cause the specific pattern signature of FCs.
Base-substitution mutation rate across the nuclear genome of Alpheus snapping shrimp and the timing of isolation by the Isthmus of Panama
Authors: Silliman Katherine , Indorf Jane L. , Knowlton Nancy , Browne William E. , Hurt Carla 
Published: May 2021

AbstractBackgroundThe formation of the Isthmus of Panama and final closure of the Central American Seaway (CAS) provides an independent calibration point for examining the rate of DNA substitutions. This vicariant event has been widely used to estimate the substitution rate across mitochondrial genomes and to date evolutionary events in other taxonomic groups. Nuclear sequence data is increasingly being used to complement mitochondrial datasets for phylogenetic and evolutionary investigations; these studies would benefit from information regarding the rate and pattern of DNA substitutions derived from the nuclear genome.ResultsTo estimate the genome-wide neutral mutation rate (µ), genotype-by-sequencing (GBS) datasets were generated for three transisthmian species pairs inAlpheussnapping shrimp. A range of bioinformatic filtering parameters were evaluated in order to minimize potential bias in mutation rate estimates that may result from SNP filtering. Using a Bayesian coalescent approach (G-PhoCS) applied to 44,960 GBS loci, we estimated µ to be 2.64E−9 substitutions/site/year, when calibrated with the closure of the CAS at 3 Ma. Post-divergence gene flow was detected in one species pair. Failure to account for this post-split migration inflates our substitution rate estimates, emphasizing the importance of demographic methods that can accommodate gene flow.ConclusionsResults from our study, both parameter estimates and bioinformatic explorations, have broad-ranging implications for phylogeographic studies in other non-model taxa using reduced representation datasets. Our best estimate of µ that accounts for coalescent and demographic processes is remarkably similar to experimentally derived mutation rates in model arthropod systems. These results contradicted recent suggestions that the closure of the Isthmus was completed much earlier (around 10 Ma), as mutation rates based on an early calibration resulted in uncharacteristically low genomic mutation rates. Also, stricter filtering parameters resulted in biased datasets that generated lower mutation rate estimates and influenced demographic parameters, serving as a cautionary tale for the adherence to conservative bioinformatic strategies when generating reduced-representation datasets at the species level. To our knowledge this is the first use of transisthmian species pairs to calibrate the rate of molecular evolution from GBS data.
LncRNA:DNA triplex-forming sites are positioned at specific areas of genome organization and are predictors for Topologically Associated Domains
Authors: Soibam Benjamin , Zhamangaraeva Ayzhamal 
Published: May 2021

Abstract
Background
Chromosomes are organized into units called topologically associated domains (TADs). TADs dictate regulatory landscapes and other DNA-dependent processes. Even though various factors that contribute to the specification of TADs have been proposed, the mechanism is not fully understood. Understanding the process for specification and maintenance of these units is essential in dissecting cellular processes and disease mechanisms.

Results
In this study, we report a genome-wide study that considers the idea of long noncoding RNAs (lncRNAs) mediating chromatin organization using lncRNA:DNA triplex-forming sites (TFSs). By analyzing the TFSs of expressed lncRNAs in multiple cell lines, we find that they are enriched in TADs, their boundaries, and loop anchors. However, they are evenly distributed across different regions of a TAD showing no preference for any specific portions within TADs. No relationship is observed between the locations of these TFSs and CTCF binding sites. However, TFSs are located not just in promoter regions but also in intronic, intergenic, and 3’UTR regions. We also show these triplex-forming sites can be used as predictors in machine learning models to discriminate TADs from other genomic regions. Finally, we compile a list of important “TAD-lncRNAs” which are top predictors for TADs identification.

Conclusions
Our observations advocate the idea that lncRNA:DNA TFSs are positioned at specific areas of the genome organization and are important predictors for TADs. LncRNA:DNA triplex formation most likely is a general mechanism of action exhibited by some lncRNAs, not just for direct gene regulation but also to mediate 3D chromatin organization.
Myocardial fibrosis combined with NT-proBNP improves the accuracy of survival prediction in ADHF patients
Authors: Yao Yiling , Feng Li , Sun Yanxiang , Wang Shifei , Sun Jie , Hu Bing 
Published: May 2021

Abstract
Background
Soluble suppression of tumorigenesis-2 (sST2), Procollagen Type III N-Terminal Peptid (PIIINP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been verified their role in predicting survival in acutely decompensated heart failure (ADHF). However, whether their combination could improve more specific and sensitive prognostic information than NT-proBNP alone remains unclear.

Methods
This was a prospective study, in which 217 ADHF patients at admission were enrolled from November 2018 and August 2019 (mean age 66.18 years ± 13.60, 63.98% male). The blood samples were collected to measure the concentrations of NT-proBNP, sST2 and PIIINP in the first 24 h of hospitalizations. All-cause mortality was registered for all patients after they were discharge over a median period of 339 days.

Results
In univariate Cox analysis, the three biomarkers were predictive of short-term mortality of ADHF patients. After adjusted for some clinical variables including age, admission systolic blood pressure, peripheral edema on admission, history of chronic obstructive pulmonary disease, admission sodium < 135 mmol/L, admission hemoglobin, NT-proBNP, sST2 and PIIINP was significantly associated with the poor outcome (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.14–1.53, P < 0.01; HR 1.21, 95% CI 1.03–1.43, P = 0.020; HR 1.40, 95% CI 1.08–1.81, P = 0.011). After added with Log2 PIIINP, but not Log2 sST2, the area under the curves (AUC) in the model of clinical variables and Log2 NT-proBNP could increase from 0.79 to 0.85 (95% CI 0.0071–0.10, P = 0.024). Furthermore, compared with the model of clinical variables, Log2 NT-proBNP, the improvement in the prognostic model of clinical variables, Log2 NT-proBNP and Log2 PIIINP had statistical significance [net reclassification improvement (NRI) 0.31, P = 0.018; integrated discrimination improvement (IDI) 0.068, P < 0.01].

Conclusions
NT-proBNP, sST2 and PIIINP are independent prognostic factors for all-cause mortality in ADHF patients. Furthermore, the combination of NT-proBNP and PIIINP may provide incremental prognostic value over NT-proBNP in the survival of ADHF patients.
Selective inhibition of soluble TNF using XPro1595 relieves pain and attenuates cerulein-induced pathology in mice
Authors: Randhi Rajasa , Damon Melissa , Dixon Kirsty J. 
Published: May 2021

Abstract
Background
Symptoms associated with acute pancreatitis can be debilitating, and treatment remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of acute pancreatitis.

Methods
Acute pancreatitis was induced in adult male C57Bl/6J mice by administering cerulein (8 injections of 50 µg/kg I.P., spaced an hour apart), with XPro1595 (10 mg/kg, S.C.) or vehicle being administered approximately 18 h after the last injection. Serum was collected 6 or 18 h after the last cerulein injection, pancreatic tissue was collected 2 and 7 days post-induction, and brain hippocampal tissue was collected at 7 days post-induction. The animal’s pain level was assessed 3, 5 and 7 days post-induction.

Results
The induction of acute pancreatitis promoted a strong increase in serum amylase levels, which had receded back to baseline levels by the next morning. XPro1595 treatment began after amylase levels had subsided at 18 h, and prevented pancreatic immune cell infiltration, that subsequently prevented tissue disruption and acinar cell death. These improvements in pathology were associated with a significant reduction in mechanical hypersensitivity (neuropathic pain). XPro1595 treatment also prevented an increase in hippocampal astrocyte reactivity, that may be associated with the prevention of neuropathic pain in this mouse model.

Conclusion
Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of cerulein-induced pancreatitis in mice, which provides support of its use in patients with pancreatitis.
Evaluation of the Psychometric Properties of PainChek® in UK Aged Care Residents with advanced dementia
Authors: Babicova Ivana , Cross Ainslea , Forman Dawn , Hughes Jeffery , Hoti Kreshnik 
Published: May 2021

AbstractBackgroundThe aim of this study was to further validate PainChek®, an electronic pain assessment instrument, with a population living with dementia in a UK care home.MethodThis study utilised a correlational design to evaluate the psychometric properties of PainChek® when compared to the Abbey Pain Scale (APS). Blinded paired pain assessments were completed at rest and immediately post-movement by a researcher and a nurse. A total of 22 participants with a diagnosis of moderate-to-severe dementia and a painful condition were recruited using opportunity sampling.ResultsOverall, 302 paired assessments were collected for 22 participants. Out of these 179 were conducted during rest and 123 were immediately post-movement. The results demonstrated a positive significant correlation between overall PainChek® pain scores and overall APS pain scores (r = 0.818,N = 302,p < .001, one-tailed), satisfactory internal consistency (α = 0.810), moderate single measure intraclass correlation (ICC = 0.680) and substantial inter-rater agreement (κ = 0.719).ConclusionsPainChek® has demonstrated to be a valid and reliable instrument to assess the presence and severity of pain in people with moderate-to-severe dementia living in aged care.
Motivating healthcare professionals (nurses, nurse assistants, physicians) to integrate new practices for preventing healthcare-associated infections into the care continuum: turning Positive Deviance into positive norms
Authors: Gesser-Edelsburg Anat , Cohen Ricky , Halavi Adva Mir , Zemach Mina 
Published: May 2021

Abstract
Background
The literature examining healthcare-associated infections (HAI) points to two main problems in conforming to infection prevention and control (IPC) guidelines among healthcare professionals (HP). One is the discrepancy between HPs’ behavioral intentions and their implementation in practice. The other refers to how HPs maintain these practices after the intervention stage ends. The method proposed in this study seeks to address both these issues by using the Positive Deviance (PD) approach to focus on the dissemination stage of interventions. The study seeks to offer a method for disseminating 27 PD practices to 135 HPs, among them nurses, nurse assistants and physicians, so as to help them maintain IPC guidelines, offer feedback on the dissemination process and examine the impact of the dissemination stage on changes in their behavior.

Methods
The theoretical model underlying this qualitative research was the Recognition-Primed Decision (RPD) model, which we implemented in the field of healthcare-associated infections (HAIs). Moreover, we used the Discovery & Action Dialogue (DAD) and Think Aloud (TA) techniques to describe the methodological development of simulations for HPs. Feedback from the HP demonstrators underwent content analysis, while descriptive statistics were used to characterize behavioral changes.

Results
HPs’ information processing regarding infection prevention shifts from peripheral/automatic processing to intuition and analytical/central processing, turning PD practices into positive norms. The HPs personally experienced finding a solution and made repeated corrections until they overcame the barriers. Most of the HPs (69.4%) reported that the practices were fully implemented, together with additional practices.

Conclusions
Implementation of the dissemination stage indicates that in order for HPs to integrate and assimilate practices that are not in the official guidelines, merely observing simulations is not sufficient. Rather, each staff member must personally carry out the procedures.