bluuebunny/crossref_metadata_2025_split huggingface dataset:
Usability of a point-of-care diagnostic to identify glucose-6-phosphate dehydrogenase deficiency: a multi-country assessment of test label comprehension and results interpretation
Authors: Gerth-Guyette Emily , Adissu Wondimagegn , Brito Marcelo , Garbin Eduardo , Macedo Marcela , Sharma Abhijit , Das Santasabuj , Lacerda Marcus V. G. , Pereira Dhélio , Talukdar Arunansu , Yilma Daniel , Pal Sampa , Zobrist Stephanie , Domingo Gonzalo J. 
Published: July 2021

Abstract
Background
Point-of-care glucose-6-phosphate dehydrogenase (G6PD) testing has the potential to make the use of radical treatment for vivax malaria safer and more effective. Widespread use of G6PD tests as part of malaria case management has been limited, in part due to due concerns regarding product usability, user training, and supervision. This study seeks to assess how well end users can understand the Standard™ G6PD Test (SD Biosensor, Suwon, South Korea) workflow, result output, and label after training. This will ultimately help inform test registration and introduction.

Methods
Potential G6PD test users who provide malaria case management at three sites in Brazil, Ethiopia, and India were trained on the use of the SD Biosensor Standard G6PD Test and assessed based on their ability to understand the test workflow and interpret results. The assessment was done through a questionnaire, designed to assess product usability against key technical product specifications and fulfill regulatory evidence requirements. Any participant who obtained 85% or above correct responses to the questionnaire was considered to adequately comprehend how to use and interpret the test.

Results
Forty-five participants, including malaria microscopists, laboratory staff, nurses, and community health workers took part in the study. Seventy-eight percent of all participants in the study (35/45) obtained passing scores on the assessment with minimal training. Responses to the multiple-choice questions indicate that most participants understood well the test intended use, safety claims, and warnings. The greatest source of error regarding the test was around the correct operating temperature. Most test results were also read and interpreted correctly, with the haemoglobin measurement being a more problematic output to interpret than the G6PD measurement.

Conclusions
These data results show how a standardized tool can be used to assess a user’s ability to run a point-of-care diagnostic and interpret results. When applied to the SD Biosensor Standard G6PD Test, this tool demonstrates that a range of users across multiple contexts can use the test and suggests improvements to the test instructions and training that can improve product usability, increase user comprehension, and ultimately contribute to more widespread effective use of point-of-care G6PD tests.
Trial registration: NCT04033640
Single-cell analysis reveals cell communication triggered by macrophages associated with the reduction and exhaustion of CD8+ T cells in COVID-19
Authors: He Lei , Zhang Quan , Zhang Yue , Fan Yixian , Yuan Fahu , Li Songming 
Published: July 2021

Abstract
Background
The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has become an ongoing pandemic. Understanding the respiratory immune microenvironment which is composed of multiple cell types, together with cell communication based on ligand–receptor interactions is important for developing vaccines, probing COVID-19 pathogenesis, and improving pandemic control measures.

Methods
A total of 102 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study. Clinical information, routine laboratory tests, and flow cytometry analysis data with different conditions were collected and assessed for predictive value in COVID-19 patients. Next, we analyzed public single-cell RNA-sequencing (scRNA-seq) data from bronchoalveolar lavage fluid, which offers the closest available view of immune cell heterogeneity as encountered in patients with varying severity of COVID-19. A weighting algorithm was used to calculate ligand–receptor interactions, revealing the communication potentially associated with outcomes across cell types. Finally, serum cytokines including IL6, IL1β, IL10, CXCL10, TNFα, GALECTIN-1, and IGF1 derived from patients were measured.

Results
Of the 102 COVID-19 patients, 42 cases (41.2%) were categorized as severe. Multivariate logistic regression analysis demonstrated that AST, D-dimer, BUN, and WBC were considered as independent risk factors for the severity of COVID-19. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe disease group were significantly lower than those in the moderate disease group. The risk model containing the above mentioned inflammatory damage parameters, and the counts of T cells, with AUROCs ranged from 0.78 to 0.87. To investigate the molecular mechanism at the cellular level, we analyzed the published scRNA-seq data and found that macrophages displayed specific functional diversity after SARS-Cov-2 infection, and the metabolic pathway activities in the identified macrophage subtypes were influenced by hypoxia status. Importantly, we described ligand–receptor interactions that are related to COVID-19 serverity involving macrophages and T cell subsets by communication analysis.

Conclusions
Our study showed that macrophages driving ligand–receptor crosstalk contributed to the reduction and exhaustion of CD8+ T cells. The identified crucial cytokine panel, including IL6, IL1β, IL10, CXCL10, IGF1, and GALECTIN-1, may offer the selective targets to improve the efficacy of COVID-19 therapy.
Trial registration: This is a retrospective observational study without a trial registration number.
Reducing fatigue in pediatric rheumatic conditions: a systematic review
Authors: Kant-Smits K. , Van Brussel M. , Nijhof S. , Van der Net J. 
Published: July 2021

Abstract
Background
Although fatigue is a prevalent distressing symptom in children and adolescents with Pediatric Rheumatic Conditions (PRCs), intervention studies designed for reducing fatigue in PRCs are limited.

Aim
To systematically review evidence regarding the efficacy of interventions intended to reduce fatigue in patients with PRCs.

Methods
Comprehensive electronic searches were performed in PubMed/ MEDLINE, Embase, Web of Science and Cinahl. The risk of bias was assessed using the ‘Revised Cochrane risk-of-bias tool for randomized trials’ and ‘Quality Assessment Tool for Before-After Studies With No Control Group’ for respectively studies with and without a control group.

Results
Ten out of 418 studies were included with a total of 240 participants (age range 5–23 years). Interventions included land-based and aquatic-based exercise therapy, prednisolone, vitamin-D and creatine supplementation, psychological therapy and a transition program into an adult rheumatology program. Fatigue was assessed with self-reported questionnaires in all included studies. Land-based exercise therapy was effective in one pre-post intervention study, whereas not effective in two randomized controlled trials. Aquatic-based exercise therapy was found more effective than land-based exercise therapy. Two placebo-controlled studies showed a significant positive effect in reducing subjective fatigue with prednisolone and vitamin-D. Creatine was not found effective. Cognitive therapy was effective in one pre-post intervention study, while one RCT did not show an effect in reducing fatigue. A transition program based on health education showed a small reducing effect, however, it was not clear if this was a significant effect. Six studies showed a high risk of bias, three studies a moderate risk, and one study had a low risk of bias.

Conclusions
Insufficient evidence is provided to substantiate the efficacy of current interventions to reduce fatigue in PRCs. The low number of studies, non-comparable interventions, risk of bias, and inconclusive outcomes of the included studies denote future research should focus on intervention studies aimed at the treatment of fatigue in children and adolescents with PRCs. Identification of possible underlying biological and psychosocial mechanisms as possible treatment targets to reduce complaints of fatigue in children and adolescents with PRCs is warranted.
Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder
Authors: Galvani Giuseppe , Mottolese Nicola , Gennaccaro Laura , Loi Manuela , Medici Giorgio , Tassinari Marianna , Fuchs Claudia , Ciani Elisabetta , Trazzi Stefania 
Published: July 2021

AbstractBackgroundCDKL5 deficiency disorder (CDD), a severe neurodevelopmental disorder characterized by early onset epilepsy, intellectual disability, and autistic features, is caused by mutations in theCDKL5gene. Evidence in animal models of CDD showed that absence of CDKL5 negatively affects neuronal survival, as well as neuronal maturation and dendritic outgrowth; however, knowledge of the substrates underlying these alterations is still limited. Neuroinflammatory processes are known to contribute to neuronal dysfunction and death. Recent evidence shows a subclinical chronic inflammatory status in plasma from CDD patients. However, to date, it is unknown whether a similar inflammatory status is present in the brain of CDD patients and, if so, whether this plays a causative or exacerbating role in the pathophysiology of CDD.MethodsWe evaluated microglia activation using AIF-1 immunofluorescence, proinflammatory cytokine expression, and signaling in the brain of a mouse model of CDD, theCdkl5KO mouse, which is characterized by an impaired survival of hippocampal neurons that worsens with age. Hippocampal neuron survival was determined by DCX, NeuN, and cleaved caspase-3 immunostaining inCdkl5KO mice treated with luteolin (10 mg/kg), a natural anti-inflammatory flavonoid. Since hippocampal neurons ofCdkl5KO mice exhibit increased susceptibility to excitotoxic stress, we evaluated neuronal survival inCdkl5KO mice injected with NMDA (60 mg/kg) after a 7-day treatment with luteolin.ResultsWe found increased microglial activation in the brain of theCdkl5KO mouse. We found alterations in microglial cell morphology and number, increased levels of AIF-1 and proinflammatory cytokines, and activation of STAT3 signaling. Remarkably, treatment with luteolin recovers microglia alterations as well as neuronal survival and maturation inCdkl5KO mice, and prevents the increase in NMDA-induced cell death in the hippocampus.ConclusionsOur results suggest that neuroinflammatory processes contribute to the pathogenesis of CDD and imply the potential usefulness of luteolin as a treatment option in CDD patients.
A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations
Authors: Canaud Guillaume , Hammill Adrienne M. , Adams Denise , Vikkula Miikka , Keppler-Noreuil Kim M. 
Published: July 2021

Abstract
Background
PIK3CA-related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result in activation of the PI3K/AKT/mTOR signaling pathway. The goals of this review are to provide education on the underlying mechanism of disease for this group of rare conditions and to summarize recent advancements in the understanding of, as well as current and emerging treatment options for PIK3CA-related disorders.

Main body
PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations, and PIK3CA-related nonvascular lesions. Somatic activating mutations (predominantly in hotspots in the helical and kinase domains of PIK3CA, but also in other domains), lead to hyperactivation of the PI3K signaling pathway, which results in abnormal tissue growth. Diagnosis is complicated by the variability and overlap in phenotypes associated with PIK3CA-related disorders and should be performed by clinicians with the required expertise along with coordinated care from a multidisciplinary team. Although tissue mosaicism presents challenges for confirmation of PIK3CA mutations, next-generation sequencing and tissue selection have improved detection. Clinical improvement, radiological response, and patient-reported outcomes are typically used to assess treatment response in clinical studies of patients with PIK3CA-related disorders, but objective assessment of treatment response is difficult using imaging (due to the heterogeneous nature of these disorders, superimposed upon patient growth and development). Despite their limitations, patient-reported outcome tools may be best suited to gauge patient improvement. New therapeutic options are needed to provide an alternative or supplement to standard approaches such as surgery and sclerotherapy. Currently, there are no systemic agents that have regulatory approval for these disorders, but the mTOR inhibitor sirolimus has been used for several years in clinical trials and off label to address symptoms. There are also other agents under investigation for PIK3CA-related disorders that act as inhibitors to target different components of the PI3K signaling pathway including AKT (miransertib) and PI3K alpha (alpelisib).

Conclusion
Management of patients with PIK3CA-related disorders requires a multidisciplinary approach. Further results from ongoing clinical studies of agents targeting the PI3K pathway are highly anticipated.
Diagnosis, treatment and postsurgical complications in a dog with epileptic seizures and a naso-ethmoidal meningoencephalocele
Authors: Mojarradi Abtin , Van Meervenne Sofie , Suarez-Bonnet Alejandro , De Decker Steven 
Published: July 2021

Abstract
Background
Naso-ethmoidal meningoencephalocele is usually a congenital anomaly consisting of a protrusion of cerebral tissue and meninges into the ethmoidal labyrinth. The condition is a rare cause of structural epilepsy in dogs. We report the clinical presentation, surgical intervention, postoperative complications and outcome in a dog with drug resistant epilepsy secondary to a meningoencephalocele.

Case presentation
A 3.3-year-old male neutered Tamaskan Dog was referred for assessment of epileptic seizures secondary to a previously diagnosed left-sided naso-ethmoidal meningoencephalocele. The dog was drug resistant to medical management with phenobarbital, potassium bromide and levetiracetam. Surgical intervention was performed by a transfrontal craniotomy with resection of the meningoencephalocele and closure of the dural defect. Twenty-four hours after surgery the dog demonstrated progressive cervical hyperaesthesia caused by tension pneumocephalus and pneumorrhachis. Replacement of the fascial graft resulted in immediate resolution of the dog’s neurological signs. Within 5 months after surgery the dog progressively developed sneezing and haemorrhagic nasal discharge, caused by sinonasal aspergillosis. Systemic medical management with oral itraconazole (7 mg/kg orally q12h) was well-tolerated and resulted in resolution of the clinical signs. The itraconazole was tapered with no relapsing upper airway signs. The dog’s frequency of epileptic seizures was not affected by surgical resection of the meningoencephalocele. No treatment adjustments of the anti-epileptic medication have been necessary during the follow-up period of 15 months.

Conclusions
Surgical resection of the meningoencephalocele did not affect the seizure frequency of the dog. Further research on prognostic factors associated with surgical treatment of meningoencephaloceles in dogs is necessary. Careful monitoring for postsurgical complications allows prompt initiation of appropriate treatment.
Effect of arterial oxygen partial pressure inflection point on Venoarterial extracorporeal membrane oxygenation for emergency cardiac support
Authors: Zhou Hao , Zhu Yi , Zhang Zhongman , Lv Jinru , Li Wei , Hu Deliang , Chen Xufeng , Mei Yong 
Published: July 2021

Abstract
Background
Temporary circulatory support is a bridge between acute circulatory failure and definitive treatment or recovery. Currently, venoarterial extracorporeal membrane oxygenation (VA-ECMO) is considered to be one of the effective circulatory support methods, although cardiac function monitoring during the treatment still needs further investigation. Inflection point of arterial oxygen partial pressure (IPPaO2) may occur at an early stage in part of patients with a good prognosis after VA-ECMO treatment, and the relationship between time of IPPaO2 (tIPPaO2) and recovery of cardiac function or prognosis remains unclear.

Methods
To investigate this relationship, we retrospectively analyzed the clinical data of 71 patients with different conditions after treatment with VA-ECMO in the emergency center of Jiangsu Province Hospital between May 2015 and July 2020. Spearman’s correlation analysis was used for the correlation between tIPPaO2 and quantitative data, and ROC curve for the predictive effect of tIPPaO2 on the 28-day mortality.

Results
Thirty-five patients were admitted because of refractory cardiogenic shock (26 of 35 survived) and the remaining 36 patients due to cardiac arrest (13 of 36 survived). The overall survival rate was 54.9% (39 of 71 survived). Acute physiology and chronic health evaluation II, ECMO time, tIPPaO2, continuous renal replacement therapy time, mechanical ventilation time, and bleeding complications in the survival group were lower than those in the non-survival group, with length of stay, intensive care unit stay, and platelet levels were being higher. The tIPPaO2 was negatively correlated with ejection fraction, and the shorter tIPPaO2 resulted in a higher 28-day survival probability, higher predictive value for acute myocardial infarction and fulminant myocarditis.

Conclusions
Therefore, tIPPaO2 could be a reliable qualitative indicator of cardiac function in patients treated with VA-ECMO, which can reveal appropriate timing for adjusting VA-ECMO flow or weaning.

Trial registration
ChiCTR1900026105.
Risk factors for overuse injuries in a cohort of elite Swedish track and field athletes
Authors: Lundberg Zachrisson Andreas , Ivarsson Andreas , Desai Pia , Karlsson Jon , Grau Stefan 
Published: July 2021

Abstract
Background
Most injuries in track and field are caused by overuse with conflicting reports concerning the underlying mechanisms. The purpose of this study was to evaluate how biomechanical and clinical factors relate to the risk of overuse injuries, and to investigate whether the relationships between potential risk factors and injury become stronger if injuries are grouped by location.

Methods
The study is a prospective cohort study conducted during a Swedish track and field season over eleven months, from October to August. The cohort consisted of elite male and female track and field athletes competing in either middle- and long-distance running, sprinting, jumping, or throwing events (n = 96). Athletes performed a baseline screening at enrollment consisting of a clinical examination, running, and strength tests. Injury data was collected during the season by medical professionals and divided according to their anatomical location into upper-body, thigh/hip, knee, or foot/shank injuries.

Results
Thirty-four (54.8%) injuries where located at the foot/shank, followed by sixteen injuries at the thigh/hip (25.8%). Only eight knee (12.9%) and four upper-body (6.5%) injuries were registered during the season and therefore not analysed. Effect sizes were calculated for all test variables. Small effect sizes (rpb = .10–.23) were found for eleven risk factors between the overall injured (all injuries combined) and non-injured athletes. By further sub-grouping the injured group into thigh/hip injuries, effect size increased in hip adduction range of motion knee flexion velocity and the muscle flexibility of the iliopsoas. For foot/shank injuries, only the hamstring:quadriceps strength ratios increased for the right side to a small effect size.

Conclusions
Injury grouping appears to increase effect size for certain risk factors. Athletes with a slower knee flexion velocity during stance phase were more likely to become injured (p-value <.03, rpb = .37). An increased cohort size to further sub-divide injuries into specific diagnoses is needed.
The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes
Authors: Beacon Tasnim H. , Delcuve Geneviève P. , López Camila , Nardocci Gino , Kovalchuk Igor , van Wijnen Andre J. , Davie James R. 
Published: July 2021

AbstractTranscriptionally active chromatin is marked by tri-methylation of histone H3 at lysine 4 (H3K4me3) located after first exons and around transcription start sites. This epigenetic mark is typically restricted to narrow regions at the 5`end of the gene body, though a small subset of genes have a broad H3K4me3 domain which extensively covers the coding region. Although most studies focus on the H3K4me3 mark, the broad H3K4me3 domain is associated with a plethora of histone modifications (e.g., H3 acetylated at K27) and is therein termed broad epigenetic domain. Genes marked with the broad epigenetic domain are involved in cell identity and essential cell functions and have clinical potential as biomarkers for patient stratification. Reducing expression of genes with the broad epigenetic domain may increase the metastatic potential of cancer cells. Enhancers and super-enhancers interact with the broad epigenetic domain marked genes forming a hub of interactions involving nucleosome-depleted regions. Together, the regulatory elements coalesce with transcription factors, chromatin modifying/remodeling enzymes, coactivators, and the Mediator and/or Integrator complex into a transcription factory which may be analogous to a liquid–liquid phase-separated condensate. The broad epigenetic domain has a dynamic chromatin structure which supports frequent transcription bursts. In this review, we present the current knowledge of broad epigenetic domains.
Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo
Authors: Mensch Maria , Dunot Jade , Yishan Sandy M. , Harris Samuel S. , Blistein Aline , Avdiu Alban , Pousinha Paula A. , Giudici Camilla , Busche Marc Aurel , Jedlicka Peter , Willem Michael , Marie Hélène 
Published: July 2021

Abstract
Background
Amyloid precursor protein (APP) processing is central to Alzheimer’s disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη–α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo.

Methods
With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-β peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology.

Results
We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-β, like Aη–α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη–α in vivo.

Conclusions
These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.