bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors associated with prehospital delay in acute myocardial infarction in Maldives
Authors: Hussain Madheeh Mohamed , Baharuddin Kamarul Aryffin , Fauzi Mohd Hashairi , Abu Bakar Mimi Azliha , Ziyan Ahmed , Ahmed Aminath Zeyba , Sunil Mohamed 
Published: April 2023

Abstract
Background
Acute myocardial infarction (AMI) is the top cause of death in Maldives. Our study aims to determine the prehospital delay and its associated factors in AMI patients in Maldives.

Methods
A cross-sectional study was conducted with 127 patients, divided into early (≤ 6 h) and delayed (> 6 h) presenters to the hospital. The data collection for the study was carried out by interviewing AMI patients, focusing on their socio-demographic characteristics, coronary artery disease risk factors, clinical symptoms, situational factors, and behavioral and cognitive responses to symptoms.

Results
The median onset-to-door time was 230 (IQR 420) minutes. The mean age of AMI patients was 50.9 (SD ± 12.9) years old, and 39.4% of them had delayed presentation to the hospital. Smokers (adj OR = 0.3; 95% CI: 0.1, 0.9; P = 0.047) and those with previous episodes of chest pain or AMI (adj OR = 0.2; 95% CI: 0.03, 0.91; P = 0.038) were significant factors for early presentation to the hospital, while denial of symptoms (adj OR = 29.3; 95% CI: 1.6, 547.2; P = 0.024) and lack of knowledge (adj OR = 7.2; 95% CI: 1.77, 29.43; P = 0.006) led to a delayed decision to seek treatment. Situational factors such as onset at the workplace (adj OR = 5.8; 95% CI: 1.24, 26.83; P = 0.025) had lower odds of delay, whereas referral cases (adj OR = 7.7; 95% CI: 1.9, 30.94; P = 0.004) and use of sea ambulance (adj OR = 11.1; 95% CI: 2.8, 43.8; P = 0.001) were prone to delay in presentation to the hospital.

Conclusion
Sea ambulance, referral cases, lack of knowledge, and denial of symptoms are significant factors associated with prehospital delay among patients with AMI. Public awareness about the benefits of early presentation and improvement of the means of transportation between islands is suggested to improve emergency cardiac care in the country.
Much effort, little success: causes for the low ecological efficacy of restoration measures in German surface waters
Authors: Brettschneider Denise Jasmin , Spring Taschina , Blumer Moritz , Welge Lukas , Dombrowski Andrea , Schulte-Oehlmann Ulrike , Sundermann Andrea , Oetken Matthias , Oehlmann Jörg 
Published: April 2023

Abstract
Background
For more than 20 years, restoration measures have been conducted on watercourses in Germany to increase habitat diversity and thus promote biodiversity. However, their ecological efficacy often proved to be limited. While some studies report an increase in species diversity, others show little evidence of improvement even many years after the implementation of restoration measures. In general, ecological efficacy of hydromorphological restoration measures is highest for terrestrial and semiaquatic groups of organisms such as floodplain vegetation and ground beetles. According to the literature, macrophytes responded most strongly to in-stream restoration measures, while fish stocks showed little improvement and macroinvertebrates showed little or no effect in terms of species richness and diversity. These findings raise the question of reasons for the low ecological efficacy of hydromorphological restoration measures, especially for macroinvertebrate communities. The following literature review and a case study for the river Horloff will provide possible indications for failing success of intensive restoration measures.

Results
One reason for the inadequate ecological status of many restored river stretches is the inappropriate scaling of restoration measures. Often, small-scale restoration measures are planned, although the respective water bodies exhibit stressors at the catchment scale that impair the ecological efficacy of restoration measures. In particular, chemical contamination of running waters is often insufficiently addressed in the planning and implementation of restoration measures and hampers efficacy of hydromorphological restoration measures. For a holistic water resource management, the planning and implementation of measures should therefore be more closely coordinated and harmonized between federal states and neighboring countries. For this purpose, the establishment of so-called river basin communities is suitable, as they already exist today on the rivers Rhine, Danube, Meuse, Weser, Elbe, Ems, Eider, Schlei/Trave, Warnow/Peene.

Conclusion
The literature review indicated that for a successful recolonization of restored river stretches by macroinvertebrates and the enhancement of the ecological status, large-scale stressors, i.e., stressors acting at the catchment scale, should be eliminated initially by restoration measures focusing on the chemical contamination and the surrounding land use. Structural restoration measures acting on the reach or local scale should ideally be implemented contemporarily to the removal of large-scale stressors like chemical contamination.
Prediction of disease-related miRNAs by voting with multiple classifiers
Authors: Gu Changlong , Li Xiaoying 
Published: April 2023

AbstractThere is strong evidence to support that mutations and dysregulation of miRNAs are associated with a variety of diseases, including cancer. However, the experimental methods used to identify disease-related miRNAs are expensive and time-consuming. Effective computational approaches to identify disease-related miRNAs are in high demand and would aid in the detection of lncRNA biomarkers for disease diagnosis, treatment, and prevention. In this study, we develop an ensemble learning framework to reveal the potential associations between miRNAs and diseases (ELMDA). The ELMDA framework does not rely on the known associations when calculating miRNA and disease similarities and uses multi-classifiers voting to predict disease-related miRNAs. As a result, the average AUC of the ELMDA framework was 0.9229 for the HMDD v2.0 database in a fivefold cross-validation. All potential associations in the HMDD V2.0 database were predicted, and 90% of the top 50 results were verified with the updated HMDD V3.2 database. The ELMDA framework was implemented to investigate gastric neoplasms, prostate neoplasms and colon neoplasms, and 100%, 94%, and 90%, respectively, of the top 50 potential miRNAs were validated by the HMDD V3.2 database. Moreover, the ELMDA framework can predict isolated disease-related miRNAs. In conclusion, ELMDA appears to be a reliable method to uncover disease-associated miRNAs.
STING controls opioid-induced itch and chronic itch via spinal tank-binding kinase 1-dependent type I interferon response in mice
Authors: Li Nan , Wang Chunyan , Zhao Yuying , Wang Yigang , Gao Tianyu , Yu Yonghao , Wang Guolin , Zhang Linlin 
Published: April 2023

Abstract
Background
Patients receiving epidural or intrathecal opioids administration for neuraxial analgesia frequently suffer from an irritating itch. STING (stimulator of interferon genes), an innate immune modulator, is strongly implicated in pain pathogenesis via neuron-immune modulation. Given that pain and itch share some common neurocircuits, we evaluate the therapeutic potential of STING agonists in opioid-induced itch and chronic itch.

Methods
Opioids (morphine, fentanyl and sufentanil) were intrathecally injected to induce acute itch. Chronic itch was induced by dry skin and contact dermatitis. Opioids analgesic effect, itch-induced scratching behavior, spinal expression of STING, phosphorylation of TBK1 (tank-binding kinase 1), IRF3 (interferon regulatory factor-3) and ERK (extracellular signal-regulated kinase), as well as production of IFN-α and IFN-β were examined. STING agonists (DMXAA and ADU-S100), TBK1 inhibitor, recombinant IFN-α and IFN-β elucidated the mechanism and treatment of itch. Whole-brain functional connectivity was evaluated using resting-state fMRI.

Results
We report the primary expression of STING protein by the spinal dorsal horn neurons. Intraperitoneal injection of DMXAA dose-dependently reduces morphine-induced scratch bouts, without impairing morphine antinociception. Simultaneously, DMXAA alleviates fentanyl- and sufentanil-induced itching-like behavior, and chronic scratching behavior caused by dry skin and contact dermatitis. Furthermore, DMXAA drastically increases spinal phosphorylation of TBK1 and IRF3 following morphine exposure, dry skin and contact dermatitis. DMXAA-induced anti-pruritus effects and spinal productions of IFN-α and IFN-β are compensated by intrathecal delivery of the TBK1 inhibitor. Also, ADU-S100, recombinant IFN-α and IFN-β exhibits remarkable attenuation in scratching behaviors after morphine injection and dermatitis. Recombinant IFN-α inhibits morphine-induced spinal phosphorylation of ERK. Finally, DMXAA prevents dermatitis-induced the increase of cerebral functional connectivity between regions of interests such as primary somatosensory cortex, piriform cortex, retrosplenial cortex, colliculus and ventral thalamus.

Conclusions
STING activation confers protection against opioid-induced itch and chronic itch through spinal up-regulation of TBK1-IRF3-type I interferon cascades in mice, suggesting that STING agonists are promising candidates in translational development for pruritus relief.
Co-modulation of TNFR1 and TNFR2 in an animal model of multiple sclerosis
Authors: Fiedler Timon , Fairless Richard , Pichi Kira , Fischer Roman , Richter Fabian , Kontermann Roland E. , Pfizenmaier Klaus , Diem Ricarda , Williams Sarah K. 
Published: April 2023

AbstractBackgroundTumour necrosis factor (TNF) is a pleiotropic cytokine and master regulator of the immune system. It acts through two receptors resulting in often opposing biological effects, which may explain the lack of therapeutic potential obtained so far in multiple sclerosis (MS) with non-receptor-specific anti-TNF therapeutics. Under neuroinflammatory conditions, such as MS, TNF receptor-1 (TNFR1) is believed to mediate the pro-inflammatory activities associated with TNF, whereas TNF receptor-2 (TNFR2) may instead induce anti-inflammatory effects as well as promote remyelination and neuroprotection. In this study, we have investigated the therapeutic potential of blocking TNFR1 whilst simultaneously stimulating TNFR2 in a mouse model of MS.MethodsExperimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein (MOG35-55) in humanized TNFR1 knock-in mice. These were treated with a human-specific TNFR1-selective antagonistic antibody (H398) and a mouse-specific TNFR2 agonist (EHD2-sc-mTNFR2), both in combination and individually. Histopathological analysis of spinal cords was performed to investigate demyelination and inflammatory infiltration, as well as axonal and neuronal degeneration. Retinas were examined for any protective effects on retinal ganglion cell (RGC) degeneration and neuroprotective signalling pathways analysed by Western blotting.ResultsTNFR modulation successfully ameliorated symptoms of EAE and reduced demyelination, inflammatory infiltration and axonal degeneration. Furthermore, the combinatorial approach of blocking TNFR1 and stimulating TNFR2 signalling increased RGC survival and promoted the phosphorylation of Akt and NF-κB, both known to mediate neuroprotection.ConclusionThese results further support the potential of regulating the balance of TNFR signalling, through the co-modulation of TNFR1 and TNFR2 activity, as a novel therapeutic approach in treating inflammatory demyelinating disease.
High affinity of β-amyloid proteins to cerebral capillaries: implications in chronic lead exposure-induced neurotoxicity in rats
Authors: Liu Luke L. , Shen Xiaoli , Gu Huiying , Zhao Gang , Du Yansheng , Zheng Wei 
Published: April 2023

AbstractLead (Pb) is a known environmental risk factor in the etiology of Alzheimer’s disease (AD). The existing reports suggest that Pb exposure increases beta-amyloid (Aβ) levels in brain tissues and cerebrospinal fluid (CSF) and facilitates the formation of amyloid plaques, which is a pathological hallmark for AD. Pb exposure has long been associated with cerebral vasculature injury. Yet it remained unclear if Pb exposure caused excessive Ab buildup in cerebral vasculature, which may damage the blood–brain barrier and cause abnormal Ab accumulation. This study was designed to investigate the impact of chronic Pb exposure on Aβ accumulation in cerebral capillary and the expression of low-density lipoprotein receptor protein-1 (LRP1), a critical Aβ transporter, in brain capillary and parenchyma. Sprague–Dawley rats received daily oral gavage at doses of 0, 14 (low-dose), and 27 (high-dose) mg Pb/kg as Pb acetate, 5 d/wk, for 4 or 8 wks. At the end of Pb exposure, a solution containing Aβ40 was infused into the brain via the cannulated internal carotid artery. Data by ELISA showed a strikingly high affinity of Ab to cerebral vasculature, which was approximately 7–14 times higher than that to the parenchymal fractions collected from control brains. Pb exposure further aggravated the Aβ accumulation in cerebral vasculature in a dose-dependent manner. Western blot analyses revealed that Pb exposure decreased LRP1 expression in cortical capillaries and hippocampal parenchyma. Immunohistochemistry (IHC) studies further revealed a disrupted distribution of LRP1 alongside hippocampal vasculature accompanied with a decreased expression in hippocampal neurons by Pb exposure. Taken together, the current study demonstrated that the cerebral vasculature naturally possessed a high affinity to Aβ present in circulating blood. Pb exposure significantly increased Aβ accumulation in cerebral vasculature; such an increased Aβ accumulation was due partly to the diminished expression of LRP1 in response to Pb in tested brain regions. Perceivably, Pb-facilitated Ab aggravation in cerebral vasculature may contribute to Pb-associated amyloid alterations.
Multifaceted implementation and sustainability of a protocol for prehospital anaesthesia: a retrospective analysis of 2115 patients from helicopter emergency medical services
Authors: Ångerman Susanne , Kirves Hetti , Nurmi Jouni 
Published: April 2023

AbstractBackgroundPrehospital emergency anaesthesia (PHEA) is a high-risk procedure. We developed a prehospital anaesthesia protocol for helicopter emergency medical services (HEMS) that standardises the process and involves ambulance crews as active team members to increase efficiency and patient safety. The aim of the current study was to evaluate this change and its sustainability in (i) on-scene time, (ii) intubation first-pass success rate, and (iii) protocol compliance after a multifaceted implementation process.MethodsThe protocol was implemented in 2015 in a HEMS unit and collaborating emergency medical service systems. The implementation comprised dissemination of information, lectures, simulations, skill stations, academic detailing, and cognitive aids. The methods were tailored based on implementation science frameworks. Data from missions were gathered from mission databases and patient records.ResultsDuring the study period (2012–2020), 2381 adults underwent PHEA. The implementation year was excluded; 656 patients were analysed before and 1459 patients after implementation of the protocol. Baseline characteristics and patient categories were similar. On-scene time was significantly redused after the implementation (median 32 [IQR 25–42] vs. 29 [IQR 21–39] minutes,p < 0.001). First pass success rate increased constantly during the follow-up period from 74.4% (95% CI 70.7–77.8%) to 97.6% (95% CI 96.7–98.3%),p = 0.0001. Use of mechanical ventilation increased from 70.6% (95% CI 67.0–73.9%) to 93.4% (95% CI 92.3–94.8%),p = 0.0001, and use of rocuronium increased from 86.4% (95% CI 83.6–88.9%) to 98.5% (95% CI 97.7–99.0%), respectively. Deterioration in compliance indicators was not observed.ConclusionsWe concluded that clinical performance in PHEA can be significantly improved through multifaceted implementation strategies.
Skin biopsy in adult patients with meningococcal purpura fulminans: a multicenter retrospective cohort study
Authors: Contou Damien , Béduneau Gaëtan , Rabault Charlotte , Sonneville Romain , Marchalot Antoine , Coudroy Rémi , Roux Damien , Cour Martin , Massol Julien , Préau Sébastien , de Prost Nicolas ,   The HOPEFUL Study Group, Pène Frédéric , Colin Gwenhaël , Barbier François , Toufik Kamel , Quelven Quentin , Schnell Guillaume , Ehrmann Stephan , Messet Hélène , Kimmoun Antoine , Beuret Pascal , Bruel Cédric , Colling Delphine , Conia Alexandre , Martin Luis Ensenyat , Reuter Danielle , Das Vincent , Challier Marion , Jozwiak Mathieu , Galbois Arnaud , Fraisse Mégan , Jaber Samir , Jochmans Sébastien , Kalfon Pierre , Conrad Marie , Lautrette Alexandre , Darreau Cédric , Lerolle Nicolas , Georges Hugues , Mégarbane Bruno , Pichereau Claire , Urbina Tomas , Maury Eric , de Prost Nicolas , Quenot Jean-Pierre , Sauneuf Bertrand , Schmidt Matthieu , Valette Xavier , Zafrani Lara , Da Silva Daniel , Rigault Guillaume , Woerther Paul-Louis 
Published: April 2023

Abstract
Background
Neisseria meningitidis is the leading responsible bacterium of Purpura Fulminans (PF) accounting for two thirds of PF. Skin biopsy is a simple and minimally invasive exam allowing to perform skin culture and polymerase chain reaction (PCR) to detect Neisseria meningitidis. We aimed to assess the sensitivity of skin biopsy in adult patients with meningococcal PF.

Methods
A 17-year multicenter retrospective cohort study including adult patients admitted to the ICU for a meningococcal PF in whom a skin biopsy with conventional and/or meningococcal PCR was performed.

Results
Among 306 patients admitted for PF, 195 had a meningococcal PF (64%) with a skin biopsy being performed in 68 (35%) of them. Skin biopsy was performed in median 1 day after the initiation of antibiotic therapy. Standard culture of skin biopsy was performed in 61/68 (90%) patients and grew Neisseria meningitidis in 28 (46%) of them. Neisseria meningitidis PCR on skin biopsy was performed in 51/68 (75%) patients and was positive in 50 (98%) of them. Among these 50 positive meningococcal PCR, five were performed 3 days or more after initiation of antibiotic therapy. Finally, skin biopsy was considered as contributive in 60/68 (88%) patients. Identification of the meningococcal serogroup was obtained with skin biopsy in 48/68 (71%) patients.

Conclusions
Skin biopsy with conventional culture and meningococcal PCR has a global sensitivity of 88% and should be systematically considered in case of suspected meningococcal PF even after the initiation of antimicrobial treatment.
DREAMS: deep read-level error model for sequencing data applied to low-frequency variant calling and circulating tumor DNA detection
Authors: Christensen Mikkel H. , Drue Simon O. , Rasmussen Mads H. , Frydendahl Amanda , Lyskjær Iben , Demuth Christina , Nors Jesper , Gotschalck Kåre A. , Iversen Lene H. , Andersen Claus L. , Pedersen Jakob Skou 
Published: April 2023

AbstractCirculating tumor DNA detection using next-generation sequencing (NGS) data of plasma DNA is promising for cancer identification and characterization. However, the tumor signal in the blood is often low and difficult to distinguish from errors. We present DREAMS (Deep Read-level Modelling of Sequencing-errors) for estimating error rates of individual read positions. Using DREAMS, we develop statistical methods for variant calling (DREAMS-vc) and cancer detection (DREAMS-cc). For evaluation, we generate deep targeted NGS data of matching tumor and plasma DNA from 85 colorectal cancer patients. The DREAMS approach performs better than state-of-the-art methods for variant calling and cancer detection.
SNV-FEAST: microbial source tracking with single nucleotide variants
Authors: Briscoe Leah , Halperin Eran , Garud Nandita R. 
Published: April 2023

AbstractElucidating the sources of a microbiome can provide insight into the ecological dynamics responsible for the formation of these communities. Source tracking approaches to date leverage species abundance information; however, single nucleotide variants (SNVs) may be more informative because of their high specificity to certain sources. To overcome the computational burden of utilizing all SNVs for a given sample, we introduce a novel method to identify signature SNVs for source tracking. Signature SNVs used as input into a previously designed source tracking algorithm, FEAST, can more accurately estimate contributions than species and provide novel insights, demonstrated in three case studies.
Boosting genome editing efficiency in human cells and plants with novel LbCas12a variants
Authors: Zhang Liyang , Li Gen , Zhang Yingxiao , Cheng Yanhao , Roberts Nathaniel , Glenn Steve E. , DeZwaan-McCabe Diane , Rube H. Tomas , Manthey Jeff , Coleman Gary , Vakulskas Christopher A. , Qi Yiping 
Published: April 2023

AbstractBackgroundCas12a (formerly known as Cpf1), the class II type V CRISPR nuclease, has been widely used for genome editing in mammalian cells and plants due to its distinct characteristics from Cas9. Despite being one of the most robust Cas12a nucleases, LbCas12a in general is less efficient than SpCas9 for genome editing in human cells, animals, and plants.ResultsTo improve the editing efficiency of LbCas12a, we conduct saturation mutagenesis inE. coliand identify 1977 positive point mutations of LbCas12a. We selectively assess the editing efficiency of 56 LbCas12a variants in human cells, identifying an optimal LbCas12a variant (RVQ: G146R/R182V/E795Q) with the most robust editing activity. We further test LbCas12a-RV, LbCas12a-RRV, and LbCas12a-RVQ in plants and find LbCas12a-RV has robust editing activity in rice and tomato protoplasts. Interestingly, LbCas12a-RRV, resulting from the stacking of RV and D156R, displays improved editing efficiency in stably transformed rice and poplar plants, leading to up to 100% editing efficiency inT0plants of both plant species. Moreover, this high-efficiency editing occurs even at the non-canonical TTV PAM sites.ConclusionsOur results demonstrate that LbCas12a-RVQ is a powerful tool for genome editing in human cells while LbCas12a-RRV confers robust genome editing in plants. Our study reveals the tremendous potential of these LbCas12a variants for advancing precision genome editing applications across a wide range of organisms.
m6A readers ECT2/ECT3/ECT4 enhance mRNA stability through direct recruitment of the poly(A) binding proteins in Arabidopsis
Authors: Song Peizhe , Wei Lianhuan , Chen Zixin , Cai Zhihe , Lu Qiang , Wang Chunling , Tian Enlin , Jia Guifang 
Published: April 2023

AbstractBackgroundRNAN6-methyladenosine (m6A) modification is critical for plant growth and crop yield. m6A reader proteins can recognize m6A modifications to facilitate the functions of m6A in gene regulation. ECT2, ECT3, and ECT4 are m6A readers that are known to redundantly regulate trichome branching and leaf growth, but their molecular functions remain unclear.ResultsHere, we show that ECT2, ECT3, and ECT4 directly interact with each other in the cytoplasm and perform genetically redundant functions in abscisic acid (ABA) response regulation during seed germination and post-germination growth. We reveal that ECT2/ECT3/ECT4 promote the stabilization of their targeted m6A-modified mRNAs, but have no function in alternative polyadenylation and translation. We find that ECT2 directly interacts with the poly(A) binding proteins, PAB2 and PAB4, and maintains the stabilization of m6A-modified mRNAs. Disruption ofECT2/ECT3/ECT4destabilizes mRNAs of ABA signaling-related genes, thereby promoting the accumulation of ABI5 and leading to ABA hypersensitivity.ConclusionOur study reveals a unified functional model of m6A mediated by m6A readers in plants. In this model, ECT2/ECT3/ECT4 promote stabilization of their target mRNAs in the cytoplasm.